Case Reports

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

 

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Most GISTs are fluorodeoxyglucose (FDG) avid on positron-emission tomography (PET) imaging. In contrast, this patient’s liver metastases had no detectable FDG uptake (not shown). A liver biopsy revealed recurrent GIST (Figure 3). 

Imatinib mesylate was begun at 400 mg per day orally. After 2 months, the liver lesions were reduced in size, with the largest lesion shrinking to 0.5 cm in greatest dimension. The liver lesions continued to decrease in size and number (Figure 2B). 

At 16 months after starting imatinib, there was no sign of tumor progression.

 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

 

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Most GISTs are fluorodeoxyglucose (FDG) avid on positron-emission tomography (PET) imaging. In contrast, this patient’s liver metastases had no detectable FDG uptake (not shown). A liver biopsy revealed recurrent GIST (Figure 3). 

Imatinib mesylate was begun at 400 mg per day orally. After 2 months, the liver lesions were reduced in size, with the largest lesion shrinking to 0.5 cm in greatest dimension. The liver lesions continued to decrease in size and number (Figure 2B). 

At 16 months after starting imatinib, there was no sign of tumor progression.

 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract, usually arising from the interstitial cells of Cajal or similar cells in the outer wall of the gastrointestinal tract.^1,2 Most GISTs have an activating mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRα). Tumor size, mitotic rate, and anatomic site are the most common pathological features used to risk stratify GIST tumors.^3-10 It is important to note when using such risk calculators that preoperative imatinib before determining tumor characteristics (such as mitoses per 50 high-power fields [hpf]) often changes the relevant parameters so that the same risk calculations may not apply. Tumors with a mitotic rate ≤5 mitoses per 50 hpf and a size ≤5 cm in greatest dimension have a lower recurrence rate after resection than tumors with a mitotic rate >5 mitoses per 50 hpf and a size >10 cm, and larger tumors can have a recurrence rate of up to 86%.^11,12 Findings from a large observational study have suggested that the prognosis of gastric GIST in Korea and Japan may be more favorable compared with that in Western countries.¹³

The primary treatment of a localized primary GIST is surgical excision, but a cure is limited by recurrence.^14,15 Imatinib is useful in the treatment of metastatic or recurrent GIST, and adjuvant treatment with imatinib after surgery has been shown to improve progression-free and overall survival in some cases.^3,16-18 Responses to adjuvant imatinib depend on tumor sensitivity to the drug and the risk of recurrence. Drug sensitivity is largely dependent on the presence of mutations in KIT or PDGFRα.^3,18 Recurrence risk is highly dependent on tumor size, tumor site, tumor rupture, and mitotic index.^{1,3,5,6,8,9,18,19} Findings on the use of gene expression patterns to predict recurrence risk have also been reported.^20-27 However, recurrence risk is poorly understood for categories in which there are few cases with known outcomes, such as very small gastric GIST with a high mitotic index. For example, few cases of gastric GIST have been reported with a tumor size ≤2 cm, a mitotic rate >5 mitoses per 50 hpf, and adequate clinical follow-up. In such cases, it is difficult to assess the risk of recurrence.⁶ We report here the long-term outcome of a patient with a 1.8-cm gastric GIST with a mitotic index of 36 mitoses per 50 hpf and a KIT exon 11 mutation.

 

Case Presentation and Summary

A 69-year-old man presented with periumbilical and epigastric pain of 6-month duration. His medical history was notable for hyperlipidemia, hypertension, coronary angioplasty, and spinal surgery. He had a 40 pack-year smoking history and consumed 2 to 4 alcoholic drinks per day. The results of a physical examination were unremarkable. A computed tomographic (CT) scan showed no abnormalities. An esophagogastroduodenoscopy (EGD) revealed gastric ulcers. He was treated successfully with omeprazole 20 mg by mouth daily.

A month later, a follow-up EGD revealed a 1.8 x 1.5-cm submucosal mass 3 cm from the gastroesophageal junction. The patient underwent a fundus wedge resection, and a submucosal mass 1.8 cm in greatest dimension was removed. Pathologic examination revealed a GIST, spindle cell type, with a mitotic rate of 36 mitoses per 50 hpf with negative margins. Immunohistochemistry was positive for CD117. An exon 11 deletion (KVV558-560NV) was present in KIT. The patient’s risk of recurrence was unclear, and his follow-up included CT scans of the abdomen and pelvis every 3 to 4 months for the first 2 years, then every 6 months for the next 2.5 years.

A CT scan about 3.5 years after primary resection revealed small nonspecific liver hypodensities that became more prominent during the next year. About 5 years after primary resection, magnetic resonance imaging (MRI) revealed several liver lesions, the largest of which measured 1.3 cm in greatest dimension. The patient’s liver metastases were readily identified by MRI (Figure 1) and CT imaging (Figure 2A). 

Most GISTs are fluorodeoxyglucose (FDG) avid on positron-emission tomography (PET) imaging. In contrast, this patient’s liver metastases had no detectable FDG uptake (not shown). A liver biopsy revealed recurrent GIST (Figure 3). 

Imatinib mesylate was begun at 400 mg per day orally. After 2 months, the liver lesions were reduced in size, with the largest lesion shrinking to 0.5 cm in greatest dimension. The liver lesions continued to decrease in size and number (Figure 2B). 

At 16 months after starting imatinib, there was no sign of tumor progression.

 

Discussion

Small gastric GISTs are sometimes found by endoscopy performed for unrelated reasons. Recent data suggest that the incidence of gastric GIST may be higher than previously thought. In a Japanese study of patients with gastric cancer in which 100 stomachs were systematically examined pathologically, 50 microscopic GISTs were found in 35 patients.²⁸ Most small gastric GISTs have a low mitotic index. Few cases have been described with a high mitotic index. In a study of 1765 cases of GIST of the stomach, 8 patients had a tumor size less than 2 cm and a mitotic index greater than 5. Of those, only 6 patients had long-term follow-up, and 3 were alive without disease at 2, 17, and 20 years of follow-up.⁷ These limited data make it impossible to predict outcomes in patients with small gastric GIST with a high mitotic index.

For patients who are at high risk of recurrence after surgery, 3 years of adjuvant imatinib treatment compared with 1 year has been shown to improve overall survival and is the current standard of care.^10,17 A study comparing 5 and 3 years of imatinib is ongoing to establish whether a longer period of adjuvant treatment is warranted. In patients with metastatic GIST, lifelong imatinib until lack of benefit is considered optimal treatment.¹⁰ All patients should undergo KIT mutation analysis. Those with the PDGFRα D842V mutation, SDH (succinate dehydrogenase) deficiency, or neurofibromatosis-related GIST should not receive adjuvant imatinib.

