Article

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

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Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

To the Editor:

A 73-year-old man was admitted to the hospital with progressive abdominal and hip pain of several weeks’ duration that was accompanied by unilateral swelling of the left leg. He had a medical history of hypertension, hyperlipidemia, and prediabetes. Computed tomography (CT) showed extensive intra-abdominal, retroperitoneal, and pelvic lymphadenopathy in addition to poorly defined hepatic lesions.

A CT-guided core biopsy of a left inguinal lymph node showed Burkitt lymphoma. Fluorescence in situ hybridization was positive for oncogene c-MYC rearrangement on chromosome 8q24 and negative for B-cell lymphoma 2 (BCL2) and B-cell lymphoma 6 (BCL6) gene rearrangements. Flow cytometry demonstrated an aberrant population of κ light chain-restricted CD5⁻CD10⁺ B lymphocytes.

The patient’s overall disease burden was consistent with stage IV Burkitt lymphoma. R-miniCHOP chemotherapy—rituximab plus a reduced dose of cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone—was initiated. Approximately 2 weeks after chemotherapy was initiated, the patient developed a firm erythematous eruption on the left hip (Figure 1A). His regimen was then switched to R-EPOCH—rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin—at the time of discharge, and he was referred to dermatology due to an initial concern of an adverse reaction to R-EPOCH chemotherapy. The patient denied any pain, pruritus, or irritation. Physical examination showed multifocal, subcutaneous, indurated, erythematous and violaceous nodules without epidermal changes. Some nodules on the lateral aspect of the hip coalesced to form firm plaques.

A punch biopsy specimen showed markedly atypical lymphocytes with enlarged nuclei and scant cytoplasm present throughout the dermis (Figures 2A and 2B). Numerous apoptotic cells and cellular debris were seen. Immunohistochemical staining demonstrated that the lymphocytic infiltrate comprised CD79a⁺ B cells that were positive for Bcl-6 and CD10 and negative for Bcl-2 (Figures 2C and 2D). There also was diminished focal expression of CD20. Ki-67 protein staining was intensely positive and demonstrated a very high proliferative index.

Taken together, these findings were consistent with a diagnosis of cutaneous metastasis of Burkitt lymphoma. The patient’s cutaneous lesions improved after continued aggressive chemotherapy. At follow-up 2 weeks after biopsy, he was receiving his second round of R-EPOCH chemotherapy with appreciable regression of skin lesions (Figure 1B). However, he then developed right-side double vision, ptosis, and right-side facial paresthesia. Although magnetic resonance imaging of the brain and lumbar puncture did not show evidence of central nervous system involvement, the chemotherapy regimen was switched to dose-adjusted CVAD-R—hypercyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone plus rituximab—for empiric treatment of central nervous system disease. Although treatment was complicated by sepsis with extended-spectrum β-lactamase-producing Enterobacter cloacae, Burkitt lymphoma was found to be in remission after 3 cycles of CVAD-R and 5 months of chemotherapy.

Burkitt lymphoma is a B-cell non-Hodgkin malignancy caused by translocation of chromosome 8 and chromosome 14, leading to overexpression of c-MYC and subsequent hyperproliferation of B lymphocytes.^1,2 The disease is divided into 3 major categories: sporadic, endemic, and immunodeficiency related.³ The endemic variant is the most prevalent subtype in Africa and is associated with Plasmodium falciparum malaria; the sporadic variant is the most common subtype in the rest of the world.⁴

Burkitt lymphoma is highly aggressive and is characterized by unusually high rates of mitosis and apoptosis that result in abundant cellular debris and a distinctive starry-sky pattern on histopathology.^5,6 Extranodal metastasis is common,⁷ but cutaneous involvement is exceedingly rare, with only a few cases having been reported.^8-14 Cutaneous metastasis of Burkitt lymphoma often is associated with a high overall disease burden and poor prognosis.^8,11

Immunodeficiency-related Burkitt lymphoma is particularly aggressive. Notably, 3 of 7 (42.9%) reported cases of cutaneous Burkitt lymphoma occurred in HIV-positive patients.^11,13 In one case, cutaneous involvement was the first sign of relapsed disease that had been in remission.¹²

