Cutaneous peripheral T-cell lymphoma, not otherwise specified: A single-center prognostic analysis.

BACKGROUND: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a rare and aggressive disease either originating in or secondarily involving the skin. OBJECTIVE: We sought to assess clinical, histopathologic, and prognostic features of patients with cutaneous PTCL-NOS. METHODS: This was a retrospective chart review of patients with cutaneous PTCL-NOS between 1993 and 2013. RESULTS: Thirty patients with PTCL-NOS were included. Fourteen had skin-only disease and 15 had concurrent skin and systemic disease at presentation. In primary cutaneous PTCL-NOS, the overall survival rate at 5 years was 61% (95% confidence interval, 37-100%; number still at risk, 2). The median overall survival was 5.6 years. Patients were diagnosed a median of 2.4 months from symptom onset. Patients with concurrent disease died a median of 2.1 years after diagnosis. The estimated overall survival rate at 5 years after diagnosis was 29% (95% confidence interval, 13-67%; number at risk, 3). The median overall survival was 3.9 years. Patients were diagnosed a median of 6 months from symptom onset, with a 53% increased risk of death for each year from symptom onset to diagnosis. LIMITATIONS: This was a retrospective study with a limited number of cases. CONCLUSIONS: Age at diagnosis and B-symptoms predict poor survival in patients with cutaneous PTCL-NOS. In addition, poorer survival is observed in patients with multifocal lesions and concomitant skin and systemic PTCL-NOS.

Unknown primary Merkel cell carcinoma: 23 new cases and a review.

BACKGROUND: Knowledge is limited regarding unknown primary Merkel cell carcinoma (UPMCC). OBJECTIVE: We sought to document the characteristics and behavior of UPMCC, and determine the most appropriate treatment. METHODS: A multicenter, retrospective, consecutive study reviewing patients given a diagnosis of UPMCC between 1981 and 2008 was completed. In addition, a literature review of cases of UPMCC was performed. RESULTS: In all, 23 patients with UPMCC are described and 34 cases from previous reports are compiled. Among the 23 new cases of UPMCC, the average age at diagnosis was 66.0 years; the majority of patients were male (87%) and Caucasian (100% of those reported). One patient was immunosuppressed, and 39% had a history of other cancer. After the initial biopsy, 16 patients had further evaluation of the involved lymph node basin. Half of these had additional positive nodes (8 of 16). The majority of patients had lymph node basin involvement only (78%), whereas 22% had lymph node basin and distant metastasis. The most common lymph node basin involved was inguinal. The median size of the involved lymph node at diagnosis was 5.0 cm. At 2 years, the overall survival of stage IIIB UPMCC was significantly improved versus stage IIIB known primary Merkel cell carcinoma (MCC): 76.9% to 36.4%. LIMITATIONS: Limited number of cases and retrospective review are limitations. CONCLUSION: Our data demonstrate improved overall survival in patients with stage IIIB UPMCC versus those with stage IIIB known primary MCC. Because of the unpredictable natural history of UPMCC, we recommend individualization of care based on the details of each patient's clinical presentation.

Prognostic factors in Merkel cell carcinoma: analysis of 240 cases.

BACKGROUND: Knowledge regarding behavior of and prognostic factors for Merkel cell carcinoma (MCC) is limited. OBJECTIVE: We sought to further understand the characteristics, behavior, prognostic factors, and optimal treatment of MCC. METHODS: A multicenter, retrospective, consecutive study of patients with known primary MCC was completed. Overall survival and survival free of locoregional recurrence were calculated and statistical analysis of characteristics and outcomes was performed. RESULTS: Among the 240 patients, the mean age at diagnosis was 70.1 years, 168 (70.0%) were male, and the majority was Caucasian. The most common location was head and neck (111, 46.3%). Immunosuppressed patients had significantly worse survival, with an overall 3-year survival of 43.4% compared with 68.1% in immunocompetent patients. In our study, patients with stage II disease had improved overall survival versus those with stage I disease, in a statistically significant manner. Patients with stage III disease had significantly worse survival compared with stage I and with stage II. Primary tumor size did not predict nodal involvement. CONCLUSION: The data presented represent one of the largest series of primary MCC in the literature and confirm that MCC of all sizes has metastatic potential, supporting sentinel lymph node biopsy for all primary MCC. Because of the unpredictable natural history of MCC, we recommend individualization of care based on the details of each patient's tumor and clinical presentation.