This case has several unusual features. The small tumor size with a very high mitotic rate is rare. Such cases have not been reported in large numbers and have therefore not been reliably incorporated into risk prediction algorithms. In addition, despite a high mitotic index, the tumor was not FDG avid on PET imaging. The diagnosis of GIST is strongly supported by the KIT mutation and response to imatinib. This particular KIT mutation in larger GISTs is associated with aggressive disease. The present case adds to the data on the biology of small gastric GISTs with a high mitotic index and suggests the mitotic index in these tumors may be a more important predictor than size. TSJ

Acknowlegement
The authors thank Michael Franklin, MS, for editorial assistance, and Sabrina Porter for media edits.

^aDepartment of Medicine, University of Minnesota Medical School; ^bDepartment of Laboratory Medicine and Pathology, University of Minnesota Medical School; and ^cMasonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.

Disclosures
The authors report no disclosures or conflicts of interest. This article was originally published in The Journal of Community and Supportive Oncology JCSO. 2018;16(3):e163-e166. ©Frontline Medical Communications. doi:10.12788/jcso.0402. It is reproduced with permission from the copyright owner. Further reproduction prohibited without permission.

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

An ultrasound of the soft tissue mass was performed, which showed a solid, heterogeneously hypoechoic 9 x 9 x 10-mm mass in the left anterior abdominal wall with mild internal vascularity (Figure 1).

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

 

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

LEND AN EGG is a useful acronym introduced by Naversen and colleagues in 1993 to characterize painful subcutaneous nodules.¹⁰ The acronym is particularly helpful because entities in this acronym are not common and are already difficult to identify as there are frequently no overlying skin changes to help characterize the lesions (Table 2).

 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

 

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

An ultrasound of the soft tissue mass was performed, which showed a solid, heterogeneously hypoechoic 9 x 9 x 10-mm mass in the left anterior abdominal wall with mild internal vascularity (Figure 1).

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

 

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

LEND AN EGG is a useful acronym introduced by Naversen and colleagues in 1993 to characterize painful subcutaneous nodules.¹⁰ The acronym is particularly helpful because entities in this acronym are not common and are already difficult to identify as there are frequently no overlying skin changes to help characterize the lesions (Table 2).

 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

 

Schwannomas are benign tumors exclusively composed of Schwann cells that arise from the peripheral nerve sheath; these tumors theoretically can present anywhere in the body where nerves reside. They tend to occur in the head and neck region (classically an acoustic neuroma) but also occur in other locations, including the retroperitoneal space and the extremities, particularly flexural surfaces. Patients with cutaneous schwannomas are most likely to present to their primary care provider’s office reporting skin findings or localized pain, and providers should be aware of schwannomas on the differential for painful nodular growths.

Case Presentation

A 70-year-old man with type 2 diabetes mellitus presented to the primary care clinic for intermittent, sharp, localized left lower quadrant abdominal wall pain that was gradually progressive over the previous few months. The patient noticed the development of a small nodule 7 to 8 months prior to the visit, at which time the pain was less frequent and less severe. He reported no postprandial association of the pain, nausea, vomiting, diarrhea, constipation, or other gastrointestinal symptoms.

Ten months prior to the presentation, he was involved in a low-impact motor vehicle collision as a pedestrian in which he fell face-first onto the hood of an oncoming car. At that time, he did not note any abdominal trauma or pain. Evaluation at a local emergency department did not reveal any major injuries. In the interim, he had self-administered insulin in his abdominal region, as he had without incident for the previous 2 years. He reported that he was not injecting near the site of the nodule since it had formed. He could not recall whether the location was a previous insulin administration site.

On examination, the patient’s vital signs were normal as were the cardiac and respiratory examinations. An abdominal exam revealed normal bowel sounds and no overlying skin changes or discoloration. Palpation revealed a 1.5 x 1 cm rubbery-to-firm, well-circumscribed subcutaneous nodule along his mid-left abdomen, about 7 cm lateral to the umbilicus. The nodule was sensitive to both light touch and deep pressure. It was firmer than expected for an abdominal wall lipoma. There was no central puncta or pore to suggest an epidermal inclusion cyst. There was no surrounding erythema or induration to suggest an abscess. 

An ultrasound of the soft tissue mass was performed, which showed a solid, heterogeneously hypoechoic 9 x 9 x 10-mm mass in the left anterior abdominal wall with mild internal vascularity (Figure 1).

The patient was referred for surgery and underwent excisional biopsy of the mass. Pathology revealed a well-circumscribed vascular/spindle-cell lesion consistent with a schwannoma. His postoperative course was uncomplicated. At 4-week follow-up the incision had healed completely and the patient was pain free.

Discussion

Soft-tissue nodules are common—about two-thirds of soft-tissue tumors are classified into 7 diagnostic categories: lipoma and lipoma variants (16%), fibrous histiocytoma (13%), nodular fasciitis (11%), hemangioma (8%), fibromatosis (7%), neurofibroma (5%), and schwannoma (5%).¹ Peripheral nerve tumors (schwannomas, neurofibromas) can be associated with pain or paresthesias, and less commonly, neurologic deficits, such as motor weakness. Peripheral nerve tumors have several classifications, such as nonneoplastic vs neoplastic, benign vs malignant, and sheath vs nonsheath origins. Schwannomas are considered part of the neoplastic subset due to their growth; otherwise, they are benign with a sheath origin. In contrast to neurofibromas, benign schwannomas have a slower rate of progression, lower association with pain, and fewer neurologic symptoms.²

 

The neural sheath is made up of 3 types of cells: the fibroblast, the Schwann cell, and the perineural cell, which lacks a basement membrane. It is the Schwann cell that can give rise to the 3 main types of cutaneous nerve tumors: neuromas, neurofibromas, and schwannomas.³ A nerve that is both entering and exiting a mass is a classic presentation for a peripheral nerve sheath tumor. If the nerve is eccentric to the lesion, then it is consistent with a schwannoma (not a neurofibroma).⁴ Schwannomas are made exclusively of Schwann cells that arise from the nerve sheath, whereas neurofibromas are made up of all the different cell types that constitute a nerve. Bilateral vestibular schwannomas (acoustic neuromas) are virtually pathognomonic of neurofibromatosis 2 (NF-2), which can manifest as hearing loss, tinnitus, and equilibrium problems. In contrast, neurofibromatosis 1 (NF-1) is more common, characterized by multiple café au lait spots, freckling in the axillary and groin regions, increased risk of cancers overall, and development of pedunculated skin growths, brain, or organ-based neurofibromas.

Diagnosis

A workup generally includes a thorough history and examination as well as imaging. In cases of superficial subcutaneous lesions, an ultrasound is often the imaging modality of choice. However, magnetic resonance imaging (MRI) and computed tomography (CT) scans are frequently used for more deep-seated lesions. There can be significant differences between malignant and benign neural lesions on MRI and CT in terms of contrast-uptake and heterogeneity of tissue, but the visual features are not consistent. Best estimates for MRI suggest 61% sensitivity and 90% specificity for the diagnosis of high-grade malignant peripheral nerve sheath tumors based on imaging alone.⁵

Definitive diagnosis requires surgical excision. Fine-needle aspiration can be used to diagnose subcutaneous nodules, but there is a possibility that degenerative changes and nuclear atypia seen on a smaller sample may be confused with a more aggressive sarcoma. For example, long-standing schwannomas are often called ancient, meaning that they break down over time, and the atypia they display is a regressive phenomenon.⁶ Therefore, a small or limited tissue sampling may not be representative of the entire lesion.⁷ As such, patients will likely need referral for surgical removal to determine the exact nature of the growth.