Although c-MYC rearrangement is required to make a diagnosis of Burkitt lymphoma, the disease also is present in a minority of cases of diffuse large B-cell lymphoma (DLBCL)(6%).¹⁵ Although DLBCL typically can be differentiated from Burkitt lymphoma by the large nuclear size and characteristic vesicular nuclei of B cells, few cases of DLBCL with c-MYC rearrangement histologically mimic Burkitt lymphoma. However, key features such as immunohistochemical staining for Bcl-2 and CD10 can be used to distinguish these 2 entities.¹⁶ Bcl-2 negativity and CD10 positivity, as seen in our patient, is considered more characteristic of Burkitt lymphoma. This staining pattern in combination with a high Ki-67 fraction (>95%) and the presence of monomorphic medium-sized cells is more consistent with a diagnosis of Burkitt lymphoma than of DLBCL.¹⁷

Earlier case reports have documented that cutaneous lesions of Burkitt lymphoma can occur in a variety of ways. Hematogenous spread is the likely route of metastasis for lesions distant to the primary site or those that have widespread distribution.¹⁸ Alternatively, other reports have suggested that cutaneous metastases can occur from local invasion and subcutaneous extension of malignant cells after a surgical procedure.^10,19 For example, cutaneous Burkitt lymphoma has been reported in the setting of celioscopy, occurring directly at the surgical site.¹⁹ In our patient, we believe that the route of metastatic spread likely was through subcutaneous invasion secondary to CT-guided core biopsy, which was supported by the observation that the onset of cutaneous manifestations was temporally related to the procedure and that the lesions occurred on the skin directly overlying the biopsy site.

In conclusion, we describe an exceedingly rare presentation of cutaneous Burkitt lymphoma in which a surgical procedure likely served as an inciting event that triggered seeding of malignant cells to the skin. Cutaneous spread of Burkitt lymphoma is infrequently reported; all such reports that provide long-term follow-up data have described it in association with high disease burden and often a lethal outcome.^8,11,12 Our patient had complete resolution of cutaneous lesions with chemotherapy. It is unclear if the presence of cutaneous lesions can serve as a prognostic indicator and requires further investigation. However, our case provides preliminary evidence to suggest that cutaneous metastases do not always represent aggressive disease and that cutaneous lesions may respond well to chemotherapy.

To the Editor:

A 73-year-old man was admitted to the hospital with progressive abdominal and hip pain of several weeks’ duration that was accompanied by unilateral swelling of the left leg. He had a medical history of hypertension, hyperlipidemia, and prediabetes. Computed tomography (CT) showed extensive intra-abdominal, retroperitoneal, and pelvic lymphadenopathy in addition to poorly defined hepatic lesions.

A CT-guided core biopsy of a left inguinal lymph node showed Burkitt lymphoma. Fluorescence in situ hybridization was positive for oncogene c-MYC rearrangement on chromosome 8q24 and negative for B-cell lymphoma 2 (BCL2) and B-cell lymphoma 6 (BCL6) gene rearrangements. Flow cytometry demonstrated an aberrant population of κ light chain-restricted CD5⁻CD10⁺ B lymphocytes.

The patient’s overall disease burden was consistent with stage IV Burkitt lymphoma. R-miniCHOP chemotherapy—rituximab plus a reduced dose of cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone—was initiated. Approximately 2 weeks after chemotherapy was initiated, the patient developed a firm erythematous eruption on the left hip (Figure 1A). His regimen was then switched to R-EPOCH—rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin—at the time of discharge, and he was referred to dermatology due to an initial concern of an adverse reaction to R-EPOCH chemotherapy. The patient denied any pain, pruritus, or irritation. Physical examination showed multifocal, subcutaneous, indurated, erythematous and violaceous nodules without epidermal changes. Some nodules on the lateral aspect of the hip coalesced to form firm plaques.

A punch biopsy specimen showed markedly atypical lymphocytes with enlarged nuclei and scant cytoplasm present throughout the dermis (Figures 2A and 2B). Numerous apoptotic cells and cellular debris were seen. Immunohistochemical staining demonstrated that the lymphocytic infiltrate comprised CD79a⁺ B cells that were positive for Bcl-6 and CD10 and negative for Bcl-2 (Figures 2C and 2D). There also was diminished focal expression of CD20. Ki-67 protein staining was intensely positive and demonstrated a very high proliferative index.