Indolent course of cutaneous gamma-delta T-cell lymphoma.

Cutaneous gamma-delta T-cell lymphoma (γδTCL) is a rare malignancy that typically displays an aggressive clinical course. We present an unusual case of a 57-year-old woman with a 3-year history of lower extremity nodules. Histopathologic, immunophenotypic and molecular genetic studies revealed a clonal, predominantly pannicular gamma-delta T-cell infiltrate, leading to a diagnosis of cutaneous γδTCL. The clinical course was characterized by rapid improvement within months of starting systemic corticosteroids, with relapse in ulcerations but no new lesions more than 3 years after onset of disease. Our case and seven previously reported patients with indolent and relatively localized cutaneous γδTCL provide evidence that not all cases of this entity carry a poor prognosis. This indolent subset adds complexity to treatment of cutaneous γδTCL.

Net-like pattern of calcification on plain soft-tissue radiographs in patients with calciphylaxis.

BACKGROUND: Calciphylaxis is a rare, life-threatening syndrome marked by vascular calcification and cutaneous necrosis. The role of radiographic imaging in assisting in diagnosis has not been established. OBJECTIVE: To investigate the potential role of plain radiographic imaging in the diagnosis of calciphylaxis. METHODS: We searched for cases of patients at our tertiary referral center with a diagnosis of calciphylaxis between Jan 1, 1996, and Dec 31, 2010. Two control patients receiving dialysis but without calciphylaxis were age- and sex-matched to each study patient. Plain radiographs were obtained from the date closest to diagnosis in patients with calciphylaxis and from matched controls at approximately the same dates. Two radiologists, masked as to cases and controls, read each image together. Size of calcified vessels, pattern and extent of calcifications, presence of net-like or other calcifications, and bone density/mineralization were recorded and analyzed. RESULTS: Twenty-nine patients with calciphylaxis (mean age, 57 years; 21 [72%] women) were identified. Mean age at diagnosis was 57 years (range, 36-75 years). Compared with those of controls, plain radiographs of patients with calciphylaxis had more vascular calcifications, more small-vessel calcifications, and a netlike pattern of calcifications. A netlike pattern of calcifications had considerable strength of association with calciphylaxis (odds ratio, 9.4) and a specificity of nearly 90%. These findings were preserved even if only one image was used per patient. LIMITATIONS: This was a retrospective study. CONCLUSION: A netlike pattern of calcifications on plain radiographs was more common in patients with calciphylaxis and may aid in diagnosis.

Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies.

Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization (FISH) for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. In all, 9 of 45 (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, FISH for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99 and 90%, respectively (P=0.00002, Fisher's exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98 and 90%, respectively (P=0.005). FISH abnormalities other than translocations and IRF4 protein expression were seen in 13 and 65% of cases, respectively, but were nonspecific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of FISH for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all FISH studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.

The role of CD10 in distinguishing atypical fibroxanthoma from sarcomatoid (spindle cell) squamous cell carcinoma.

BACKGROUND: The role of CD10 needs clarification in a broader immunohistochemical battery for distinguishing atypical fibroxanthoma (AFX) from spindle cell squamous cell carcinoma (sSCC). METHODS: We retrospectively reviewed 23 cutaneous spindle cell tumors previously classified as AFX (n = 11) or as sSCC (n = 12). Each tumor was stained with CD10, S-100, p63 and two or more cytokeratin stains. Defining AFX as a diagnosis of exclusion based on multiple negative cytokeratin stains and negative p63 staining, we reclassified four squamous cell carcinomas (SCCs) as AFX. CD10 staining was reviewed and graded in all tumors. RESULTS: Fifteen tumors were classified as AFX. Strongly positive CD10 staining was observed in all 15 AFXs, as well as four (50%) of the eight SCCs. Expression of p63 was seen in six sSCCs (75%). CONCLUSIONS: CD10 is consistently expressed by AFX. However, CD10 is also often strongly expressed by sSCC. Positive staining with p63 favors a diagnosis of sSCC. An immunohistochemical battery useful for distinguishing AFX from sSCC may include CD10, p63 and two cytokeratin markers. However, CD10 alone should not be relied upon in the distinction of these entities.