Although schwannomas are uncommon overall, the highest incidence is in the fourth decade of life with a slight predominance in females. They are often incidentally found as a palpable mass but can be symptomatic with paresthesias, pain, or neurologic changes—particularly when identified in the retroperitoneum or along joints. Schwannomas are most commonly found in the retroperitoneum (32%), mediastinum (23%), head and neck (18%), and extremities (16%).⁸ The majority of cases (about 90%) are sporadic; whereas 2% are related to NF-2.⁹ The abdominal wall schwannoma is rare. Our review of English-language literature in PubMed and EMBASE found only 5 other case reports (Table 1).

On physical examination, superficial lesions are freely movable except for a single point of attachment, which is generally along the long axis of the nerve. 

LEND AN EGG is a useful acronym introduced by Naversen and colleagues in 1993 to characterize painful subcutaneous nodules.¹⁰ The acronym is particularly helpful because entities in this acronym are not common and are already difficult to identify as there are frequently no overlying skin changes to help characterize the lesions (Table 2).

 

Pathology

On gross pathology examination, schwannomas have a well-circumscribed smooth external surface. On microscopy, schwannomas are truly encapsulated, uninodular, spindle-cell proliferations arranged in a streaming pattern within a background of thick, hyalinized blood vessels. Classic schwannomas typically exhibit a biphasic pattern of alternating areas of high and low cellularity and are named for Swedish neurologist Nils Antoni. The more cellular regions are referred to as Antoni A areas and consist of streaming fascicles of compact spindle cells that often palisade around acellular eosinophilic areas of fibrillary processes known as Verocay bodies.

In contrast, the lower cellularity regions (Antoni B areas) consist of multipolar, loosely textured cells with abundant cytoplasm, haphazardly arranged processes, and an overall myxoid appearance.¹¹ Schwannomas are known to have widely variable proportions of Antoni A and Antoni B areas; in this case, the excised specimen was noted to have predominately Antoni A areas without well-defined Verocay bodies and only scattered foci showing some suggestion of the hypocellular Antoni B architecture (Figure 2).^9,12 

Immunohistochemical stains for S100 and SOX10 (used to identify cells derived from a neural crest lineage) were strongly positive, which is characteristic of schwannomas.¹³ Although there have only been rare reports of extracranial schwannomas undergoing malignant transformation, it is critical to rule out the possibility of a de novo malignant peripheral nerve sheath tumor (MPNST).¹³ In general, MPNSTs tend to be more cellular, have brisk mitotic activity, areas of necrosis, hyperchromatic nuclei, and conspicuous pleomorphism. Mitotic figures, which can be concerning for malignant potential if present in high number, were noted occasionally in our patient; however, occasional mitosis may be seen in classic schwannomas. Clinically, MPNSTs have a poor prognosis. Based on case reports, disease-specific survival at 10 years is 31.6% for localized disease and only 7.5% for metastatic disease.¹⁴ In this case, there was no evidence of any of the high-grade features of a malignant peripheral nerve sheath tumor, thus supporting the diagnosis of schwannoma (neurilemmoma).

Treatment

Schwannomas are exclusively treated by excision. Prognosis is good with low recurrence rates. It is unknown what the recurrence rates are for completely resected abdominal wall schwannomas since there are so few reports in the literature. For other well-known entities, such as vestibular schwannoma (acoustic neuromas), the recurrence rates are generally 2% to 3%.¹⁵ Transformation of schwannomas into MPNSTs are so unusual that they are only described in single case reports.

Conclusion

Soft-tissue masses are a common complaint. Most are benign and do not require excision unless it interferes with the quality of life of the patient or if the diagnosis is uncertain. It is important to be aware of schwannomas in the differential diagnosis of soft-tissue masses. Diagnosis may be achieved through the combination of imaging and biopsy, but the definitive diagnosis is made on complete excision of the mass.

Acknowledgments
Contributors: Michael Lewis, MD, Department of Pathology, VA Greater Los Angeles Healthcare System. Written permission also was obtained from the patient.

 

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

 

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

 

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; [email protected]

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

 

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

 

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; [email protected]

THE CASE

A 37-year-old man presented with a sudden-onset, nonpruritic, nonpainful, papular rash of 1 month’s duration on his trunk and both arms and legs. Two weeks prior to the current presentation, he consulted a general practitioner, who treated the rash with a course of unknown oral antibiotics; the patient showed no improvement. He recalled that on a few occasions, he used his fingers to express a creamy discharge from some of the lesions. This temporarily reduced the size of those papules.

His medical history was unremarkable except for morbid obesity. He did not drink alcohol regularly and was not taking any medications prior to the onset of the rash. He had no family history of hyperlipidemia, but his mother had a history of diabetes mellitus.

Physical examination showed numerous discrete erythematous papules with a creamy center on his trunk and his arms and legs. The lesions were more numerous on the extensor surfaces of the arms and legs. Some of the papules coalesced to form small plaques (FIGURE). There was no scaling, and the lesions were firm in texture. The patient’s face was spared, and there was no mucosal involvement. The patient was otherwise systemically well.

THE DIAGNOSIS

Based on the morphology, distribution, and abrupt onset of the diffuse nonpruritic papules in this morbidly obese (but otherwise systemically well) middle-aged man, a clinical diagnosis of eruptive xanthoma was suspected. Subsequent blood testing revealed an elevated serum triglyceride level of 47.8 mmol/L (reference range, <1.7 mmol/L), elevated serum total cholesterol of 7.1 mmol/L (reference range, <6.2 mmol/L), and low serum high-density lipoprotein cholesterol of 0.7 mmol/L (reference range, >1 mmol/L in men). He also had an elevated fasting serum glucose level of 12.9 mmol/L (reference range, 3.9–5.6 mmol/L) and an elevated hemoglobin A1c (glycated hemoglobin) level of 10.9%.

Subsequent thyroid, liver, and renal function tests were normal, but the patient had heavy proteinuria, with an elevated urine albumin-to-creatinine ratio of 355.6 mg/mmol (reference range, ≤2.5 mg/mmol). The patient was referred to a dermatologist, who confirmed the clinical diagnosis without the need for a skin biopsy.