Taken together, these findings were consistent with a diagnosis of cutaneous metastasis of Burkitt lymphoma. The patient’s cutaneous lesions improved after continued aggressive chemotherapy. At follow-up 2 weeks after biopsy, he was receiving his second round of R-EPOCH chemotherapy with appreciable regression of skin lesions (Figure 1B). However, he then developed right-side double vision, ptosis, and right-side facial paresthesia. Although magnetic resonance imaging of the brain and lumbar puncture did not show evidence of central nervous system involvement, the chemotherapy regimen was switched to dose-adjusted CVAD-R—hypercyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone plus rituximab—for empiric treatment of central nervous system disease. Although treatment was complicated by sepsis with extended-spectrum β-lactamase-producing Enterobacter cloacae, Burkitt lymphoma was found to be in remission after 3 cycles of CVAD-R and 5 months of chemotherapy.

Burkitt lymphoma is a B-cell non-Hodgkin malignancy caused by translocation of chromosome 8 and chromosome 14, leading to overexpression of c-MYC and subsequent hyperproliferation of B lymphocytes.^1,2 The disease is divided into 3 major categories: sporadic, endemic, and immunodeficiency related.³ The endemic variant is the most prevalent subtype in Africa and is associated with Plasmodium falciparum malaria; the sporadic variant is the most common subtype in the rest of the world.⁴

Burkitt lymphoma is highly aggressive and is characterized by unusually high rates of mitosis and apoptosis that result in abundant cellular debris and a distinctive starry-sky pattern on histopathology.^5,6 Extranodal metastasis is common,⁷ but cutaneous involvement is exceedingly rare, with only a few cases having been reported.^8-14 Cutaneous metastasis of Burkitt lymphoma often is associated with a high overall disease burden and poor prognosis.^8,11

Immunodeficiency-related Burkitt lymphoma is particularly aggressive. Notably, 3 of 7 (42.9%) reported cases of cutaneous Burkitt lymphoma occurred in HIV-positive patients.^11,13 In one case, cutaneous involvement was the first sign of relapsed disease that had been in remission.¹²

Although c-MYC rearrangement is required to make a diagnosis of Burkitt lymphoma, the disease also is present in a minority of cases of diffuse large B-cell lymphoma (DLBCL)(6%).¹⁵ Although DLBCL typically can be differentiated from Burkitt lymphoma by the large nuclear size and characteristic vesicular nuclei of B cells, few cases of DLBCL with c-MYC rearrangement histologically mimic Burkitt lymphoma. However, key features such as immunohistochemical staining for Bcl-2 and CD10 can be used to distinguish these 2 entities.¹⁶ Bcl-2 negativity and CD10 positivity, as seen in our patient, is considered more characteristic of Burkitt lymphoma. This staining pattern in combination with a high Ki-67 fraction (>95%) and the presence of monomorphic medium-sized cells is more consistent with a diagnosis of Burkitt lymphoma than of DLBCL.¹⁷

Earlier case reports have documented that cutaneous lesions of Burkitt lymphoma can occur in a variety of ways. Hematogenous spread is the likely route of metastasis for lesions distant to the primary site or those that have widespread distribution.¹⁸ Alternatively, other reports have suggested that cutaneous metastases can occur from local invasion and subcutaneous extension of malignant cells after a surgical procedure.^10,19 For example, cutaneous Burkitt lymphoma has been reported in the setting of celioscopy, occurring directly at the surgical site.¹⁹ In our patient, we believe that the route of metastatic spread likely was through subcutaneous invasion secondary to CT-guided core biopsy, which was supported by the observation that the onset of cutaneous manifestations was temporally related to the procedure and that the lesions occurred on the skin directly overlying the biopsy site.

In conclusion, we describe an exceedingly rare presentation of cutaneous Burkitt lymphoma in which a surgical procedure likely served as an inciting event that triggered seeding of malignant cells to the skin. Cutaneous spread of Burkitt lymphoma is infrequently reported; all such reports that provide long-term follow-up data have described it in association with high disease burden and often a lethal outcome.^8,11,12 Our patient had complete resolution of cutaneous lesions with chemotherapy. It is unclear if the presence of cutaneous lesions can serve as a prognostic indicator and requires further investigation. However, our case provides preliminary evidence to suggest that cutaneous metastases do not always represent aggressive disease and that cutaneous lesions may respond well to chemotherapy.