Paucity of intraepidermal FoxP3-positive T cells in cutaneous T-cell lymphoma in contrast with spongiotic and lichenoid dermatitis.

BACKGROUND: FoxP3 is the most specific available marker for regulatory T cells (Tregs). Tumor-associated FoxP3-positive Tregs have been identified in various neoplasms, including cutaneous T-cell lymphoma (CTCL). FoxP3 expression in CTCL varies across groups; few studies have compared CTCL with inflammatory conditions. METHODS: Lesional skin biopsies from 20 patients with CTCL [13 mycosis fungoides (MF); 7 Sézary syndrome (SS)] and 22 with inflammatory dermatoses (11 spongiotic; 11 lichenoid or interface) were examined for FoxP3 expression by immunohistochemistry. Epidermal FoxP3-positive lymphocytes were counted as a percentage of the total epidermal CD3-positive T-cell population. RESULTS: FoxP3-positive T cells composed the minority of infiltrate in all major categories. Lower numbers of epidermal FoxP3-positive T cells were observed in CTCL, particularly MF, than in inflammatory dermatoses (P < .001). CTCL neoplastic T cells did not express FoxP3. CONCLUSION: FoxP3-positive T cells are less frequently encountered in MF than in inflammatory dermatoses. FoxP3-positive T cells occur in higher proportions in the dermis than in the epidermis and probably correlate with coexisting inflammatory components. CTCL neoplastic cells do not typically express a Treg phenotype and are associated with low numbers of FoxP3-positive Tregs in the infiltrate. FoxP3 expression by immunohistochemistry may aid histologic evaluation of these conditions.

Effects of chronic lymphocytic leukemia on the development and progression of malignant melanoma.

BACKGROUND: An association exists between chronic lymphocytic leukemia and malignant melanoma. OBJECTIVES: To study the clinical behavior of malignant melanoma in patients with chronic lymphocytic leukemia. METHODS: A retrospective chart review was conducted of patients with chronic lymphocytic leukemia and malignant melanoma. RESULTS: Sixty-nine patients had malignant melanoma and chronic lymphocytic leukemia. The recurrence-free and metastasis-free survival rates at 2, 5, and 10 years were 93.4% and 89.1%, 83.8% and 93.4%, and 87.4% and 82.1%, respectively. No significant difference was observed in age- and sex-adjusted mortality rates between patients with chronic lymphocytic leukemia diagnosed before malignant melanoma and those with chronic lymphocytic leukemia diagnosed after malignant melanoma. LIMITATIONS: Retrospective study and small patient population. CONCLUSION: Patients with malignant melanoma and chronic lymphocytic leukemia were not shown to have worse survival rates than those with stage IA, IB, and IIA disease. Further research and prospective study are needed.

Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B.

The clinical syndrome of calciphylaxis is characterized by arteriolar medial calcification, thrombotic cutaneous ischemia, necrotic skin ulceration, and a high mortality rate. This review integrates calciphylaxis risk factors with the molecular processes governing osseous and extraosseous mineralization. As the pathogenesis of calciphylaxis is better understood, targeted therapies aimed at disease prevention and reversal will follow.

Outcomes of melanoma in recipients of solid organ transplant.