DISCUSSION

Xanthomas are lipid deposits in the skin and subcutaneous tissues that arise in the setting of hyperlipidemia and are caused by underlying familial or acquired disorders. Xanthomas associated with dyslipidemias include eruptive xanthoma, tendinous xanthoma, xanthoma palpebrarum, and xanthoma tuberosum (TABLE).^1-3 Other non–dyslipidemia-related xanthomas include xanthoma planum, xanthoma disseminatum, linear palmar xanthomas, and verrucous xanthoma. One retrospective cohort study reported an 8.5% (8/95) prevalence of eruptive xanthomas in patients with severe hypertriglyceridemia (ie, triglyceride levels >1770 mg/dL).⁴ Data on the prevalence of other variants of xanthoma are lacking.

Diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other conditions in the differential diagnosis can’t be ruled out or if the lesions do not resolve with treatment.

Eruptive xanthoma is characterized by an abrupt onset of crops of multiple yellowish to brownish papules that can coalesce into small plaques. The lesions can be generalized, but tend to be more densely distributed on the extensor surfaces of the arms and legs, buttocks, and thighs.⁵ Eruptive xanthoma often is associated with hypertriglyceridemia, which can be primary—as a result of a genetic defect caused by familial hypertriglyceridemia—or secondary, associated with poorly controlled diabetes mellitus, morbid obesity, excessive alcohol consumption, nephrotic syndrome, hypothyroidism, primary biliary cholangitis, and drugs like estrogen replacement therapies, corticosteroids, and isotretinoin.⁶ Pruritus and tenderness may or may not be present, and the Köbner phenomenon may occur.⁷

Continue to: The differential diagnosis

 

The differential diagnosis for eruptive xanthoma includes xanthoma disseminatum, non–Langerhans cell histiocytoses (eg, generalized eruptive histiocytosis), and cutaneous mastocytosis.¹

Xanthoma disseminatum is an extremely rare, but benign, disorder of non–Langerhans cell origin. The average age of onset is older than 40 years. The rash consists of multiple red-yellow papules and nodules that most commonly present in flexural areas. Forty percent to 60% of patients have mucosal involvement, and rarely the central nervous system is involved.⁸

Generalized eruptive histiocytosis is another rare non–Langerhans cell histiocytosis that occurs mainly in adults and is characterized by widespread, symmetric, red-brown papules on the trunk, arms, and legs, and rarely the mucous membranes.⁹

Cutaneous mastocytosis, especially xanthelasmoid mastocytosis, consists of multiple pruritic, yellowish, papular or nodular lesions that may mimic eruptive xanthoma. It occurs mainly in children and rarely in adults.¹⁰

Confirming the diagnosis, initiating treatment

The diagnosis of eruptive xanthoma can be confirmed by skin biopsy if other differential diagnoses cannot be ruled out or the lesions do not resolve with treatment. Skin biopsy will reveal lipid-laden macrophages (known as foam cells) deposited in the dermis.⁷

Continue to: Treatment of eruptive xanthoma

 

Treatment of eruptive xanthoma involves management of the underlying causes of the condition. In most cases, dietary control, intensive triglyceride-lowering therapies, and treatment of other secondary causes of hypertriglyceridemia result in complete resolution of the lesions within several weeks.⁵

Our patient’s outcome

Our patient’s sudden-onset rash alerted us to the presence of type 2 diabetes mellitus, hypertriglyceridemia, and heavy proteinuria, which he was not aware of previously. We counselled him about stringent low-sugar, low-lipid diet control and exercise, and we started him on metformin and gemfibrozil. He was referred to an internal medicine specialist for further assessment and management of his severe hypertriglyceridemia and heavy proteinuria.

Eruptive xanthoma may be an indicator of severe hypertriglyceri- demia, which can be associated with an increased risk for acute pancreatitis.

The rash started to wane 1 month after the patient started the metformin and gemfibrozil, and his drug regimen was changed to combination therapy with metformin/glimepiride and fenofibrate/simvastatin 6 weeks later when he was seen in the medical specialty clinic. Fundus photography performed 1 month after starting oral antidiabetic therapy showed no diabetic retinopathy or lipemia retinalis.

After 3 months of treatment, his serum triglycerides and hemoglobin A1c levels dropped to 3.8 mmol/L and 8.7%, respectively. The rash also resolved considerably, with only residual papules on the abdomen. This rapid clinical response to treatment of the underlying hypertriglyceridemia and diabetes further supported the clinical diagnosis of eruptive xanthoma.

THE TAKEAWAY

Eruptive xanthoma is relatively rare, but it is important for family physicians to recognize this clinical presentation as a potential indicator of severe hypertriglyceridemia. Recognizing hypertriglyceridemia early is important, as it can be associated with an increased risk for acute pancreatitis. Moreover, eruptive xanthoma might be the sole presenting symptom of underlying diabetes mellitus or familial hyperlipidemia, both of which can lead to a significant increase in cardiovascular risk if uncontrolled.

CORRESPONDENCE
Chan Kam Sum, MBChB, FRACGP, Tseung Kwan O Jockey Club General Out-patient Clinic, 99 Po Lam Road North, G/F, Tseung Kwan O, Kowloon, Hong Kong; [email protected]

Case Report

A 60-year-old Cambodian woman presented with recurrent fever (temperature, up to 38.8°C) 7 months after receiving a kidney transplant secondary to polycystic kidney disease. Fever was attributed to recurrent pyelonephritis of the native kidneys while on mycophenolate mofetil, tacrolimus, and prednisone. As a result, she underwent a bilateral native nephrectomy and was found to have peritoneal nodules. Pathology of both native kidneys and peritoneal tissue revealed caseating granulomas and acid-fast bacilli (AFB) diagnostic for kidney and peritoneal tuberculosis (TB). She had no history of TB, and a TB skin test (purified protein derivative [PPD]) upon entering the United States from Cambodia a decade earlier was negative. Additionally, her pretransplantation PPD was negative.

Treatment with isoniazid, ethambutol, pyrazinamide, and levofloxacin was initiated immediately upon diagnosis, and all of her immunosuppressive medications—mycophenolate mofetil, tacrolimus, and prednisone—were discontinued. Her symptoms subsided within 1 week, and she was discharged from the hospital. Over the next 2 months, her immunosuppressive medications were restarted, and her TB medications were periodically discontinued by the Tuberculosis Control Program at the Department of Health (Philadelphia, Pennsylvania) due to severe thrombocytopenia. During this time, she was closely monitored twice weekly in the clinic with blood draws performed weekly.

Approximately 10 weeks after initiation of treatment, she noted recurrent subjective fever (temperature, up to 38.8°C) and painful lesions on the right side of the flank, left breast, and left arm of 3 days’ duration. Physical examination revealed a warm, dull red, tender nodule on the right side of the flank (Figure 1) and subcutaneous nodules with no overlying skin changes on the left breast and left arm. A biopsy of the lesion on the right side of the flank was performed, which resulted in substantial purulent drainage. Histologic analysis showed an inflammatory infiltrate within the deep dermis composed of neutrophils, macrophages, and giant cells, indicative of suppurative granulomatous dermatitis (Figure 2). Ziehl-Neelsen stain demonstrated rare AFB within the cytoplasm of macrophages, suggestive of Mycobacterium tuberculosis infection (Figure 3). A repeat chest radiograph was normal.

