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Foscarnet-Induced Ulceration

Viral swabs were negative for herpes simplex virus. The diagnosis of foscarnet-induced ulceration was reached and the drug was discontinued. Symptomatic treatment with soap substitutes and lidocaine ointment was used.

Foscarnet is an antiviral agent used when resistance develops to first-line therapies.¹ It is a pyrophosphate analogue that inhibits viral DNA polymerase, thereby preventing viral replication. It is used in treating cytomegalovirus and herpes simplex virus, which are resistant to first-line therapies, or patients who develop hematologic toxicity from antivirals. The main side effects of foscarnet include nephrotoxicity, alteration of calcium homeostasis, and malaise. Genital ulceration is a known side effect of therapy, though it is rare and more commonly seen in uncircumcised males. Approximately 94% of the drug is excreted unchanged in the urine, which causes an irritant dermatitis that is more pronounced in males as the urine stays in the subpreputial area.¹

Vulval ulceration² and penile ulceration³ has been reported in AIDS patients treated with foscarnet. In these patients, the onset of ulceration is temporally related to foscarnet therapy, occurring at approximately day 7 to 24 of treatment and resolving after discontinuation of therapy.

Foscarnet-Induced Ulceration

Viral swabs were negative for herpes simplex virus. The diagnosis of foscarnet-induced ulceration was reached and the drug was discontinued. Symptomatic treatment with soap substitutes and lidocaine ointment was used.

Foscarnet is an antiviral agent used when resistance develops to first-line therapies.¹ It is a pyrophosphate analogue that inhibits viral DNA polymerase, thereby preventing viral replication. It is used in treating cytomegalovirus and herpes simplex virus, which are resistant to first-line therapies, or patients who develop hematologic toxicity from antivirals. The main side effects of foscarnet include nephrotoxicity, alteration of calcium homeostasis, and malaise. Genital ulceration is a known side effect of therapy, though it is rare and more commonly seen in uncircumcised males. Approximately 94% of the drug is excreted unchanged in the urine, which causes an irritant dermatitis that is more pronounced in males as the urine stays in the subpreputial area.¹

Vulval ulceration² and penile ulceration³ has been reported in AIDS patients treated with foscarnet. In these patients, the onset of ulceration is temporally related to foscarnet therapy, occurring at approximately day 7 to 24 of treatment and resolving after discontinuation of therapy.

Foscarnet-Induced Ulceration

Viral swabs were negative for herpes simplex virus. The diagnosis of foscarnet-induced ulceration was reached and the drug was discontinued. Symptomatic treatment with soap substitutes and lidocaine ointment was used.

Foscarnet is an antiviral agent used when resistance develops to first-line therapies.¹ It is a pyrophosphate analogue that inhibits viral DNA polymerase, thereby preventing viral replication. It is used in treating cytomegalovirus and herpes simplex virus, which are resistant to first-line therapies, or patients who develop hematologic toxicity from antivirals. The main side effects of foscarnet include nephrotoxicity, alteration of calcium homeostasis, and malaise. Genital ulceration is a known side effect of therapy, though it is rare and more commonly seen in uncircumcised males. Approximately 94% of the drug is excreted unchanged in the urine, which causes an irritant dermatitis that is more pronounced in males as the urine stays in the subpreputial area.¹

Vulval ulceration² and penile ulceration³ has been reported in AIDS patients treated with foscarnet. In these patients, the onset of ulceration is temporally related to foscarnet therapy, occurring at approximately day 7 to 24 of treatment and resolving after discontinuation of therapy.

The Diagnosis: Blaschkoid Graft-vs-host Disease

The patient had a history of myelodysplastic syndrome and underwent a bone marrow transplant 1 year prior to presentation. She had acute graft-vs-host disease (GVHD) 6 weeks following the transplant, which resolved with high-dose prednisone followed by UVB phototherapy. Skin biopsy demonstrated lichenoid dermatitis with vacuolar degeneration, dyskeratosis, and prominent pigment incontinence (Figure). Based on these findings and her clinical presentation, a diagnosis of blaschkoid GVHD was made.

Although acute GVHD is the result of immunocompetent donor T cells recognizing host tissues as foreign and initiating an immune response, the pathophysiology of chronic GVHD is not well understood.^1,2 Theories for disease pathogenesis in chronic GVHD suggest an underlying autoimmune and/or alloreactive process.^2-5 The skin often is the first organ affected in acute GVHD, and patients generally present with a pruritic morbilliform eruption that begins on the trunk and spreads to the rest of the body.^1,2 Cutaneous manifestations of chronic GVHD may be protean. Lesions can resemble systemic sclerosis or morphea, lichen planus, psoriasis, ichthyosis, and many other conditions.²

The differential diagnosis of linear dermatoses includes herpes zoster, contact dermatitis, lichen striatus (blaschkitis), nevus unius lateris, inflammatory linear verrucous epidermal nevus, and incontinentia pigmenti.^6,7 Lichen planus-like chronic GVHD occurring in a linear distribution has been described.^6-14 Distinction between dermatomal and blaschkoid processes is diagnostically important. In the case of GVHD, dermatomal distribution may suggest an association between GVHD and prior herpes simplex virus or varicella-zoster virus infection.^6,8 Herpesvirus may alter surface antigens of keratinocytes, rendering them targets of donor lymphocytes, and antibodies to viral particles may cross-react with host keratinocyte HLA antigens. It also is possible that dermatomal GVHD may simply be a type of isomorphic response (Köbner phenomenon).⁸

When cutaneous GVHD follows Blaschko lines, other mechanisms appear to be at play.^9-14 It is plausible that these patients have an underlying genetic mosaicism, perhaps the result of a postzygotic mutation, that results in a daughter cell population that expresses surface antigens different from those of the primary cell population found elsewhere in the skin. Donor lymphocytes may selectively react to this mosaic population, leading to the clinical picture of chronic GVHD oriented along Blaschko lines.^10,11,13,14 

In conclusion, lichenoid linear GVHD following Blaschko lines is an uncommon presentation of chronic GVHD that highlights the heterogeneity of this disease and should be considered in the appropriate clinical setting.

The Diagnosis: Blaschkoid Graft-vs-host Disease

The patient had a history of myelodysplastic syndrome and underwent a bone marrow transplant 1 year prior to presentation. She had acute graft-vs-host disease (GVHD) 6 weeks following the transplant, which resolved with high-dose prednisone followed by UVB phototherapy. Skin biopsy demonstrated lichenoid dermatitis with vacuolar degeneration, dyskeratosis, and prominent pigment incontinence (Figure). Based on these findings and her clinical presentation, a diagnosis of blaschkoid GVHD was made.

Although acute GVHD is the result of immunocompetent donor T cells recognizing host tissues as foreign and initiating an immune response, the pathophysiology of chronic GVHD is not well understood.^1,2 Theories for disease pathogenesis in chronic GVHD suggest an underlying autoimmune and/or alloreactive process.^2-5 The skin often is the first organ affected in acute GVHD, and patients generally present with a pruritic morbilliform eruption that begins on the trunk and spreads to the rest of the body.^1,2 Cutaneous manifestations of chronic GVHD may be protean. Lesions can resemble systemic sclerosis or morphea, lichen planus, psoriasis, ichthyosis, and many other conditions.²

The differential diagnosis of linear dermatoses includes herpes zoster, contact dermatitis, lichen striatus (blaschkitis), nevus unius lateris, inflammatory linear verrucous epidermal nevus, and incontinentia pigmenti.^6,7 Lichen planus-like chronic GVHD occurring in a linear distribution has been described.^6-14 Distinction between dermatomal and blaschkoid processes is diagnostically important. In the case of GVHD, dermatomal distribution may suggest an association between GVHD and prior herpes simplex virus or varicella-zoster virus infection.^6,8 Herpesvirus may alter surface antigens of keratinocytes, rendering them targets of donor lymphocytes, and antibodies to viral particles may cross-react with host keratinocyte HLA antigens. It also is possible that dermatomal GVHD may simply be a type of isomorphic response (Köbner phenomenon).⁸

When cutaneous GVHD follows Blaschko lines, other mechanisms appear to be at play.^9-14 It is plausible that these patients have an underlying genetic mosaicism, perhaps the result of a postzygotic mutation, that results in a daughter cell population that expresses surface antigens different from those of the primary cell population found elsewhere in the skin. Donor lymphocytes may selectively react to this mosaic population, leading to the clinical picture of chronic GVHD oriented along Blaschko lines.^10,11,13,14 

In conclusion, lichenoid linear GVHD following Blaschko lines is an uncommon presentation of chronic GVHD that highlights the heterogeneity of this disease and should be considered in the appropriate clinical setting.