BACKGROUND: There is concern that the immunologic tumor malignant melanoma (MM) may have worse outcomes in immunosuppressed hosts than in the general population. OBJECTIVE: We sought to describe outcomes of MM in immunosuppressed solid organ transplant recipients and compare them with the general population. METHODS: We conducted a retrospective review of medical charts and pathology slides of cases of MM and solid organ transplantation between 1978 and 2007, with comparison of outcomes. RESULTS: In all, 48 MMs were identified in 43 transplant recipients. No patient with MM before transplant receipt had melanoma recurrence, subsequent metastasis, or death caused by melanoma. Of patients with MM diagnosed after transplantation, metastases developed in 3 patients, and two patients died of melanoma. LIMITATIONS: Retrospective review and low number of cases are limitations. CONCLUSIONS: Outcomes of MM in immunosuppressed transplant recipients appeared similar to those in prognostically matched nonimmunosuppressed hosts. The small number of cases limited statistical comparisons.

Dermal and pannicular manifestations of internal malignancy.

The concept that noncutaneous malignancies may induce paraneoplastic inflammatory reactions and neoplastic or non-neoplastic proliferations in the skin is well known. Previous work on this subject primarily provides lists and descriptions of dermatologic entities that are exclusively or occasionally associated with specific or varied internal cancers or precancerous states. This review seeks to provide a different perspective to this subject by emphasizing components of the skin (the dermis and subcutis) as focal points of paraneoplastic phenomena, with the intent of broadening thinking and differential diagnoses when the findings described are encountered in dermatology clinics and dermatopathology laboratories.

Skin ulcers misdiagnosed as pyoderma gangrenosum.

BACKGROUND: Pyoderma gangrenosum is a diagnosis of exclusion, and the misdiagnosis of pyoderma gangrenosum can result in substantial complications in patients who have other causes of severe cutaneous ulceration. METHODS: We reviewed the charts of 240 patients with a diagnosis of pyoderma gangrenosum who were evaluated at our institution from 1975 through 2000, including 157 consecutive patients treated for presumed pyoderma gangrenosum from 1984 through 1992. We also reviewed the English-language literature. RESULTS: Ninety-five patients (49 from our institution and 46 described in the literature) had skin ulcers with a clinical resemblance to pyoderma gangrenosum. The final diagnoses were vascular occlusive or venous disease, vasculitis, cancer, primary infection, drug-induced or exogenous tissue injury, and other inflammatory disorders. Of the 95 patients studied, 64 had been treated for pyoderma gangrenosum for a median of 10 months (range, 3 to 180). These 64 included 15 of the 157 consecutive patients treated for pyoderma gangrenosum at our institution (10 percent). Of the ulcers in the 64 patients treated for pyoderma gangrenosum, it was clear that those in 23 patients (36 percent) did not respond to treatment directed at pyoderma gangrenosum, those in 8 (12 percent) were exacerbated by such treatment, and those in 15 (23 percent) improved with such treatment. CONCLUSIONS: The misdiagnosis of pyoderma gangrenosum is not uncommon and exposes patients to risks associated with its treatment. A thorough evaluation is required in all patients suspected of having pyoderma gangrenosum in order to rule out alternative diagnoses.

Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis.

Malignant melanoma is an aggressive, therapy-resistant malignancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public health problem. Exposure to solar UV radiation, fair skin, dysplastic nevi syndrome, and a family history of melanoma are major risk factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanomagenesis are currently the subject of ongoing research. Avoidance of UV radiation and surveillance of high-risk patients have the potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are required for optimal diagnosis and staging. Several clinically relevant pathologic subtypes have been identified and need to be recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. Management of systemic melanoma is a challenge because of a paucity of active treatment modalities. In the first part of this 2-part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will appear in the April 2007 issue) will review melanoma staging, prognosis, and treatment.

Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment.

Critical to the clinical management of a patient with malignant melanoma is an understanding of its natural history. As with most malignant disorders, prognosis is highly dependent on the clinical stage (extent of tumor burden) at the time of diagnosis. The patient's clinical stage at diagnosis dictates selection of therapy. We review the state of the art in melanoma staging, prognosis, and therapy. Substantial progress has been made in this regard during the past 2 decades. This progress is primarily reflected in the development of sentinel lymph node biopsies as a means of reducing the morbidity associated with regional lymph node dissection, increased understanding of the role of neoangiogenesis in the natural history of melanoma and its potential as a treatment target, and emergence of innovative multimodal therapeutic strategies, resulting in significant objective response rates in a disease commonly believed to be drug resistant. Although much work remains to be done to improve the survival of patients with melanoma, clinically meaningful results seem within reach.