Based on the patient’s history and clinical presentation, she was continued on isoniazid, ethambutol, and levofloxacin, with complete resolution of symptoms and cutaneous lesions. Over the subsequent 2 months, the therapy was modified to rifabutin, pyrazinamide, and levofloxacin, and subsequently pyrazinamide was stopped. A subsequent biopsy of the left breast and histologic analysis indicated that the specimen was benign; stains for AFB were negative. Currently, both the fever and skin lesions have completely resolved, and she remains on anti-TB therapy.

 

Comment

Clinical Presentation
Cutaneous TB is an uncommon manifestation of TB that can occur either exogenously or endogenously.¹ It tends to occur primarily in previously infected TB patients through hematogenous, lymphatic, or contiguous spread.² Due to their immunocompromised state, solid organ transplant recipients have an increased incidence of primary and reactivated latent TB reported to be 20 to 74 times greater than the general population.^3,4 One report stated the total incidence of posttransplant TB as 0.48% in the West and 11.8% in endemic regions such as India.⁵ The occurrence of cutaneous TB is rare among solid organ transplant recipients.¹ On average, a diagnosis of latent TB is made 9 months after transplantation because of the opportunistic nature of M tuberculosis in an immunosuppressed environment.⁶

TB Subtypes
Cutaneous TB can be in the form of localized disease (eg, primary tuberculous chancre, TB verrucosa cutis, lupus vulgaris, smear-negative scrofuloderma), disseminated disease (eg, disseminated TB, TB gumma, orificial TB, miliary cutaneous TB), or tuberculids (eg, papulonecrotic tuberculid, lichen scrofulosorum, erythema induratum).⁷ Due to the pustular epithelioid cell granulomas and AFB positivity of the involved cutaneous lesions, our patient’s TB can be classified as a metastatic TB abscess or gummatous TB.⁷

Metastatic TB abscess, an uncommon subtype of cutaneous TB, generally is only seen in malnourished children and notably immunocompromised individuals.^2,8,9 In these individuals, systemic failure of cell-mediated immunity enables M tuberculosis to hematogenously infect various organs of the body, resulting in alternative forms of TB, such as gummatous-type TB.¹⁰ One study reported that of the 0.1% of dermatology patients presenting with cutaneous TB, only 5.4% of these individuals had the rarer gummatous form.⁷ These metastatic TB abscesses begin as a single or multiple nontender subcutaneous nodule(s), which breaks down and softens to form a draining sinus abscess.^2,8,9 Abscesses are most commonly seen on the trunk and extremities; however, they can be found nearly anywhere on the body.⁸ The pathology of cutaneous TB lesions demonstrates caseating necrosis with epithelioid and giant cells forming a surrounding rim.⁹

Diagnosis
Diagnosis may be difficult because of the vast number of dermatologic conditions that resemble cutaneous TB, including mycoses, sarcoidosis, leishmaniasis, leprosy, syphilis, other non-TB mycobacteria, and Wegener granulomatosis.⁹ Thus, confirmatory diagnosis is made via clinical presentation, detailed history and physical examination, and laboratory tests.¹¹ These tests include the Mantoux tuberculin skin test (PPD or TST) or IFN-γ release assays (QuantiFERON-TB Gold test), identification of AFB on skin biopsy, and isolation of M tuberculosis from tissue culture or polymerase chain reaction.¹¹Given our patient’s history, clinical presentation, and the identification of mycobacteria with AFB stain, the diagnosis of cutaneous gummatous TB was confirmed.

At-Risk Populations
The recommendation for the identification of at-risk populations for latent TB testing and treatment have been clearly defined by the World Health Organization (Table).¹² Our patient met 2 of these criteria: she had been preparing for organ transplantation and was from a country with high TB burden. Such at-risk patients should be tested for a latent TB infection with either IFN-γ release assays or PPD.¹²These recommendations are supported by the American Thoracic Society, which specifies that a positive PPD test in a solid organ transplant recipient is defined as having induration greater than 5 mm.¹³ However, even with a high index of suspicion, it has been reported that as many as 75% to 80% of organ recipients who developed TB had a false-negative pretransplantation PPD due to anergy from immunosuppression.¹⁴ Given the notable risk for TB in organ transplant recipients on immunosuppressive medications, these patients should receive screening tests with high sensitivity and specificity, while controlling for possible anergy. Unfortunately, the role of anergy testing in the diagnosis of latent TB is not well defined, and thus not recommended at this time.^13,15 It is recommended to repeat PPD testing 7 to 10 days after the first test as a booster effect to rule out false-negative results.¹⁵

Treatment
The recommended treatment of active TB in transplant recipients is based on randomized trials in immunocompetent hosts, and thus the same as that used by the general population.¹⁶ This anti-TB regimen includes the use of 4 drugs—typically rifampicin, isoniazid, ethambutol, and pyrazinamide—for a 6-month duration.¹¹ Unfortunately, the management of TB in an immunocompromised patient is more challenging due to the potential side effects and drug interactions.

Finally, thrombocytopenia is an infrequent, life-threatening complication that can be acquired by immunocompromised patients on anti-TB therapy.¹⁷ Drug-induced thrombocytopenia can be caused by a variety of medications, including rifampicin, isoniazid, ethambutol, and pyrazinamide. Diagnosis of drug-induced thrombocytopenia can be confirmed only after discontinuation of the suspected drug and subsequent resolution of the thrombocytopenia.¹⁷ Our patient initially became thrombocytopenic while taking isoniazid, ethambutol, pyrazinamide, and levofloxacin. However, her platelet levels improved once the pyrazinamide was discontinued, thereby suggesting pyrazinamide-induced thrombocytopenia.

Conclusion

The risk for infectious disease reactivation in an immunocompromised patient undergoing transplant surgery is notable. Our findings emphasize the value of a comprehensive pretransplant evaluation, vigilance even when test results appear negative, and treatment of latent TB within this population.^16,18,19 Furthermore, this case illustrates a noteworthy example of a rare form of cutaneous TB, which should be considered and included in the differential for cutaneous lesions in an immunosuppressed patient.

Case Report

A 60-year-old Cambodian woman presented with recurrent fever (temperature, up to 38.8°C) 7 months after receiving a kidney transplant secondary to polycystic kidney disease. Fever was attributed to recurrent pyelonephritis of the native kidneys while on mycophenolate mofetil, tacrolimus, and prednisone. As a result, she underwent a bilateral native nephrectomy and was found to have peritoneal nodules. Pathology of both native kidneys and peritoneal tissue revealed caseating granulomas and acid-fast bacilli (AFB) diagnostic for kidney and peritoneal tuberculosis (TB). She had no history of TB, and a TB skin test (purified protein derivative [PPD]) upon entering the United States from Cambodia a decade earlier was negative. Additionally, her pretransplantation PPD was negative.