The Diagnosis: Blaschkoid Graft-vs-host Disease

The patient had a history of myelodysplastic syndrome and underwent a bone marrow transplant 1 year prior to presentation. She had acute graft-vs-host disease (GVHD) 6 weeks following the transplant, which resolved with high-dose prednisone followed by UVB phototherapy. Skin biopsy demonstrated lichenoid dermatitis with vacuolar degeneration, dyskeratosis, and prominent pigment incontinence (Figure). Based on these findings and her clinical presentation, a diagnosis of blaschkoid GVHD was made.

Although acute GVHD is the result of immunocompetent donor T cells recognizing host tissues as foreign and initiating an immune response, the pathophysiology of chronic GVHD is not well understood.^1,2 Theories for disease pathogenesis in chronic GVHD suggest an underlying autoimmune and/or alloreactive process.^2-5 The skin often is the first organ affected in acute GVHD, and patients generally present with a pruritic morbilliform eruption that begins on the trunk and spreads to the rest of the body.^1,2 Cutaneous manifestations of chronic GVHD may be protean. Lesions can resemble systemic sclerosis or morphea, lichen planus, psoriasis, ichthyosis, and many other conditions.²

The differential diagnosis of linear dermatoses includes herpes zoster, contact dermatitis, lichen striatus (blaschkitis), nevus unius lateris, inflammatory linear verrucous epidermal nevus, and incontinentia pigmenti.^6,7 Lichen planus-like chronic GVHD occurring in a linear distribution has been described.^6-14 Distinction between dermatomal and blaschkoid processes is diagnostically important. In the case of GVHD, dermatomal distribution may suggest an association between GVHD and prior herpes simplex virus or varicella-zoster virus infection.^6,8 Herpesvirus may alter surface antigens of keratinocytes, rendering them targets of donor lymphocytes, and antibodies to viral particles may cross-react with host keratinocyte HLA antigens. It also is possible that dermatomal GVHD may simply be a type of isomorphic response (Köbner phenomenon).⁸

When cutaneous GVHD follows Blaschko lines, other mechanisms appear to be at play.^9-14 It is plausible that these patients have an underlying genetic mosaicism, perhaps the result of a postzygotic mutation, that results in a daughter cell population that expresses surface antigens different from those of the primary cell population found elsewhere in the skin. Donor lymphocytes may selectively react to this mosaic population, leading to the clinical picture of chronic GVHD oriented along Blaschko lines.^10,11,13,14 

In conclusion, lichenoid linear GVHD following Blaschko lines is an uncommon presentation of chronic GVHD that highlights the heterogeneity of this disease and should be considered in the appropriate clinical setting.

The Diagnosis: Chronic Hyperplastic Candidiasis (Nodular Form)

Chronic hyperplastic candidiasis (CHC) is a rare form of oropharyngeal candidiasis. The most frequent clinical presentation is a white plaque that cannot be detached (also known as candidal leukoplakia). It usually involves the anterior buccal mucosa, mainly the commissural area, though the palate and tongue also can be affected. The nodular type of CHC is even less common. Our patient exhibited the typical clinical presentation of the nodular type of CHC.^1-3 The differential diagnosis includes leukoplakia, premalignant and malignant epithelial lesions, granular cell tumor, and florid oral papillomatosis.^1,3 A biopsy usually is required for diagnostic confirmation. Histologically, CHC is characterized by parakeratosis and a hyperplastic epithelium invaded by Candida hyphae.⁴ Because Candida species are commensal in up to 50% of the healthy population, superficial colonization of tissues is not enough to indicate notable disease.¹ In our patient, the histopathology revealed a hyperplastic mucosa without atypia and numerous hyphae (Figure). Both lingual swab and tissue cultures revealed high growth of Candida albicans. 

Infection by C albicans depends on pathogen virulence and host factors such as wearing dentures, reduced salivary production, smoking habit, or immunosuppression.^1,4 Apart from wearing dentures, our patient did not present with other predisposing factors. It is possible that the immunosuppressive status related to old age and associated oral changes contributed to Candida infection in this case. 

Topical or systemic antifungal agents together with the elimination of predisposing factors are usual first-line treatments. Because of the relationship with atypia and the possibility of evolving into carcinoma in untreated or persistent lesions, follow-up is necessary to verify complete resolution after treatment.^1,3,4 In the case reported herein, the lesions disappeared after 15 days of oral fluconazole treatment.

The Diagnosis: Chronic Hyperplastic Candidiasis (Nodular Form)

Chronic hyperplastic candidiasis (CHC) is a rare form of oropharyngeal candidiasis. The most frequent clinical presentation is a white plaque that cannot be detached (also known as candidal leukoplakia). It usually involves the anterior buccal mucosa, mainly the commissural area, though the palate and tongue also can be affected. The nodular type of CHC is even less common. Our patient exhibited the typical clinical presentation of the nodular type of CHC.^1-3 The differential diagnosis includes leukoplakia, premalignant and malignant epithelial lesions, granular cell tumor, and florid oral papillomatosis.^1,3 A biopsy usually is required for diagnostic confirmation. Histologically, CHC is characterized by parakeratosis and a hyperplastic epithelium invaded by Candida hyphae.⁴ Because Candida species are commensal in up to 50% of the healthy population, superficial colonization of tissues is not enough to indicate notable disease.¹ In our patient, the histopathology revealed a hyperplastic mucosa without atypia and numerous hyphae (Figure). Both lingual swab and tissue cultures revealed high growth of Candida albicans. 

Infection by C albicans depends on pathogen virulence and host factors such as wearing dentures, reduced salivary production, smoking habit, or immunosuppression.^1,4 Apart from wearing dentures, our patient did not present with other predisposing factors. It is possible that the immunosuppressive status related to old age and associated oral changes contributed to Candida infection in this case. 

Topical or systemic antifungal agents together with the elimination of predisposing factors are usual first-line treatments. Because of the relationship with atypia and the possibility of evolving into carcinoma in untreated or persistent lesions, follow-up is necessary to verify complete resolution after treatment.^1,3,4 In the case reported herein, the lesions disappeared after 15 days of oral fluconazole treatment.

The Diagnosis: Chronic Hyperplastic Candidiasis (Nodular Form)

Chronic hyperplastic candidiasis (CHC) is a rare form of oropharyngeal candidiasis. The most frequent clinical presentation is a white plaque that cannot be detached (also known as candidal leukoplakia). It usually involves the anterior buccal mucosa, mainly the commissural area, though the palate and tongue also can be affected. The nodular type of CHC is even less common. Our patient exhibited the typical clinical presentation of the nodular type of CHC.^1-3 The differential diagnosis includes leukoplakia, premalignant and malignant epithelial lesions, granular cell tumor, and florid oral papillomatosis.^1,3 A biopsy usually is required for diagnostic confirmation. Histologically, CHC is characterized by parakeratosis and a hyperplastic epithelium invaded by Candida hyphae.⁴ Because Candida species are commensal in up to 50% of the healthy population, superficial colonization of tissues is not enough to indicate notable disease.¹ In our patient, the histopathology revealed a hyperplastic mucosa without atypia and numerous hyphae (Figure). Both lingual swab and tissue cultures revealed high growth of Candida albicans. 