To the Editor:

A 73-year-old man was admitted to the hospital with progressive abdominal and hip pain of several weeks’ duration that was accompanied by unilateral swelling of the left leg. He had a medical history of hypertension, hyperlipidemia, and prediabetes. Computed tomography (CT) showed extensive intra-abdominal, retroperitoneal, and pelvic lymphadenopathy in addition to poorly defined hepatic lesions.

A CT-guided core biopsy of a left inguinal lymph node showed Burkitt lymphoma. Fluorescence in situ hybridization was positive for oncogene c-MYC rearrangement on chromosome 8q24 and negative for B-cell lymphoma 2 (BCL2) and B-cell lymphoma 6 (BCL6) gene rearrangements. Flow cytometry demonstrated an aberrant population of κ light chain-restricted CD5⁻CD10⁺ B lymphocytes.

The patient’s overall disease burden was consistent with stage IV Burkitt lymphoma. R-miniCHOP chemotherapy—rituximab plus a reduced dose of cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone—was initiated. Approximately 2 weeks after chemotherapy was initiated, the patient developed a firm erythematous eruption on the left hip (Figure 1A). His regimen was then switched to R-EPOCH—rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin—at the time of discharge, and he was referred to dermatology due to an initial concern of an adverse reaction to R-EPOCH chemotherapy. The patient denied any pain, pruritus, or irritation. Physical examination showed multifocal, subcutaneous, indurated, erythematous and violaceous nodules without epidermal changes. Some nodules on the lateral aspect of the hip coalesced to form firm plaques.

A punch biopsy specimen showed markedly atypical lymphocytes with enlarged nuclei and scant cytoplasm present throughout the dermis (Figures 2A and 2B). Numerous apoptotic cells and cellular debris were seen. Immunohistochemical staining demonstrated that the lymphocytic infiltrate comprised CD79a⁺ B cells that were positive for Bcl-6 and CD10 and negative for Bcl-2 (Figures 2C and 2D). There also was diminished focal expression of CD20. Ki-67 protein staining was intensely positive and demonstrated a very high proliferative index.

Taken together, these findings were consistent with a diagnosis of cutaneous metastasis of Burkitt lymphoma. The patient’s cutaneous lesions improved after continued aggressive chemotherapy. At follow-up 2 weeks after biopsy, he was receiving his second round of R-EPOCH chemotherapy with appreciable regression of skin lesions (Figure 1B). However, he then developed right-side double vision, ptosis, and right-side facial paresthesia. Although magnetic resonance imaging of the brain and lumbar puncture did not show evidence of central nervous system involvement, the chemotherapy regimen was switched to dose-adjusted CVAD-R—hypercyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone plus rituximab—for empiric treatment of central nervous system disease. Although treatment was complicated by sepsis with extended-spectrum β-lactamase-producing Enterobacter cloacae, Burkitt lymphoma was found to be in remission after 3 cycles of CVAD-R and 5 months of chemotherapy.

Burkitt lymphoma is a B-cell non-Hodgkin malignancy caused by translocation of chromosome 8 and chromosome 14, leading to overexpression of c-MYC and subsequent hyperproliferation of B lymphocytes.^1,2 The disease is divided into 3 major categories: sporadic, endemic, and immunodeficiency related.³ The endemic variant is the most prevalent subtype in Africa and is associated with Plasmodium falciparum malaria; the sporadic variant is the most common subtype in the rest of the world.⁴

Burkitt lymphoma is highly aggressive and is characterized by unusually high rates of mitosis and apoptosis that result in abundant cellular debris and a distinctive starry-sky pattern on histopathology.^5,6 Extranodal metastasis is common,⁷ but cutaneous involvement is exceedingly rare, with only a few cases having been reported.^8-14 Cutaneous metastasis of Burkitt lymphoma often is associated with a high overall disease burden and poor prognosis.^8,11

Immunodeficiency-related Burkitt lymphoma is particularly aggressive. Notably, 3 of 7 (42.9%) reported cases of cutaneous Burkitt lymphoma occurred in HIV-positive patients.^11,13 In one case, cutaneous involvement was the first sign of relapsed disease that had been in remission.¹²