Treatment with isoniazid, ethambutol, pyrazinamide, and levofloxacin was initiated immediately upon diagnosis, and all of her immunosuppressive medications—mycophenolate mofetil, tacrolimus, and prednisone—were discontinued. Her symptoms subsided within 1 week, and she was discharged from the hospital. Over the next 2 months, her immunosuppressive medications were restarted, and her TB medications were periodically discontinued by the Tuberculosis Control Program at the Department of Health (Philadelphia, Pennsylvania) due to severe thrombocytopenia. During this time, she was closely monitored twice weekly in the clinic with blood draws performed weekly.

Approximately 10 weeks after initiation of treatment, she noted recurrent subjective fever (temperature, up to 38.8°C) and painful lesions on the right side of the flank, left breast, and left arm of 3 days’ duration. Physical examination revealed a warm, dull red, tender nodule on the right side of the flank (Figure 1) and subcutaneous nodules with no overlying skin changes on the left breast and left arm. A biopsy of the lesion on the right side of the flank was performed, which resulted in substantial purulent drainage. Histologic analysis showed an inflammatory infiltrate within the deep dermis composed of neutrophils, macrophages, and giant cells, indicative of suppurative granulomatous dermatitis (Figure 2). Ziehl-Neelsen stain demonstrated rare AFB within the cytoplasm of macrophages, suggestive of Mycobacterium tuberculosis infection (Figure 3). A repeat chest radiograph was normal.

Based on the patient’s history and clinical presentation, she was continued on isoniazid, ethambutol, and levofloxacin, with complete resolution of symptoms and cutaneous lesions. Over the subsequent 2 months, the therapy was modified to rifabutin, pyrazinamide, and levofloxacin, and subsequently pyrazinamide was stopped. A subsequent biopsy of the left breast and histologic analysis indicated that the specimen was benign; stains for AFB were negative. Currently, both the fever and skin lesions have completely resolved, and she remains on anti-TB therapy.

 

Comment

Clinical Presentation
Cutaneous TB is an uncommon manifestation of TB that can occur either exogenously or endogenously.¹ It tends to occur primarily in previously infected TB patients through hematogenous, lymphatic, or contiguous spread.² Due to their immunocompromised state, solid organ transplant recipients have an increased incidence of primary and reactivated latent TB reported to be 20 to 74 times greater than the general population.^3,4 One report stated the total incidence of posttransplant TB as 0.48% in the West and 11.8% in endemic regions such as India.⁵ The occurrence of cutaneous TB is rare among solid organ transplant recipients.¹ On average, a diagnosis of latent TB is made 9 months after transplantation because of the opportunistic nature of M tuberculosis in an immunosuppressed environment.⁶

TB Subtypes
Cutaneous TB can be in the form of localized disease (eg, primary tuberculous chancre, TB verrucosa cutis, lupus vulgaris, smear-negative scrofuloderma), disseminated disease (eg, disseminated TB, TB gumma, orificial TB, miliary cutaneous TB), or tuberculids (eg, papulonecrotic tuberculid, lichen scrofulosorum, erythema induratum).⁷ Due to the pustular epithelioid cell granulomas and AFB positivity of the involved cutaneous lesions, our patient’s TB can be classified as a metastatic TB abscess or gummatous TB.⁷

Metastatic TB abscess, an uncommon subtype of cutaneous TB, generally is only seen in malnourished children and notably immunocompromised individuals.^2,8,9 In these individuals, systemic failure of cell-mediated immunity enables M tuberculosis to hematogenously infect various organs of the body, resulting in alternative forms of TB, such as gummatous-type TB.¹⁰ One study reported that of the 0.1% of dermatology patients presenting with cutaneous TB, only 5.4% of these individuals had the rarer gummatous form.⁷ These metastatic TB abscesses begin as a single or multiple nontender subcutaneous nodule(s), which breaks down and softens to form a draining sinus abscess.^2,8,9 Abscesses are most commonly seen on the trunk and extremities; however, they can be found nearly anywhere on the body.⁸ The pathology of cutaneous TB lesions demonstrates caseating necrosis with epithelioid and giant cells forming a surrounding rim.⁹

Diagnosis
Diagnosis may be difficult because of the vast number of dermatologic conditions that resemble cutaneous TB, including mycoses, sarcoidosis, leishmaniasis, leprosy, syphilis, other non-TB mycobacteria, and Wegener granulomatosis.⁹ Thus, confirmatory diagnosis is made via clinical presentation, detailed history and physical examination, and laboratory tests.¹¹ These tests include the Mantoux tuberculin skin test (PPD or TST) or IFN-γ release assays (QuantiFERON-TB Gold test), identification of AFB on skin biopsy, and isolation of M tuberculosis from tissue culture or polymerase chain reaction.¹¹Given our patient’s history, clinical presentation, and the identification of mycobacteria with AFB stain, the diagnosis of cutaneous gummatous TB was confirmed.

At-Risk Populations
The recommendation for the identification of at-risk populations for latent TB testing and treatment have been clearly defined by the World Health Organization (Table).¹² Our patient met 2 of these criteria: she had been preparing for organ transplantation and was from a country with high TB burden. Such at-risk patients should be tested for a latent TB infection with either IFN-γ release assays or PPD.¹²These recommendations are supported by the American Thoracic Society, which specifies that a positive PPD test in a solid organ transplant recipient is defined as having induration greater than 5 mm.¹³ However, even with a high index of suspicion, it has been reported that as many as 75% to 80% of organ recipients who developed TB had a false-negative pretransplantation PPD due to anergy from immunosuppression.¹⁴ Given the notable risk for TB in organ transplant recipients on immunosuppressive medications, these patients should receive screening tests with high sensitivity and specificity, while controlling for possible anergy. Unfortunately, the role of anergy testing in the diagnosis of latent TB is not well defined, and thus not recommended at this time.^13,15 It is recommended to repeat PPD testing 7 to 10 days after the first test as a booster effect to rule out false-negative results.¹⁵

Treatment
The recommended treatment of active TB in transplant recipients is based on randomized trials in immunocompetent hosts, and thus the same as that used by the general population.¹⁶ This anti-TB regimen includes the use of 4 drugs—typically rifampicin, isoniazid, ethambutol, and pyrazinamide—for a 6-month duration.¹¹ Unfortunately, the management of TB in an immunocompromised patient is more challenging due to the potential side effects and drug interactions.

Finally, thrombocytopenia is an infrequent, life-threatening complication that can be acquired by immunocompromised patients on anti-TB therapy.¹⁷ Drug-induced thrombocytopenia can be caused by a variety of medications, including rifampicin, isoniazid, ethambutol, and pyrazinamide. Diagnosis of drug-induced thrombocytopenia can be confirmed only after discontinuation of the suspected drug and subsequent resolution of the thrombocytopenia.¹⁷ Our patient initially became thrombocytopenic while taking isoniazid, ethambutol, pyrazinamide, and levofloxacin. However, her platelet levels improved once the pyrazinamide was discontinued, thereby suggesting pyrazinamide-induced thrombocytopenia.