Infection by C albicans depends on pathogen virulence and host factors such as wearing dentures, reduced salivary production, smoking habit, or immunosuppression.^1,4 Apart from wearing dentures, our patient did not present with other predisposing factors. It is possible that the immunosuppressive status related to old age and associated oral changes contributed to Candida infection in this case. 

Topical or systemic antifungal agents together with the elimination of predisposing factors are usual first-line treatments. Because of the relationship with atypia and the possibility of evolving into carcinoma in untreated or persistent lesions, follow-up is necessary to verify complete resolution after treatment.^1,3,4 In the case reported herein, the lesions disappeared after 15 days of oral fluconazole treatment.

The Diagnosis: Metastatic Renal Cell Carcinoma

A shave biopsy of the right occipital scalp lesion demonstrated large clear cells arranged in oval nests with mildly atypical central nuclei (Figure). The findings were consistent with the clear cell type of metastatic renal cell carcinoma (mRCC) with tumor involvement in the deep margin. PAX8 immunostain was positive in the tumor, further supporting the diagnosis of mRCC.

The most common patient demographic diagnosed with renal cell carcinoma (RCC) is men in the sixth and seventh decades of life.^1,2 The classic presentation of RCC includes the triad of flank pain, hematuria, and a palpable abdominal mass. Other symptoms may include fatigue, weight loss, and anemia; however, small localized tumors rarely are symptomatic, and less than 10% of patients with RCC present with this classic triad.³ Many RCCs are diagnosed from incidental findings on abdominal imaging or from the presentation of metastatic disease.^1,2 The lungs, bones, and liver are the most common sites of metastases, while skin metastases are rare.² One study found only 3.3% (10/306) of RCC cases had cutaneous metastases and the scalp was the most common location. In half of these patients, the skin metastases were present at initial RCC diagnosis.⁴

The most common presentation of a cutaneous metastasis of RCC entails the rapid development of a reddish blue nodule on the face or scalp.^4,5 The differential diagnosis may include basal cell carcinoma, hemangioma, cutaneous angiosarcoma, pyogenic granuloma, and atypical fibroxanthoma. Careful elicitation of a medical history indicating any of the classic or systemic signs associated with RCC or a personal history of RCC should raise the suspicion for mRCC and prompt a biopsy.

Clear cell RCC is the most common type of primary RCC and 81% of mRCCs were found to be of the clear cell type. Clear cell RCC classically exhibits clear ballooned cytoplasm with distinct cell borders.⁶ Immunohistochemistry stains with PAX2 and PAX8 are helpful in diagnosing the renal origin of the metastatic tissue, with PAX8 being especially helpful (89% sensitivity).⁷

The von Hippel-Lindau gene, VHL, is involved in up to 60% of sporadic clear cell RCC cases, in addition to its involvement in VHL syndrome.1 von Hippel-Lindau syndrome is associated with clear cell RCC, retinal angiomas, hemangioblastomas of the central nervous system, and pheochromocytomas.¹ The mutated VHL gene is associated with an increased expression of vascular endothelial growth factor (VEGF), which promotes angiogenesis, endothelial mutagenesis, and vascular permeability.⁸ These physiologic responses are likely responsible for the proliferation and dissemination of neoplastic cells in clear cell RCC.⁹ The understanding of this pathogenic mechanism has led to the development of targeted effective treatments in RCC.

Systemic treatments for mRCC are rapidly evolving and improving.⁹ Vascular endothelial growth factor tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib, as well as the VEGF monoclonal antibody bevacizumab, have all demonstrated notable efficacy in the treatment of RCC. Phase 3 clinical trials for the treatment of mRCC have demonstrated that the new, more biochemically potent VEGF tyrosine kinase inhibitor axitinib has superior efficacy to sorafenib, the prior standard of care.⁹ Our patient noted that the cutaneous mRCC lesion seemed to be improving after starting treatment with axitinib 2 months prior to presentation. In addition to systemic chemotherapy, the surgical removal of lesions often is indicated for the treatment of cutaneous mRCC.^5,10 Our patient has continued axitinib and is doing well.

The Diagnosis: Metastatic Renal Cell Carcinoma

A shave biopsy of the right occipital scalp lesion demonstrated large clear cells arranged in oval nests with mildly atypical central nuclei (Figure). The findings were consistent with the clear cell type of metastatic renal cell carcinoma (mRCC) with tumor involvement in the deep margin. PAX8 immunostain was positive in the tumor, further supporting the diagnosis of mRCC.

The most common patient demographic diagnosed with renal cell carcinoma (RCC) is men in the sixth and seventh decades of life.^1,2 The classic presentation of RCC includes the triad of flank pain, hematuria, and a palpable abdominal mass. Other symptoms may include fatigue, weight loss, and anemia; however, small localized tumors rarely are symptomatic, and less than 10% of patients with RCC present with this classic triad.³ Many RCCs are diagnosed from incidental findings on abdominal imaging or from the presentation of metastatic disease.^1,2 The lungs, bones, and liver are the most common sites of metastases, while skin metastases are rare.² One study found only 3.3% (10/306) of RCC cases had cutaneous metastases and the scalp was the most common location. In half of these patients, the skin metastases were present at initial RCC diagnosis.⁴

The most common presentation of a cutaneous metastasis of RCC entails the rapid development of a reddish blue nodule on the face or scalp.^4,5 The differential diagnosis may include basal cell carcinoma, hemangioma, cutaneous angiosarcoma, pyogenic granuloma, and atypical fibroxanthoma. Careful elicitation of a medical history indicating any of the classic or systemic signs associated with RCC or a personal history of RCC should raise the suspicion for mRCC and prompt a biopsy.

Clear cell RCC is the most common type of primary RCC and 81% of mRCCs were found to be of the clear cell type. Clear cell RCC classically exhibits clear ballooned cytoplasm with distinct cell borders.⁶ Immunohistochemistry stains with PAX2 and PAX8 are helpful in diagnosing the renal origin of the metastatic tissue, with PAX8 being especially helpful (89% sensitivity).⁷

The von Hippel-Lindau gene, VHL, is involved in up to 60% of sporadic clear cell RCC cases, in addition to its involvement in VHL syndrome.1 von Hippel-Lindau syndrome is associated with clear cell RCC, retinal angiomas, hemangioblastomas of the central nervous system, and pheochromocytomas.¹ The mutated VHL gene is associated with an increased expression of vascular endothelial growth factor (VEGF), which promotes angiogenesis, endothelial mutagenesis, and vascular permeability.⁸ These physiologic responses are likely responsible for the proliferation and dissemination of neoplastic cells in clear cell RCC.⁹ The understanding of this pathogenic mechanism has led to the development of targeted effective treatments in RCC.

Systemic treatments for mRCC are rapidly evolving and improving.⁹ Vascular endothelial growth factor tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib, as well as the VEGF monoclonal antibody bevacizumab, have all demonstrated notable efficacy in the treatment of RCC. Phase 3 clinical trials for the treatment of mRCC have demonstrated that the new, more biochemically potent VEGF tyrosine kinase inhibitor axitinib has superior efficacy to sorafenib, the prior standard of care.⁹ Our patient noted that the cutaneous mRCC lesion seemed to be improving after starting treatment with axitinib 2 months prior to presentation. In addition to systemic chemotherapy, the surgical removal of lesions often is indicated for the treatment of cutaneous mRCC.^5,10 Our patient has continued axitinib and is doing well.

The Diagnosis: Metastatic Renal Cell Carcinoma

A shave biopsy of the right occipital scalp lesion demonstrated large clear cells arranged in oval nests with mildly atypical central nuclei (Figure). The findings were consistent with the clear cell type of metastatic renal cell carcinoma (mRCC) with tumor involvement in the deep margin. PAX8 immunostain was positive in the tumor, further supporting the diagnosis of mRCC.