Calciphylaxis: natural history, risk factor analysis, and outcome.

BACKGROUND: Calciphylaxis is characterized by ischemic cutaneous ulceration, high mortality, and ineffective treatment. METHODS: We conducted a retrospective study of 64 patients with calciphylaxis (including 49 dialysis patients age- and sex-matched to 98 dialysis controls). RESULTS: The estimated 1-year survival rate of calciphylaxis was 45.8%. Risk factors for calciphylaxis included obesity, liver disease, systemic corticosteroid use, calcium-phosphate product more than 70 mg(2)/dL(2), and serum aluminum greater than 25 ng/mL. Survival rates were similar for 16 patients who received parathyroidectomy and 47 who did not. An estimated 1-year survival rate of 61.6% was observed for 17 patients receiving surgical debridement compared with 27.4% for the 46 who did not (P = .008). LIMITATIONS: The study was limited by its retrospective design and there was no control group for the 15 nondialysis cases. CONCLUSIONS: Calciphylaxis is multifactorial and usually fatal. Prevention of calciphylaxis may include correction of risk factors identified in this study. Surgical debridement was associated with improved survival, but parathyroidectomy was not.

The role of the hospital dermatologist in the diagnosis and treatment of calciphylaxis and nephrogenic systemic fibrosis.

Calciphylaxis and nephrogenic systemic fibrosis are rapidly progressive diseases associated with renal impairment with high rates of mortality and morbidity. In this review, we highlight the role of the dermatologist in the multispecialty team approach to the diagnosis, treatment, and management of these patients. We present sample cases from our hospital practice to emphasize the importance of diagnosis, clinicopathologic correlation, rapid intervention, and treatment of these challenging skin disorders.

Thyroid dermopathy: an underrecognized cause of leg edema.

Leg edema is a common clinical problem and the differential diagnosis is extensive. We present 4 patients in whom thyroid dermopathy was the cause of leg edema. Examination of the eyes and the nature of the edema were clues to the diagnosis of thyroid dermopathy. Clinical signs should be documented and analysis of skin biopsy specimens should be performed in patients suspected to have thyroid dermopathy.

Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density.

The histopathology of primary erythromelalgia has been poorly characterized. A total of 33 skin biopsy specimens from 29 patients with a diagnosis of primary erythromelalgia were re-examined. Histopathologic findings were nonspecific. Vascular thrombi were not identified. A relative decrease in small nerve fiber density was noted in specimens from 13 of 16 patients.

Clinical outcome of patients with subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma. The objective of this study was to characterize the clinical presentation, treatment, and prognosis of patients with SPTCL. Twenty-one patients with SPTCL were seen at Mayo Clinic (Rochester, Minnesota, USA) between July 1973 and June 2004. The median age at diagnosis was 42 years (range 23-80 years) and 15 (71%) were women. Constitutional symptoms occurred in 14 (67%) patients, including fever, serositis, arthralgias and myalgias. The Eastern Cooperative Oncology Group performance score was poor (3-4) in 3 (15%) patients. Liver enzymes (at least 2 enzymes, Aspartate aminotransferase (AST), alkaline phosphatase and/or lactate dehydrogenase) were elevated in 11 (52%) patients. Therapy consisted of chemotherapy in 13 (62%) patients, or other therapeutic interventions in 8 (38%) patients, including surgical excision, corticosteroids alone or in combination with either plaquenil, colchicine, hydroxychoroquine, or azathioprine. Bone marrow transplantation was performed in 5 (24%) patients, 3 autologous and 2 allogeneic. The median overall survival from diagnosis was 15 months (range 0.1-104 months). Two groups of patients were identified and categorized as having a favorable or unfavorable disease course. The factors associated with an unfavorable disease course were a low white blood cell count or elevated lactate dehydrogenase. Patients treated aggressively with stem cell transplantation appeared to have an improved overall survival.