Conclusion

The risk for infectious disease reactivation in an immunocompromised patient undergoing transplant surgery is notable. Our findings emphasize the value of a comprehensive pretransplant evaluation, vigilance even when test results appear negative, and treatment of latent TB within this population.^16,18,19 Furthermore, this case illustrates a noteworthy example of a rare form of cutaneous TB, which should be considered and included in the differential for cutaneous lesions in an immunosuppressed patient.

Case Report

A 60-year-old Cambodian woman presented with recurrent fever (temperature, up to 38.8°C) 7 months after receiving a kidney transplant secondary to polycystic kidney disease. Fever was attributed to recurrent pyelonephritis of the native kidneys while on mycophenolate mofetil, tacrolimus, and prednisone. As a result, she underwent a bilateral native nephrectomy and was found to have peritoneal nodules. Pathology of both native kidneys and peritoneal tissue revealed caseating granulomas and acid-fast bacilli (AFB) diagnostic for kidney and peritoneal tuberculosis (TB). She had no history of TB, and a TB skin test (purified protein derivative [PPD]) upon entering the United States from Cambodia a decade earlier was negative. Additionally, her pretransplantation PPD was negative.

Treatment with isoniazid, ethambutol, pyrazinamide, and levofloxacin was initiated immediately upon diagnosis, and all of her immunosuppressive medications—mycophenolate mofetil, tacrolimus, and prednisone—were discontinued. Her symptoms subsided within 1 week, and she was discharged from the hospital. Over the next 2 months, her immunosuppressive medications were restarted, and her TB medications were periodically discontinued by the Tuberculosis Control Program at the Department of Health (Philadelphia, Pennsylvania) due to severe thrombocytopenia. During this time, she was closely monitored twice weekly in the clinic with blood draws performed weekly.

Approximately 10 weeks after initiation of treatment, she noted recurrent subjective fever (temperature, up to 38.8°C) and painful lesions on the right side of the flank, left breast, and left arm of 3 days’ duration. Physical examination revealed a warm, dull red, tender nodule on the right side of the flank (Figure 1) and subcutaneous nodules with no overlying skin changes on the left breast and left arm. A biopsy of the lesion on the right side of the flank was performed, which resulted in substantial purulent drainage. Histologic analysis showed an inflammatory infiltrate within the deep dermis composed of neutrophils, macrophages, and giant cells, indicative of suppurative granulomatous dermatitis (Figure 2). Ziehl-Neelsen stain demonstrated rare AFB within the cytoplasm of macrophages, suggestive of Mycobacterium tuberculosis infection (Figure 3). A repeat chest radiograph was normal.

Based on the patient’s history and clinical presentation, she was continued on isoniazid, ethambutol, and levofloxacin, with complete resolution of symptoms and cutaneous lesions. Over the subsequent 2 months, the therapy was modified to rifabutin, pyrazinamide, and levofloxacin, and subsequently pyrazinamide was stopped. A subsequent biopsy of the left breast and histologic analysis indicated that the specimen was benign; stains for AFB were negative. Currently, both the fever and skin lesions have completely resolved, and she remains on anti-TB therapy.

 

Comment

Clinical Presentation
Cutaneous TB is an uncommon manifestation of TB that can occur either exogenously or endogenously.¹ It tends to occur primarily in previously infected TB patients through hematogenous, lymphatic, or contiguous spread.² Due to their immunocompromised state, solid organ transplant recipients have an increased incidence of primary and reactivated latent TB reported to be 20 to 74 times greater than the general population.^3,4 One report stated the total incidence of posttransplant TB as 0.48% in the West and 11.8% in endemic regions such as India.⁵ The occurrence of cutaneous TB is rare among solid organ transplant recipients.¹ On average, a diagnosis of latent TB is made 9 months after transplantation because of the opportunistic nature of M tuberculosis in an immunosuppressed environment.⁶

TB Subtypes
Cutaneous TB can be in the form of localized disease (eg, primary tuberculous chancre, TB verrucosa cutis, lupus vulgaris, smear-negative scrofuloderma), disseminated disease (eg, disseminated TB, TB gumma, orificial TB, miliary cutaneous TB), or tuberculids (eg, papulonecrotic tuberculid, lichen scrofulosorum, erythema induratum).⁷ Due to the pustular epithelioid cell granulomas and AFB positivity of the involved cutaneous lesions, our patient’s TB can be classified as a metastatic TB abscess or gummatous TB.⁷

Metastatic TB abscess, an uncommon subtype of cutaneous TB, generally is only seen in malnourished children and notably immunocompromised individuals.^2,8,9 In these individuals, systemic failure of cell-mediated immunity enables M tuberculosis to hematogenously infect various organs of the body, resulting in alternative forms of TB, such as gummatous-type TB.¹⁰ One study reported that of the 0.1% of dermatology patients presenting with cutaneous TB, only 5.4% of these individuals had the rarer gummatous form.⁷ These metastatic TB abscesses begin as a single or multiple nontender subcutaneous nodule(s), which breaks down and softens to form a draining sinus abscess.^2,8,9 Abscesses are most commonly seen on the trunk and extremities; however, they can be found nearly anywhere on the body.⁸ The pathology of cutaneous TB lesions demonstrates caseating necrosis with epithelioid and giant cells forming a surrounding rim.⁹

Diagnosis
Diagnosis may be difficult because of the vast number of dermatologic conditions that resemble cutaneous TB, including mycoses, sarcoidosis, leishmaniasis, leprosy, syphilis, other non-TB mycobacteria, and Wegener granulomatosis.⁹ Thus, confirmatory diagnosis is made via clinical presentation, detailed history and physical examination, and laboratory tests.¹¹ These tests include the Mantoux tuberculin skin test (PPD or TST) or IFN-γ release assays (QuantiFERON-TB Gold test), identification of AFB on skin biopsy, and isolation of M tuberculosis from tissue culture or polymerase chain reaction.¹¹Given our patient’s history, clinical presentation, and the identification of mycobacteria with AFB stain, the diagnosis of cutaneous gummatous TB was confirmed.