The most common patient demographic diagnosed with renal cell carcinoma (RCC) is men in the sixth and seventh decades of life.^1,2 The classic presentation of RCC includes the triad of flank pain, hematuria, and a palpable abdominal mass. Other symptoms may include fatigue, weight loss, and anemia; however, small localized tumors rarely are symptomatic, and less than 10% of patients with RCC present with this classic triad.³ Many RCCs are diagnosed from incidental findings on abdominal imaging or from the presentation of metastatic disease.^1,2 The lungs, bones, and liver are the most common sites of metastases, while skin metastases are rare.² One study found only 3.3% (10/306) of RCC cases had cutaneous metastases and the scalp was the most common location. In half of these patients, the skin metastases were present at initial RCC diagnosis.⁴

The most common presentation of a cutaneous metastasis of RCC entails the rapid development of a reddish blue nodule on the face or scalp.^4,5 The differential diagnosis may include basal cell carcinoma, hemangioma, cutaneous angiosarcoma, pyogenic granuloma, and atypical fibroxanthoma. Careful elicitation of a medical history indicating any of the classic or systemic signs associated with RCC or a personal history of RCC should raise the suspicion for mRCC and prompt a biopsy.

Clear cell RCC is the most common type of primary RCC and 81% of mRCCs were found to be of the clear cell type. Clear cell RCC classically exhibits clear ballooned cytoplasm with distinct cell borders.⁶ Immunohistochemistry stains with PAX2 and PAX8 are helpful in diagnosing the renal origin of the metastatic tissue, with PAX8 being especially helpful (89% sensitivity).⁷

The von Hippel-Lindau gene, VHL, is involved in up to 60% of sporadic clear cell RCC cases, in addition to its involvement in VHL syndrome.1 von Hippel-Lindau syndrome is associated with clear cell RCC, retinal angiomas, hemangioblastomas of the central nervous system, and pheochromocytomas.¹ The mutated VHL gene is associated with an increased expression of vascular endothelial growth factor (VEGF), which promotes angiogenesis, endothelial mutagenesis, and vascular permeability.⁸ These physiologic responses are likely responsible for the proliferation and dissemination of neoplastic cells in clear cell RCC.⁹ The understanding of this pathogenic mechanism has led to the development of targeted effective treatments in RCC.

Systemic treatments for mRCC are rapidly evolving and improving.⁹ Vascular endothelial growth factor tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib, as well as the VEGF monoclonal antibody bevacizumab, have all demonstrated notable efficacy in the treatment of RCC. Phase 3 clinical trials for the treatment of mRCC have demonstrated that the new, more biochemically potent VEGF tyrosine kinase inhibitor axitinib has superior efficacy to sorafenib, the prior standard of care.⁹ Our patient noted that the cutaneous mRCC lesion seemed to be improving after starting treatment with axitinib 2 months prior to presentation. In addition to systemic chemotherapy, the surgical removal of lesions often is indicated for the treatment of cutaneous mRCC.^5,10 Our patient has continued axitinib and is doing well.

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Epidermotropic CD8⁺ T-Cell Lymphoma

Epidermotropic CD8⁺ T-cell lymphoma is a rare aggressive form of cutaneous T-cell lymphoma (CTCL), accounting for less than 1% of all cases.¹ Since this subtype of CTCL was first described in 1999 by Berti et al,² approximately 45 cases have been reported in the literature.¹ It typically is found in elderly men and presents as disseminated or localized papules, patches, plaques, nodules, and tumors, often with central necrosis, ulceration, crusting, and hemorrhage (Figure 1).^1,3 These lesions rapidly progress and can affect any skin site, but acral accentuation and mucosal involvement are common.⁴ Due to the rapidly progressive nature of this disease, patients typically present with widespread plaque- and tumor-stage disease.³ Frequency of systemic spread is high, with metastasis to the central nervous system, lungs, and testes being most common. Lymph nodes typically are spared, helping to differentiate this form of CTCL from classic mycosis fungoides.

Diagnosis of epidermotropic CD8⁺ T-cell lymphoma is based on a combination of clinical, histopathologic, and immunohistochemical features. Histopathologic components include epidermotropism, particularly in the basal cell layer, in a pagetoid or linear pattern. A second feature is a dermal infiltrate consisting of a nodular or diffuse pattern of atypical lymphocytes that extend to the subcutaneous fat (Figure 2). All cases of epidermotropic CD8⁺ T-cell lymphoma express the CD8⁺ phenotype and most have a high Ki-67 proliferation index and are CD3, CD45RA, and/or T-cell intracellular antigen 1 positive.¹

Due to its aggressive nature, epidermotropic CD8⁺ T-cell lymphoma has a poor prognosis, with an average 5-year survival rate of 18% and median survival of 22.5 months.³ Treatment proves difficult as conventional therapies for CD4⁺ CTCL have proven ineffective for epidermotropic CD8⁺ T-cell lymphoma. Partial response has been seen with bexarotene alone and with total skin electron beam therapy combined with oral retinoids.¹

The Diagnosis: Dental Sinus Secondary to Osteonecrosis of the Jaw

Cone beam computed tomography revealed an area of lucency measuring 40×20 mm in the body of the right mandible (Figure). The patient subsequently underwent curettage of the wound with sequestrectomy of the involved area.

Osteonecrosis of the jaw is a form of avascular necrosis. It is an uncommon but potentially serious side effect of bisphosphonate use.¹ Bisphosphonates commonly are used as first-line therapy for osteoporosis, with proven efficacy to reduce fracture risk by exerting an antiresorptive effect on bones.² Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined by the American Association of Oral and Maxillofacial Surgeons as the presence of exposed necrotic bone in the maxillofacial region that has persisted for more than 8 weeks, with current or prior treatment with a bisphosphonate and absence of prior radiation therapy to the jaw.3 Bisphosphonate-related osteonecrosis of the jaw can be associated with infections, pathologic fractures, extraoral fistulae, or osteolysis extending to the inferior border.

Our patient had a dental sinus that resulted from the underlying BRONJ. The jawbones, unlike the long bones, are in a special environment in that both acute and chronic infections occur often within the bone, and surgical procedures as well as masticatory trauma expose the bone to a bacteria-laden environment.⁴ Infection around the root apex of a tooth results in a dental abscess and a sinus tract can develop from the abscess, draining either intraorally or extraorally.⁵ Facial sinus tracts can be either odontogenic or nonodontogenic, and sometimes the lesions of dental origin may be confused with dermatological lesions.

Bisphosphonates inhibit osteoclasts, which are responsible for bone resorption. Antiangiogenetic effects also have been reported in bisphosphonates, resulting in devitalized bone.⁶ The potent and prolonged inhibition of bone remodeling likely plays an important role in BRONJ. The more frequently occurring microdamage inflicted on the lower jawbone with mastication also may represent a contributory factor.⁷

Bisphosphonate-related osteonecrosis of the jaw more often is associated with the use of high-dose intravenous (IV) bisphosphonate in cancer-related hypercalcemia and less so with oral bisphosphonates, which are generally used to treat osteoporosis.³ In a Swedish study conducted from 2003 to 2010, 55 cases of BRONJ were documented in a population of 1.2 million individuals. The prevalence of BRONJ in patients on oral bisphosphonates and IV bisphosphonates was estimated to be 0.024% and 2.8%, respectively.⁸

Bisphosphonates are widely used worldwide as the main treatment of osteoporosis. The association between osteonecrosis of the jaw and oral bisphosphonates is contentious among the osteoporosis population, as most studies focus on IV bisphosphonate use in cancer patients.⁹ Bisphosphonate-related osteonecrosis of the jaw adversely affects the patient's quality of life, producing notable morbidity in afflicted patients. Thus, a complete dental assessment and treatment is recommended before the initiation of bisphosphonate treatment. The risk for developing BRONJ associated with oral bisphosphonates increases when the duration of therapy exceeds 3 years.³ It has been reported that antifracture efficacy would persist for 1 to 2 years following discontinuation of alendronate or risedronate that had been taken for 3 to 5 years, but patients with low bone mineral density at the femoral neck (T-score below -2.5) after 3 to 5 years of treatment of bisphosphonates are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of therapy.¹⁰ For dental procedures, the American Association of Oral and Maxillofacial Surgeons suggests that if systemic conditions persist, the clinician might consider discontinuation of oral bisphosphonates for a 3-month period before and after elective invasive dental surgery to lower the risk for BRONJ.³ When possible, invasive dentoalveolar procedures such as extractions should be avoided; conservative endodontic treatment is preferable.