Although c-MYC rearrangement is required to make a diagnosis of Burkitt lymphoma, the disease also is present in a minority of cases of diffuse large B-cell lymphoma (DLBCL)(6%).¹⁵ Although DLBCL typically can be differentiated from Burkitt lymphoma by the large nuclear size and characteristic vesicular nuclei of B cells, few cases of DLBCL with c-MYC rearrangement histologically mimic Burkitt lymphoma. However, key features such as immunohistochemical staining for Bcl-2 and CD10 can be used to distinguish these 2 entities.¹⁶ Bcl-2 negativity and CD10 positivity, as seen in our patient, is considered more characteristic of Burkitt lymphoma. This staining pattern in combination with a high Ki-67 fraction (>95%) and the presence of monomorphic medium-sized cells is more consistent with a diagnosis of Burkitt lymphoma than of DLBCL.¹⁷

Earlier case reports have documented that cutaneous lesions of Burkitt lymphoma can occur in a variety of ways. Hematogenous spread is the likely route of metastasis for lesions distant to the primary site or those that have widespread distribution.¹⁸ Alternatively, other reports have suggested that cutaneous metastases can occur from local invasion and subcutaneous extension of malignant cells after a surgical procedure.^10,19 For example, cutaneous Burkitt lymphoma has been reported in the setting of celioscopy, occurring directly at the surgical site.¹⁹ In our patient, we believe that the route of metastatic spread likely was through subcutaneous invasion secondary to CT-guided core biopsy, which was supported by the observation that the onset of cutaneous manifestations was temporally related to the procedure and that the lesions occurred on the skin directly overlying the biopsy site.

In conclusion, we describe an exceedingly rare presentation of cutaneous Burkitt lymphoma in which a surgical procedure likely served as an inciting event that triggered seeding of malignant cells to the skin. Cutaneous spread of Burkitt lymphoma is infrequently reported; all such reports that provide long-term follow-up data have described it in association with high disease burden and often a lethal outcome.^8,11,12 Our patient had complete resolution of cutaneous lesions with chemotherapy. It is unclear if the presence of cutaneous lesions can serve as a prognostic indicator and requires further investigation. However, our case provides preliminary evidence to suggest that cutaneous metastases do not always represent aggressive disease and that cutaneous lesions may respond well to chemotherapy.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

Migraines are episodic or chronic headaches, typically occurring on one side of the head, that have distinct characteristics and definitions from the International Classification of Headache Disorders, 3rd edition (ICHD 3). Migraine can occur at any age and is thought to affect about 5% of children before puberty, increases in prevalence after puberty, and reaches about 30% prevalence at age 25-30 years. Patients with migraine with aura have recurrent, fully reversible symptoms that can include diplopia, motor or sensory disturbances, and/or trouble with language that generally precede headache development. In some cases, aura may develop and resolve without headache. Migraine with aura can present at any age from early childhood onward and is present in about 30% of children and adolescents with migraine. In general, migraine with aura is more prevalent in female than in male individuals, especially adolescents. 

Migraine with brainstem aura, as is the case here, is a specific subtype of migraine with aura, in which the aura specifically reflects an origin within the brainstem. Brainstem symptoms include diplopia, vertigo, difficulty controlling speech muscles, tinnitus, hearing loss, loss of coordination, and possibly impaired consciousness. For the diagnosis of migraine with brainstem aura, patients must not have motor or retinal symptoms. Aura development often is preceded by premonitory symptoms, such as fatigue, hunger or food cravings, and mood elevations.

Migraine without aura, in contrast, is characterized by recurrent moderate to severe pulsating headache lasting from a few hours to up to 3 days. Migraine without aura often causes nausea and sensitivity to light and/or sound.

Chronic migraine is defined as headache (with or without aura) occurring 15 or more days per month for at least the past 3 months. This patient's history does not fit the definition of chronic migraine.

Tension-type headaches generally are bilateral, with durations ranging from minutes to days. They tend to be mild to moderate in intensity and symptoms are not worsened by physical activity. In addition to their bilateral nature, these headaches differ from migraine in lacking associated visual, cortical, or other symptoms. 

Any diagnosis of migraine requires assessment over time, using diagnostic criteria established by the International Headache Society in ICHD 3. It is not necessary to perform neuroimaging studies or CT in patients with migraine symptoms and an otherwise normal neurologic exam.