At-Risk Populations
The recommendation for the identification of at-risk populations for latent TB testing and treatment have been clearly defined by the World Health Organization (Table).¹² Our patient met 2 of these criteria: she had been preparing for organ transplantation and was from a country with high TB burden. Such at-risk patients should be tested for a latent TB infection with either IFN-γ release assays or PPD.¹²These recommendations are supported by the American Thoracic Society, which specifies that a positive PPD test in a solid organ transplant recipient is defined as having induration greater than 5 mm.¹³ However, even with a high index of suspicion, it has been reported that as many as 75% to 80% of organ recipients who developed TB had a false-negative pretransplantation PPD due to anergy from immunosuppression.¹⁴ Given the notable risk for TB in organ transplant recipients on immunosuppressive medications, these patients should receive screening tests with high sensitivity and specificity, while controlling for possible anergy. Unfortunately, the role of anergy testing in the diagnosis of latent TB is not well defined, and thus not recommended at this time.^13,15 It is recommended to repeat PPD testing 7 to 10 days after the first test as a booster effect to rule out false-negative results.¹⁵

Treatment
The recommended treatment of active TB in transplant recipients is based on randomized trials in immunocompetent hosts, and thus the same as that used by the general population.¹⁶ This anti-TB regimen includes the use of 4 drugs—typically rifampicin, isoniazid, ethambutol, and pyrazinamide—for a 6-month duration.¹¹ Unfortunately, the management of TB in an immunocompromised patient is more challenging due to the potential side effects and drug interactions.

Finally, thrombocytopenia is an infrequent, life-threatening complication that can be acquired by immunocompromised patients on anti-TB therapy.¹⁷ Drug-induced thrombocytopenia can be caused by a variety of medications, including rifampicin, isoniazid, ethambutol, and pyrazinamide. Diagnosis of drug-induced thrombocytopenia can be confirmed only after discontinuation of the suspected drug and subsequent resolution of the thrombocytopenia.¹⁷ Our patient initially became thrombocytopenic while taking isoniazid, ethambutol, pyrazinamide, and levofloxacin. However, her platelet levels improved once the pyrazinamide was discontinued, thereby suggesting pyrazinamide-induced thrombocytopenia.

Conclusion

The risk for infectious disease reactivation in an immunocompromised patient undergoing transplant surgery is notable. Our findings emphasize the value of a comprehensive pretransplant evaluation, vigilance even when test results appear negative, and treatment of latent TB within this population.^16,18,19 Furthermore, this case illustrates a noteworthy example of a rare form of cutaneous TB, which should be considered and included in the differential for cutaneous lesions in an immunosuppressed patient.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Course and Treatment
Laboratory studies revealed leukopenia. Prior to histopathologic results, empiric treatment was started with doxycycline 100 mg twice daily for 2 weeks. Once pathology confirmed the diagnosis of Rosai-Dorfman disease (RDD), computed tomography of the chest, abdomen, and pelvis was performed and within normal limits. Due to the lack of systemic involvement, we diagnosed the rare form of purely cutaneous Rosai-Dorfman disease (CRDD). In subsequent visits, treatment with oral prednisone (40 mg daily for 1 week followed by 20 mg daily for 1 week) and intralesional triamcinolone acetonide (5 areas on the right medial thigh were injected with 1.0 mL of 10 mg/mL) was attempted with mild improvement, though the patient declined surgical excision.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

 

Approximately 10% of RDD patients exhibit skin lesions, and in 3% it is contained solely in the skin.³ Pure CRDD was first documented in 1978 by Thawerani et al⁴ who presented the case of a 48-year-old man with a solitary nodule on the shoulder.

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Course and Treatment
Laboratory studies revealed leukopenia. Prior to histopathologic results, empiric treatment was started with doxycycline 100 mg twice daily for 2 weeks. Once pathology confirmed the diagnosis of Rosai-Dorfman disease (RDD), computed tomography of the chest, abdomen, and pelvis was performed and within normal limits. Due to the lack of systemic involvement, we diagnosed the rare form of purely cutaneous Rosai-Dorfman disease (CRDD). In subsequent visits, treatment with oral prednisone (40 mg daily for 1 week followed by 20 mg daily for 1 week) and intralesional triamcinolone acetonide (5 areas on the right medial thigh were injected with 1.0 mL of 10 mg/mL) was attempted with mild improvement, though the patient declined surgical excision.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

 

Approximately 10% of RDD patients exhibit skin lesions, and in 3% it is contained solely in the skin.³ Pure CRDD was first documented in 1978 by Thawerani et al⁴ who presented the case of a 48-year-old man with a solitary nodule on the shoulder.

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Course and Treatment
Laboratory studies revealed leukopenia. Prior to histopathologic results, empiric treatment was started with doxycycline 100 mg twice daily for 2 weeks. Once pathology confirmed the diagnosis of Rosai-Dorfman disease (RDD), computed tomography of the chest, abdomen, and pelvis was performed and within normal limits. Due to the lack of systemic involvement, we diagnosed the rare form of purely cutaneous Rosai-Dorfman disease (CRDD). In subsequent visits, treatment with oral prednisone (40 mg daily for 1 week followed by 20 mg daily for 1 week) and intralesional triamcinolone acetonide (5 areas on the right medial thigh were injected with 1.0 mL of 10 mg/mL) was attempted with mild improvement, though the patient declined surgical excision.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

 

Approximately 10% of RDD patients exhibit skin lesions, and in 3% it is contained solely in the skin.³ Pure CRDD was first documented in 1978 by Thawerani et al⁴ who presented the case of a 48-year-old man with a solitary nodule on the shoulder.

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

 

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

 

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

 

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

 

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

 

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

 

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

 

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Pathophysiology
The pathophysiology of DDA remains unclear. It has been hypothesized that ischemia or inflammation creates local hypoxia, leading to an increase in vascular endothelial growth factor with subsequent endothelial proliferation and neovascularization.⁵ Rongioletti and Robora² supported this hypothesis, proposing that occlusion or inflammation of the vasculature creates microthrombi and thus hypoxia. Afterward, histiocytes are recruited to reabsorb the microthrombi while hyperplasia of endothelial cells and pericytes ensues.⁷ Complete resolution of skin lesions following revascularization provides support for this theory.⁸

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

 

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

 

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Pathophysiology
The pathophysiology of DDA remains unclear. It has been hypothesized that ischemia or inflammation creates local hypoxia, leading to an increase in vascular endothelial growth factor with subsequent endothelial proliferation and neovascularization.⁵ Rongioletti and Robora² supported this hypothesis, proposing that occlusion or inflammation of the vasculature creates microthrombi and thus hypoxia. Afterward, histiocytes are recruited to reabsorb the microthrombi while hyperplasia of endothelial cells and pericytes ensues.⁷ Complete resolution of skin lesions following revascularization provides support for this theory.⁸

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

 

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

 

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Pathophysiology
The pathophysiology of DDA remains unclear. It has been hypothesized that ischemia or inflammation creates local hypoxia, leading to an increase in vascular endothelial growth factor with subsequent endothelial proliferation and neovascularization.⁵ Rongioletti and Robora² supported this hypothesis, proposing that occlusion or inflammation of the vasculature creates microthrombi and thus hypoxia. Afterward, histiocytes are recruited to reabsorb the microthrombi while hyperplasia of endothelial cells and pericytes ensues.⁷ Complete resolution of skin lesions following revascularization provides support for this theory.⁸

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

 

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.