Bisphosphonate-related osteonecrosis of the jaw is a devastating condition that is difficult to treat and manage, thus the focus should be on prevention through dental clearance prior to starting bisphosphonates. It also is crucial to have a high index of suspicion for BRONJ in patients presenting with orofacial lesions so that they can be treated expediently.

The Diagnosis: Dental Sinus Secondary to Osteonecrosis of the Jaw

Cone beam computed tomography revealed an area of lucency measuring 40×20 mm in the body of the right mandible (Figure). The patient subsequently underwent curettage of the wound with sequestrectomy of the involved area.

Osteonecrosis of the jaw is a form of avascular necrosis. It is an uncommon but potentially serious side effect of bisphosphonate use.¹ Bisphosphonates commonly are used as first-line therapy for osteoporosis, with proven efficacy to reduce fracture risk by exerting an antiresorptive effect on bones.² Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined by the American Association of Oral and Maxillofacial Surgeons as the presence of exposed necrotic bone in the maxillofacial region that has persisted for more than 8 weeks, with current or prior treatment with a bisphosphonate and absence of prior radiation therapy to the jaw.3 Bisphosphonate-related osteonecrosis of the jaw can be associated with infections, pathologic fractures, extraoral fistulae, or osteolysis extending to the inferior border.

Our patient had a dental sinus that resulted from the underlying BRONJ. The jawbones, unlike the long bones, are in a special environment in that both acute and chronic infections occur often within the bone, and surgical procedures as well as masticatory trauma expose the bone to a bacteria-laden environment.⁴ Infection around the root apex of a tooth results in a dental abscess and a sinus tract can develop from the abscess, draining either intraorally or extraorally.⁵ Facial sinus tracts can be either odontogenic or nonodontogenic, and sometimes the lesions of dental origin may be confused with dermatological lesions.

Bisphosphonates inhibit osteoclasts, which are responsible for bone resorption. Antiangiogenetic effects also have been reported in bisphosphonates, resulting in devitalized bone.⁶ The potent and prolonged inhibition of bone remodeling likely plays an important role in BRONJ. The more frequently occurring microdamage inflicted on the lower jawbone with mastication also may represent a contributory factor.⁷

Bisphosphonate-related osteonecrosis of the jaw more often is associated with the use of high-dose intravenous (IV) bisphosphonate in cancer-related hypercalcemia and less so with oral bisphosphonates, which are generally used to treat osteoporosis.³ In a Swedish study conducted from 2003 to 2010, 55 cases of BRONJ were documented in a population of 1.2 million individuals. The prevalence of BRONJ in patients on oral bisphosphonates and IV bisphosphonates was estimated to be 0.024% and 2.8%, respectively.⁸

Bisphosphonates are widely used worldwide as the main treatment of osteoporosis. The association between osteonecrosis of the jaw and oral bisphosphonates is contentious among the osteoporosis population, as most studies focus on IV bisphosphonate use in cancer patients.⁹ Bisphosphonate-related osteonecrosis of the jaw adversely affects the patient's quality of life, producing notable morbidity in afflicted patients. Thus, a complete dental assessment and treatment is recommended before the initiation of bisphosphonate treatment. The risk for developing BRONJ associated with oral bisphosphonates increases when the duration of therapy exceeds 3 years.³ It has been reported that antifracture efficacy would persist for 1 to 2 years following discontinuation of alendronate or risedronate that had been taken for 3 to 5 years, but patients with low bone mineral density at the femoral neck (T-score below -2.5) after 3 to 5 years of treatment of bisphosphonates are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of therapy.¹⁰ For dental procedures, the American Association of Oral and Maxillofacial Surgeons suggests that if systemic conditions persist, the clinician might consider discontinuation of oral bisphosphonates for a 3-month period before and after elective invasive dental surgery to lower the risk for BRONJ.³ When possible, invasive dentoalveolar procedures such as extractions should be avoided; conservative endodontic treatment is preferable.

Bisphosphonate-related osteonecrosis of the jaw is a devastating condition that is difficult to treat and manage, thus the focus should be on prevention through dental clearance prior to starting bisphosphonates. It also is crucial to have a high index of suspicion for BRONJ in patients presenting with orofacial lesions so that they can be treated expediently.

The Diagnosis: Dental Sinus Secondary to Osteonecrosis of the Jaw

Cone beam computed tomography revealed an area of lucency measuring 40×20 mm in the body of the right mandible (Figure). The patient subsequently underwent curettage of the wound with sequestrectomy of the involved area.

Osteonecrosis of the jaw is a form of avascular necrosis. It is an uncommon but potentially serious side effect of bisphosphonate use.¹ Bisphosphonates commonly are used as first-line therapy for osteoporosis, with proven efficacy to reduce fracture risk by exerting an antiresorptive effect on bones.² Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is defined by the American Association of Oral and Maxillofacial Surgeons as the presence of exposed necrotic bone in the maxillofacial region that has persisted for more than 8 weeks, with current or prior treatment with a bisphosphonate and absence of prior radiation therapy to the jaw.3 Bisphosphonate-related osteonecrosis of the jaw can be associated with infections, pathologic fractures, extraoral fistulae, or osteolysis extending to the inferior border.

Our patient had a dental sinus that resulted from the underlying BRONJ. The jawbones, unlike the long bones, are in a special environment in that both acute and chronic infections occur often within the bone, and surgical procedures as well as masticatory trauma expose the bone to a bacteria-laden environment.⁴ Infection around the root apex of a tooth results in a dental abscess and a sinus tract can develop from the abscess, draining either intraorally or extraorally.⁵ Facial sinus tracts can be either odontogenic or nonodontogenic, and sometimes the lesions of dental origin may be confused with dermatological lesions.

Bisphosphonates inhibit osteoclasts, which are responsible for bone resorption. Antiangiogenetic effects also have been reported in bisphosphonates, resulting in devitalized bone.⁶ The potent and prolonged inhibition of bone remodeling likely plays an important role in BRONJ. The more frequently occurring microdamage inflicted on the lower jawbone with mastication also may represent a contributory factor.⁷

Bisphosphonate-related osteonecrosis of the jaw more often is associated with the use of high-dose intravenous (IV) bisphosphonate in cancer-related hypercalcemia and less so with oral bisphosphonates, which are generally used to treat osteoporosis.³ In a Swedish study conducted from 2003 to 2010, 55 cases of BRONJ were documented in a population of 1.2 million individuals. The prevalence of BRONJ in patients on oral bisphosphonates and IV bisphosphonates was estimated to be 0.024% and 2.8%, respectively.⁸

Bisphosphonates are widely used worldwide as the main treatment of osteoporosis. The association between osteonecrosis of the jaw and oral bisphosphonates is contentious among the osteoporosis population, as most studies focus on IV bisphosphonate use in cancer patients.⁹ Bisphosphonate-related osteonecrosis of the jaw adversely affects the patient's quality of life, producing notable morbidity in afflicted patients. Thus, a complete dental assessment and treatment is recommended before the initiation of bisphosphonate treatment. The risk for developing BRONJ associated with oral bisphosphonates increases when the duration of therapy exceeds 3 years.³ It has been reported that antifracture efficacy would persist for 1 to 2 years following discontinuation of alendronate or risedronate that had been taken for 3 to 5 years, but patients with low bone mineral density at the femoral neck (T-score below -2.5) after 3 to 5 years of treatment of bisphosphonates are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of therapy.¹⁰ For dental procedures, the American Association of Oral and Maxillofacial Surgeons suggests that if systemic conditions persist, the clinician might consider discontinuation of oral bisphosphonates for a 3-month period before and after elective invasive dental surgery to lower the risk for BRONJ.³ When possible, invasive dentoalveolar procedures such as extractions should be avoided; conservative endodontic treatment is preferable.