When a diagnosis of migraine with brainstem aura is established, pediatric or adolescent patients and their families should first be counseled on nonpharmacologic interventions. These interventions, which have demonstrated benefits in reducing headache frequency, include lifestyle modifications, regular sleep and meal schedules, adequate fluid intake, cognitive-behavioral therapy, stress management techniques, massage, and biofeedback techniques. Recommended for acute treatment of migraine are nonsteroidal anti-inflammatory drugs, acetaminophen, and triptans. There is limited evidence in pediatric or adolescent patients with use of preventive medications, such as topiramate, amitriptyline, or onabotulinumtoxinA. In clinical trials, patients receiving placebo saw improvements, and active treatments were only marginally, if at all, more effective. Current guidelines recommend a frank discussion with parents about the limitations of preventive therapies before making decisions to use them. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Migraines are episodic or chronic headaches, typically occurring on one side of the head, that have distinct characteristics and definitions from the International Classification of Headache Disorders, 3rd edition (ICHD 3). Migraine can occur at any age and is thought to affect about 5% of children before puberty, increases in prevalence after puberty, and reaches about 30% prevalence at age 25-30 years. Patients with migraine with aura have recurrent, fully reversible symptoms that can include diplopia, motor or sensory disturbances, and/or trouble with language that generally precede headache development. In some cases, aura may develop and resolve without headache. Migraine with aura can present at any age from early childhood onward and is present in about 30% of children and adolescents with migraine. In general, migraine with aura is more prevalent in female than in male individuals, especially adolescents. 

Migraine with brainstem aura, as is the case here, is a specific subtype of migraine with aura, in which the aura specifically reflects an origin within the brainstem. Brainstem symptoms include diplopia, vertigo, difficulty controlling speech muscles, tinnitus, hearing loss, loss of coordination, and possibly impaired consciousness. For the diagnosis of migraine with brainstem aura, patients must not have motor or retinal symptoms. Aura development often is preceded by premonitory symptoms, such as fatigue, hunger or food cravings, and mood elevations.

Migraine without aura, in contrast, is characterized by recurrent moderate to severe pulsating headache lasting from a few hours to up to 3 days. Migraine without aura often causes nausea and sensitivity to light and/or sound.

Chronic migraine is defined as headache (with or without aura) occurring 15 or more days per month for at least the past 3 months. This patient's history does not fit the definition of chronic migraine.

Tension-type headaches generally are bilateral, with durations ranging from minutes to days. They tend to be mild to moderate in intensity and symptoms are not worsened by physical activity. In addition to their bilateral nature, these headaches differ from migraine in lacking associated visual, cortical, or other symptoms. 

Any diagnosis of migraine requires assessment over time, using diagnostic criteria established by the International Headache Society in ICHD 3. It is not necessary to perform neuroimaging studies or CT in patients with migraine symptoms and an otherwise normal neurologic exam.

When a diagnosis of migraine with brainstem aura is established, pediatric or adolescent patients and their families should first be counseled on nonpharmacologic interventions. These interventions, which have demonstrated benefits in reducing headache frequency, include lifestyle modifications, regular sleep and meal schedules, adequate fluid intake, cognitive-behavioral therapy, stress management techniques, massage, and biofeedback techniques. Recommended for acute treatment of migraine are nonsteroidal anti-inflammatory drugs, acetaminophen, and triptans. There is limited evidence in pediatric or adolescent patients with use of preventive medications, such as topiramate, amitriptyline, or onabotulinumtoxinA. In clinical trials, patients receiving placebo saw improvements, and active treatments were only marginally, if at all, more effective. Current guidelines recommend a frank discussion with parents about the limitations of preventive therapies before making decisions to use them. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Migraines are episodic or chronic headaches, typically occurring on one side of the head, that have distinct characteristics and definitions from the International Classification of Headache Disorders, 3rd edition (ICHD 3). Migraine can occur at any age and is thought to affect about 5% of children before puberty, increases in prevalence after puberty, and reaches about 30% prevalence at age 25-30 years. Patients with migraine with aura have recurrent, fully reversible symptoms that can include diplopia, motor or sensory disturbances, and/or trouble with language that generally precede headache development. In some cases, aura may develop and resolve without headache. Migraine with aura can present at any age from early childhood onward and is present in about 30% of children and adolescents with migraine. In general, migraine with aura is more prevalent in female than in male individuals, especially adolescents. 