Bisphosphonate-related osteonecrosis of the jaw is a devastating condition that is difficult to treat and manage, thus the focus should be on prevention through dental clearance prior to starting bisphosphonates. It also is crucial to have a high index of suspicion for BRONJ in patients presenting with orofacial lesions so that they can be treated expediently.

The Diagnosis: Sister Mary Joseph Nodule

The umbilical skin biopsy revealed a moderately differentiated adenocarcinoma (Figure) that was positive for cytokeratin 20 and CDX2 and negative for cytokeratin 7 and transcription termination factor 1. The patient subsequently underwent computed tomography of the abdomen and pelvis, which showed multiple soft-tissue nodules on the greater omentum, a soft-tissue density at the umbilicus, and thickening of the gastric mucosa. An upper endoscopy was then performed, which revealed a large fungating ulcerated mass in the stomach. Biopsy of this mass showed an invasive moderately differentiated adenocarcinoma, which was ERBB2 (formerly HER2) negative. Histopathologically, these pleomorphic glands looked similar to the glands seen in the original skin biopsy. With this diagnosis of metastatic gastric adenocarcinoma, our patient chose palliative chemotherapy but declined precipitously and died 2 months after the initial skin biopsy of the umbilical lesion.

When encountering a patient with an umbilical lesion, it is important to consider benign and malignant lesions in the differential diagnosis. A benign lesion may include scar, cyst, pyogenic granuloma, hemangioma, umbilical hernia, endometriosis, polyp, abscess, or the presence of an omphalith.¹ Inflammatory dermatoses such as psoriasis or eczema also should be considered. Malignant lesions could be either primary or secondary, with metastatic disease being the most common.² Sister Mary Joseph nodule (SMJN) is the eponymgiven to an umbilical lesion representing metastatic disease. Sister Mary Joseph was a nurse and surgical assistant to Dr. William Mayo in Rochester, Minnesota, in what is now known as the Mayo Clinic. She is credited to be the first to observe and note the association between an umbilical nodule and intra-abdominal malignancy. Metastasis to the umbilicus is thought to occur by way of contiguous, hematogenous, lymphatic, or direct spread through embryologic remnants from primary cancers of nearby gastrointestinal or pelvic viscera. It is a rare cutaneous sign of internal malignancy, with an estimated prevalence of 1% to 3%.³ The most common primary cancer is gastric adenocarcinoma, though cases of metastasis from pancreatic, endometrial, and less commonly hematopoietic or supradiaphragmatic cancers have been reported.⁴ It is more common in women, likely due to the addition of gynecologic malignancies.¹

The use of dermoscopy has been advocated as an adjuvant tool in delineating benign and malignant umbilical lesions when an atypical polymorphous vascular pattern indicating neovascularization has been observed with neoplastic growth.⁵ Once a suspicious umbilical lesion is identified, the first step should be to obtain a skin biopsy or to use fine needle aspiration for cytology.⁶ Biopsy is especially relevant in the background of cancer history because SMJN may present with cancer recurrence.3 Once one of these is obtained, histological and immunohistochemical analysis will guide further workup and diagnosis of the umbilical lesion.

The importance of reviewing such cases lies in the variable presentation of cutaneous metastases such as SMJN and the grim prognosis that accompanies this finding. It presents as a firm indurated plaque or nodule that may present with systemic symptoms suggestive of malignancy, though in 30% of cases it is the sole initial sign.⁷ The nodule may be painful if ulcerated or fissured. Bloody, serous, or purulent discharge may be present. After diagnosis of an SMJN, most patients succumb to the disease within 12 months. Thus, it is vital for dermatologists to investigate umbilical lesions with great caution and a high index of suspicion.

The Diagnosis: Sister Mary Joseph Nodule

The umbilical skin biopsy revealed a moderately differentiated adenocarcinoma (Figure) that was positive for cytokeratin 20 and CDX2 and negative for cytokeratin 7 and transcription termination factor 1. The patient subsequently underwent computed tomography of the abdomen and pelvis, which showed multiple soft-tissue nodules on the greater omentum, a soft-tissue density at the umbilicus, and thickening of the gastric mucosa. An upper endoscopy was then performed, which revealed a large fungating ulcerated mass in the stomach. Biopsy of this mass showed an invasive moderately differentiated adenocarcinoma, which was ERBB2 (formerly HER2) negative. Histopathologically, these pleomorphic glands looked similar to the glands seen in the original skin biopsy. With this diagnosis of metastatic gastric adenocarcinoma, our patient chose palliative chemotherapy but declined precipitously and died 2 months after the initial skin biopsy of the umbilical lesion.

When encountering a patient with an umbilical lesion, it is important to consider benign and malignant lesions in the differential diagnosis. A benign lesion may include scar, cyst, pyogenic granuloma, hemangioma, umbilical hernia, endometriosis, polyp, abscess, or the presence of an omphalith.¹ Inflammatory dermatoses such as psoriasis or eczema also should be considered. Malignant lesions could be either primary or secondary, with metastatic disease being the most common.² Sister Mary Joseph nodule (SMJN) is the eponymgiven to an umbilical lesion representing metastatic disease. Sister Mary Joseph was a nurse and surgical assistant to Dr. William Mayo in Rochester, Minnesota, in what is now known as the Mayo Clinic. She is credited to be the first to observe and note the association between an umbilical nodule and intra-abdominal malignancy. Metastasis to the umbilicus is thought to occur by way of contiguous, hematogenous, lymphatic, or direct spread through embryologic remnants from primary cancers of nearby gastrointestinal or pelvic viscera. It is a rare cutaneous sign of internal malignancy, with an estimated prevalence of 1% to 3%.³ The most common primary cancer is gastric adenocarcinoma, though cases of metastasis from pancreatic, endometrial, and less commonly hematopoietic or supradiaphragmatic cancers have been reported.⁴ It is more common in women, likely due to the addition of gynecologic malignancies.¹

The use of dermoscopy has been advocated as an adjuvant tool in delineating benign and malignant umbilical lesions when an atypical polymorphous vascular pattern indicating neovascularization has been observed with neoplastic growth.⁵ Once a suspicious umbilical lesion is identified, the first step should be to obtain a skin biopsy or to use fine needle aspiration for cytology.⁶ Biopsy is especially relevant in the background of cancer history because SMJN may present with cancer recurrence.3 Once one of these is obtained, histological and immunohistochemical analysis will guide further workup and diagnosis of the umbilical lesion.

The importance of reviewing such cases lies in the variable presentation of cutaneous metastases such as SMJN and the grim prognosis that accompanies this finding. It presents as a firm indurated plaque or nodule that may present with systemic symptoms suggestive of malignancy, though in 30% of cases it is the sole initial sign.⁷ The nodule may be painful if ulcerated or fissured. Bloody, serous, or purulent discharge may be present. After diagnosis of an SMJN, most patients succumb to the disease within 12 months. Thus, it is vital for dermatologists to investigate umbilical lesions with great caution and a high index of suspicion.

The Diagnosis: Sister Mary Joseph Nodule

The umbilical skin biopsy revealed a moderately differentiated adenocarcinoma (Figure) that was positive for cytokeratin 20 and CDX2 and negative for cytokeratin 7 and transcription termination factor 1. The patient subsequently underwent computed tomography of the abdomen and pelvis, which showed multiple soft-tissue nodules on the greater omentum, a soft-tissue density at the umbilicus, and thickening of the gastric mucosa. An upper endoscopy was then performed, which revealed a large fungating ulcerated mass in the stomach. Biopsy of this mass showed an invasive moderately differentiated adenocarcinoma, which was ERBB2 (formerly HER2) negative. Histopathologically, these pleomorphic glands looked similar to the glands seen in the original skin biopsy. With this diagnosis of metastatic gastric adenocarcinoma, our patient chose palliative chemotherapy but declined precipitously and died 2 months after the initial skin biopsy of the umbilical lesion.

When encountering a patient with an umbilical lesion, it is important to consider benign and malignant lesions in the differential diagnosis. A benign lesion may include scar, cyst, pyogenic granuloma, hemangioma, umbilical hernia, endometriosis, polyp, abscess, or the presence of an omphalith.¹ Inflammatory dermatoses such as psoriasis or eczema also should be considered. Malignant lesions could be either primary or secondary, with metastatic disease being the most common.² Sister Mary Joseph nodule (SMJN) is the eponymgiven to an umbilical lesion representing metastatic disease. Sister Mary Joseph was a nurse and surgical assistant to Dr. William Mayo in Rochester, Minnesota, in what is now known as the Mayo Clinic. She is credited to be the first to observe and note the association between an umbilical nodule and intra-abdominal malignancy. Metastasis to the umbilicus is thought to occur by way of contiguous, hematogenous, lymphatic, or direct spread through embryologic remnants from primary cancers of nearby gastrointestinal or pelvic viscera. It is a rare cutaneous sign of internal malignancy, with an estimated prevalence of 1% to 3%.³ The most common primary cancer is gastric adenocarcinoma, though cases of metastasis from pancreatic, endometrial, and less commonly hematopoietic or supradiaphragmatic cancers have been reported.⁴ It is more common in women, likely due to the addition of gynecologic malignancies.¹

The use of dermoscopy has been advocated as an adjuvant tool in delineating benign and malignant umbilical lesions when an atypical polymorphous vascular pattern indicating neovascularization has been observed with neoplastic growth.⁵ Once a suspicious umbilical lesion is identified, the first step should be to obtain a skin biopsy or to use fine needle aspiration for cytology.⁶ Biopsy is especially relevant in the background of cancer history because SMJN may present with cancer recurrence.3 Once one of these is obtained, histological and immunohistochemical analysis will guide further workup and diagnosis of the umbilical lesion.

The importance of reviewing such cases lies in the variable presentation of cutaneous metastases such as SMJN and the grim prognosis that accompanies this finding. It presents as a firm indurated plaque or nodule that may present with systemic symptoms suggestive of malignancy, though in 30% of cases it is the sole initial sign.⁷ The nodule may be painful if ulcerated or fissured. Bloody, serous, or purulent discharge may be present. After diagnosis of an SMJN, most patients succumb to the disease within 12 months. Thus, it is vital for dermatologists to investigate umbilical lesions with great caution and a high index of suspicion.

The Diagnosis: Lichen Striatus

Lichen striatus (LS) is an acquired and self-limited linear inflammatory dermatosis that most frequently occurs in children and less commonly in adults.^1-3 Clinically, it is characterized by the sudden onset of an eruption consisting of slightly pigmented, erythematous, flat-topped papules with minimal scaling. These papules quickly coalesce to form a linear band that extends along a limb, the trunk, or the face, within Blaschko lines.^1,4 In the adult form, patients tend to experience more diffuse lesions as well as severe pruritus with higher rates of relapse. It occasionally manifests in a dermatomal manner.¹ 

The differential diagnosis includes other linear acquired inflammatory dermatoses such as blaschkitis, lichen planus, inflammatory linear verrucous epidermal nevus, and psoriasis. Blaschkitis has been described as a rare dermatosis that occurs along the Blaschko lines, affecting adults preferentially over children. Controversy exists whether blaschkitis and lichen striatus are the same disease or 2 separate entities.⁵ Clinically, both blaschkitis and lichen striatus can present with multiple linear papules and vesicles predominantly on the trunk. In blaschkitis, there is a predilection for males, with an older mean age at onset of 40 years.⁵ Lesions quickly resolve over months with frequent relapse compared to lichen striatus, which can persist for months to years. 

Histopathologically, blaschkitis demonstrates spongiosis, usually without involvement of the adnexal structures. Lichenoid and spongiotic changes with adnexal extension are the hallmark features of lichen striatus. In our patient, biopsy showed several dense bandlike foci of lymphohistiocytic infiltrates along the dermoepidermal junction with spongiosis, basal cell liquefactive degeneration, and pigmentary incontinence (Figure 1). The focal areas were surfaced by parakeratotic and orthohyperkeratotic scale. Deep dermal perivascular and periadnexal extension was present (Figure 2). Periodic acid-Schiff stain was negative for fungi.

The pathogenesis of lichen striatus is not entirely understood, but it has been postulated that trauma, vaccinations, or viral infections may induce loss of immunologic tolerance to keratinocytes.¹ This loss of tolerance can result in a T cell-mediated autoimmune reaction against malpighian cells, which show genetic mosaicism and are arranged along Blaschko lines.^1,3 Familial cases also have been reported, suggesting that there may be an epigenetic mosaicism that contributes to this group of skin diseases.^6,7

Lichen striatus tends to resolve on its own after approximately 6 to 9 months.⁸ Treatment typically consists of application of topical corticosteroids.¹ Cases also have been successfully treated with tacrolimus and pimecrolimus.^1,8 Our patient was treated with a midpotency topical steroid with improvement of the appearance but not complete resolution.

The Diagnosis: Lichen Striatus

Lichen striatus (LS) is an acquired and self-limited linear inflammatory dermatosis that most frequently occurs in children and less commonly in adults.^1-3 Clinically, it is characterized by the sudden onset of an eruption consisting of slightly pigmented, erythematous, flat-topped papules with minimal scaling. These papules quickly coalesce to form a linear band that extends along a limb, the trunk, or the face, within Blaschko lines.^1,4 In the adult form, patients tend to experience more diffuse lesions as well as severe pruritus with higher rates of relapse. It occasionally manifests in a dermatomal manner.¹ 

The differential diagnosis includes other linear acquired inflammatory dermatoses such as blaschkitis, lichen planus, inflammatory linear verrucous epidermal nevus, and psoriasis. Blaschkitis has been described as a rare dermatosis that occurs along the Blaschko lines, affecting adults preferentially over children. Controversy exists whether blaschkitis and lichen striatus are the same disease or 2 separate entities.⁵ Clinically, both blaschkitis and lichen striatus can present with multiple linear papules and vesicles predominantly on the trunk. In blaschkitis, there is a predilection for males, with an older mean age at onset of 40 years.⁵ Lesions quickly resolve over months with frequent relapse compared to lichen striatus, which can persist for months to years. 

Histopathologically, blaschkitis demonstrates spongiosis, usually without involvement of the adnexal structures. Lichenoid and spongiotic changes with adnexal extension are the hallmark features of lichen striatus. In our patient, biopsy showed several dense bandlike foci of lymphohistiocytic infiltrates along the dermoepidermal junction with spongiosis, basal cell liquefactive degeneration, and pigmentary incontinence (Figure 1). The focal areas were surfaced by parakeratotic and orthohyperkeratotic scale. Deep dermal perivascular and periadnexal extension was present (Figure 2). Periodic acid-Schiff stain was negative for fungi.