Migraine with brainstem aura, as is the case here, is a specific subtype of migraine with aura, in which the aura specifically reflects an origin within the brainstem. Brainstem symptoms include diplopia, vertigo, difficulty controlling speech muscles, tinnitus, hearing loss, loss of coordination, and possibly impaired consciousness. For the diagnosis of migraine with brainstem aura, patients must not have motor or retinal symptoms. Aura development often is preceded by premonitory symptoms, such as fatigue, hunger or food cravings, and mood elevations.

Migraine without aura, in contrast, is characterized by recurrent moderate to severe pulsating headache lasting from a few hours to up to 3 days. Migraine without aura often causes nausea and sensitivity to light and/or sound.

Chronic migraine is defined as headache (with or without aura) occurring 15 or more days per month for at least the past 3 months. This patient's history does not fit the definition of chronic migraine.

Tension-type headaches generally are bilateral, with durations ranging from minutes to days. They tend to be mild to moderate in intensity and symptoms are not worsened by physical activity. In addition to their bilateral nature, these headaches differ from migraine in lacking associated visual, cortical, or other symptoms. 

Any diagnosis of migraine requires assessment over time, using diagnostic criteria established by the International Headache Society in ICHD 3. It is not necessary to perform neuroimaging studies or CT in patients with migraine symptoms and an otherwise normal neurologic exam.

When a diagnosis of migraine with brainstem aura is established, pediatric or adolescent patients and their families should first be counseled on nonpharmacologic interventions. These interventions, which have demonstrated benefits in reducing headache frequency, include lifestyle modifications, regular sleep and meal schedules, adequate fluid intake, cognitive-behavioral therapy, stress management techniques, massage, and biofeedback techniques. Recommended for acute treatment of migraine are nonsteroidal anti-inflammatory drugs, acetaminophen, and triptans. There is limited evidence in pediatric or adolescent patients with use of preventive medications, such as topiramate, amitriptyline, or onabotulinumtoxinA. In clinical trials, patients receiving placebo saw improvements, and active treatments were only marginally, if at all, more effective. Current guidelines recommend a frank discussion with parents about the limitations of preventive therapies before making decisions to use them. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

Click to view the Digital Edition.

In this issue: 

Hepatocellular Carcinoma
Special care for veterans, changes in staging, and biomarkers for early diagnosis

Lung Cancer
Guideline updates and racial disparities in veterans

Multiple Myeloma
Improving survival in the VA

Colorectal Cancer
Barriers to follow-up colonoscopies after FIT testing 

B-Cell Lymphomas
Findings from the VA's National TeleOncology Program and recent therapy updates

Breast Cancer
A look at the VA's Risk Assessment Pipeline and incidence among veterans vs the general population

Genitourinary Cancers
Molecular testing in prostate cancer, improving survival for metastatic RCC, and links between bladder cancer and Agent Orange exposure

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

Click to view the Digital Edition.

In this issue: 

Hepatocellular Carcinoma
Special care for veterans, changes in staging, and biomarkers for early diagnosis

Lung Cancer
Guideline updates and racial disparities in veterans

Multiple Myeloma
Improving survival in the VA

Colorectal Cancer
Barriers to follow-up colonoscopies after FIT testing 

B-Cell Lymphomas
Findings from the VA's National TeleOncology Program and recent therapy updates

Breast Cancer
A look at the VA's Risk Assessment Pipeline and incidence among veterans vs the general population

Genitourinary Cancers
Molecular testing in prostate cancer, improving survival for metastatic RCC, and links between bladder cancer and Agent Orange exposure

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

Click to view the Digital Edition.

In this issue: 

Hepatocellular Carcinoma
Special care for veterans, changes in staging, and biomarkers for early diagnosis

Lung Cancer
Guideline updates and racial disparities in veterans

Multiple Myeloma
Improving survival in the VA

Colorectal Cancer
Barriers to follow-up colonoscopies after FIT testing 

B-Cell Lymphomas
Findings from the VA's National TeleOncology Program and recent therapy updates

Breast Cancer
A look at the VA's Risk Assessment Pipeline and incidence among veterans vs the general population

Genitourinary Cancers
Molecular testing in prostate cancer, improving survival for metastatic RCC, and links between bladder cancer and Agent Orange exposure