The pathogenesis of lichen striatus is not entirely understood, but it has been postulated that trauma, vaccinations, or viral infections may induce loss of immunologic tolerance to keratinocytes.¹ This loss of tolerance can result in a T cell-mediated autoimmune reaction against malpighian cells, which show genetic mosaicism and are arranged along Blaschko lines.^1,3 Familial cases also have been reported, suggesting that there may be an epigenetic mosaicism that contributes to this group of skin diseases.^6,7

Lichen striatus tends to resolve on its own after approximately 6 to 9 months.⁸ Treatment typically consists of application of topical corticosteroids.¹ Cases also have been successfully treated with tacrolimus and pimecrolimus.^1,8 Our patient was treated with a midpotency topical steroid with improvement of the appearance but not complete resolution.

The Diagnosis: Lichen Striatus

Lichen striatus (LS) is an acquired and self-limited linear inflammatory dermatosis that most frequently occurs in children and less commonly in adults.^1-3 Clinically, it is characterized by the sudden onset of an eruption consisting of slightly pigmented, erythematous, flat-topped papules with minimal scaling. These papules quickly coalesce to form a linear band that extends along a limb, the trunk, or the face, within Blaschko lines.^1,4 In the adult form, patients tend to experience more diffuse lesions as well as severe pruritus with higher rates of relapse. It occasionally manifests in a dermatomal manner.¹ 

The differential diagnosis includes other linear acquired inflammatory dermatoses such as blaschkitis, lichen planus, inflammatory linear verrucous epidermal nevus, and psoriasis. Blaschkitis has been described as a rare dermatosis that occurs along the Blaschko lines, affecting adults preferentially over children. Controversy exists whether blaschkitis and lichen striatus are the same disease or 2 separate entities.⁵ Clinically, both blaschkitis and lichen striatus can present with multiple linear papules and vesicles predominantly on the trunk. In blaschkitis, there is a predilection for males, with an older mean age at onset of 40 years.⁵ Lesions quickly resolve over months with frequent relapse compared to lichen striatus, which can persist for months to years. 

Histopathologically, blaschkitis demonstrates spongiosis, usually without involvement of the adnexal structures. Lichenoid and spongiotic changes with adnexal extension are the hallmark features of lichen striatus. In our patient, biopsy showed several dense bandlike foci of lymphohistiocytic infiltrates along the dermoepidermal junction with spongiosis, basal cell liquefactive degeneration, and pigmentary incontinence (Figure 1). The focal areas were surfaced by parakeratotic and orthohyperkeratotic scale. Deep dermal perivascular and periadnexal extension was present (Figure 2). Periodic acid-Schiff stain was negative for fungi.

The pathogenesis of lichen striatus is not entirely understood, but it has been postulated that trauma, vaccinations, or viral infections may induce loss of immunologic tolerance to keratinocytes.¹ This loss of tolerance can result in a T cell-mediated autoimmune reaction against malpighian cells, which show genetic mosaicism and are arranged along Blaschko lines.^1,3 Familial cases also have been reported, suggesting that there may be an epigenetic mosaicism that contributes to this group of skin diseases.^6,7

Lichen striatus tends to resolve on its own after approximately 6 to 9 months.⁸ Treatment typically consists of application of topical corticosteroids.¹ Cases also have been successfully treated with tacrolimus and pimecrolimus.^1,8 Our patient was treated with a midpotency topical steroid with improvement of the appearance but not complete resolution.

The Diagnosis: Lipoid Proteinosis

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease, is a rare autosomal-recessive disorder. It is characterized by deposition of hyalinelike material in multiple organs including the skin, oral mucosa, larynx, and brain. The underlying defect is mutations in the extracellular matrix protein 1 gene, ECM1, which binds to various proteins (eg, perlecan, fibulins, matrix metalloproteinase 9) and plays a role in angiogenesis and epidermal differentiation.^1-4 

The clinical spectrum of LP is primarily related to respiratory, skin, and neurologic manifestations, but any organ involvement may be seen. A childhood-onset weak cry or hoarseness usually is the first clinical sign of LP due to infiltration of the laryngeal mucosa.^3-6 A thickened frenulum, which manifests as restricted tongue movements, is another reliable clinical sign of LP.⁷ In addition, yellow-white submucous infiltrates on other mucosal surfaces (eg, pharynx, tongue, soft palate, esophagus)(Figure 1), occlusion of the salivary ducts (recurrent parotitis), dental anomalies, and dental caries (Figure 2) also may be seen.^5,7

Histologically, deposition of eosinophilic homogeneous material is seen around the blood vessels and sweat glands as well as in the dermis and dermoepidermal junction (Figure 4).^1,5 Although most patients with LP have a slowly progressive benign course that stabilizes in early adult life, some morbidities and complications may occur (eg, rarely upper respiratory tract involvement can progress and require tracheostomy). There presently is no cure for LP, but some drugs (eg, oral dimethyl sulfoxide, etretinate, acitretin, penicillamine) and laser ablation/dermabrasion of papules are helpful in some cases.^1,7

The Diagnosis: Lipoid Proteinosis

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease, is a rare autosomal-recessive disorder. It is characterized by deposition of hyalinelike material in multiple organs including the skin, oral mucosa, larynx, and brain. The underlying defect is mutations in the extracellular matrix protein 1 gene, ECM1, which binds to various proteins (eg, perlecan, fibulins, matrix metalloproteinase 9) and plays a role in angiogenesis and epidermal differentiation.^1-4 

The clinical spectrum of LP is primarily related to respiratory, skin, and neurologic manifestations, but any organ involvement may be seen. A childhood-onset weak cry or hoarseness usually is the first clinical sign of LP due to infiltration of the laryngeal mucosa.^3-6 A thickened frenulum, which manifests as restricted tongue movements, is another reliable clinical sign of LP.⁷ In addition, yellow-white submucous infiltrates on other mucosal surfaces (eg, pharynx, tongue, soft palate, esophagus)(Figure 1), occlusion of the salivary ducts (recurrent parotitis), dental anomalies, and dental caries (Figure 2) also may be seen.^5,7

Histologically, deposition of eosinophilic homogeneous material is seen around the blood vessels and sweat glands as well as in the dermis and dermoepidermal junction (Figure 4).^1,5 Although most patients with LP have a slowly progressive benign course that stabilizes in early adult life, some morbidities and complications may occur (eg, rarely upper respiratory tract involvement can progress and require tracheostomy). There presently is no cure for LP, but some drugs (eg, oral dimethyl sulfoxide, etretinate, acitretin, penicillamine) and laser ablation/dermabrasion of papules are helpful in some cases.^1,7

The Diagnosis: Lipoid Proteinosis

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease, is a rare autosomal-recessive disorder. It is characterized by deposition of hyalinelike material in multiple organs including the skin, oral mucosa, larynx, and brain. The underlying defect is mutations in the extracellular matrix protein 1 gene, ECM1, which binds to various proteins (eg, perlecan, fibulins, matrix metalloproteinase 9) and plays a role in angiogenesis and epidermal differentiation.^1-4 

The clinical spectrum of LP is primarily related to respiratory, skin, and neurologic manifestations, but any organ involvement may be seen. A childhood-onset weak cry or hoarseness usually is the first clinical sign of LP due to infiltration of the laryngeal mucosa.^3-6 A thickened frenulum, which manifests as restricted tongue movements, is another reliable clinical sign of LP.⁷ In addition, yellow-white submucous infiltrates on other mucosal surfaces (eg, pharynx, tongue, soft palate, esophagus)(Figure 1), occlusion of the salivary ducts (recurrent parotitis), dental anomalies, and dental caries (Figure 2) also may be seen.^5,7

Histologically, deposition of eosinophilic homogeneous material is seen around the blood vessels and sweat glands as well as in the dermis and dermoepidermal junction (Figure 4).^1,5 Although most patients with LP have a slowly progressive benign course that stabilizes in early adult life, some morbidities and complications may occur (eg, rarely upper respiratory tract involvement can progress and require tracheostomy). There presently is no cure for LP, but some drugs (eg, oral dimethyl sulfoxide, etretinate, acitretin, penicillamine) and laser ablation/dermabrasion of papules are helpful in some cases.^1,7