Search

Benign lichenoid keratosis (BLK) is a cutaneous lesion that can clinically mimic malignancy and may represent regression of a pre-existing lesion. BLK may show epidermal pseudo-nests prompting evaluation for a melanocytic lesion. False positivity of MART-1/Melan-A immunostaining in pseudonests has been showed; however, the value of SRY-related HMG-box 10 (SOX10) staining in BLK with features suspicious for a melanocytic proliferation has not been previously reported.Twenty-one cases of BLK from 2015 to 2020 were identified. Slides were reviewed and SOX10 immunohistochemistry was performed on each case. Subsequently, Melan-A immunohistochemical staining was performed on all cases.In 10 cases (47.6%), unexpected SOX10 staining was seen in rare to numerous small, single cells in the epidermis above the basal cell layer. No malignancy was identified. Of the 10 cases, 8 (80%) showed suprabasal SOX10 staining did not show similar suprabasal Melan-A staining; 2 (20%) cases showed scattered suprabasal cells positive for Melan-A.SOX10 immunostaining in BLK can highlight scattered cells in the epidermis (not easily noticeable on routine stain). Performing SOX10 immunostain alone on BLK can prompt a misdiagnosis of a melanocytic lesion and should be done with caution.

Background Melanoma, particularly nevoid melanoma, can masquerade as benign. Helpful differentiating features include nuclear pleomorphism, atypia, prominent nucleoli, absent maturation, and increased mitotic figures. These can be subtle and easily missed unless carefully sought. Thus, the "puffy shirt appearance" concept was born from a Seinfeld episode in which the namesake character unintentionally agreed to wear a pirate-like puffy shirt. Consequently, he found himself out of place, sporting an outfit with "too much shirt in too little space". Similarly, at low-power, nevoid melanoma appears to have "too many cells in too little space". This is more pronounced and easier to appreciate when there is an associated nevus, where crowded, subtly malignant melanocytes stand out from the evenly distributed, more spaced out benign melanocytes. Methods Twelve practicing dermatopathologists familiar with the puffy shirt concept in the context of melanoma were surveyed. Results Hundred percent of participants found it most helpful as a triaging tool, prompting additional work up including higher magnification evaluation, additional levels, consultation, and/or immunohistochemistry. Conclusions The crowded cells in the "puffy shirt appearance" catch the eye and should provoke a more thorough inspection of the lesion. This sign is not pathognomonic for melanoma, but prompts more careful evaluation and helps prevent misdiagnosis.

A 51-year-old white woman with a past medical history significant for steroid-dependent ulcerative colitis, rheumatoid arthritis, and diabetes mellitus presented to the hospital with fever and painful, erythematous subcutaneous nodules on the medical aspects of both thighs. Histopathologic examination showed features suggestive of an abscess, but her condition failed to improve with intravenous broad-spectrum antibiotics. Molecular studies detected T cell receptor-β gene rearrangements. The lesions later exhibited signs of necrosis, requiring multiple debridements as well as therapy with hyperbaric oxygen. She was later referred to the MD Anderson Cancer Center for evaluation for possible subcutaneous panniculitis-like T cell lymphoma.

Radiation therapy is a mainstream strategy in the treatment of several cancer types that are surgically unresectable. Unfortunately, cancer patients often suffer from unintended consequences of radiotherapy, including the development of skin inflammation (dermatitis), which may progress to fibrosis. These morbid complications often require interruption of radiotherapy and threaten the relapse of underlying cancer. Current treatment options for radiation dermatitis are suboptimal and compel the need to develop safer, more effective therapies. In this study, we assessed the biophysical properties of topically-formulated esomeprazole (here referred to as dermaprazole) and performed proof-of-concept studies to evaluate its efficacy in vitro and in vivo. We found that dermaprazole induced nuclear translocation of erythroid 2-related factor 2 (Nrf2) and significantly upregulated heme oxygenase 1 (HO1) gene and protein expression in a 3D human skin model. Our animal study demonstrated that dermaprazole improved macroscopic appearance of the irradiated skin and accelerated healing of the wounds. Histopathology data corroborated the photographic evidence and confirmed that both prophylactically and therapeutically administered dermaprazole conferred potent anti-inflammatory and antifibrotic effects. Gene expression data showed that dermaprazole downregulated several pro-oxidant, pro-inflammatory and profibrotic genes. In conclusion, topical formulation of the FDA-approved drug esomeprazole is highly effective in attenuating dermal inflammation and fibrosis.

Pathological staging of primary anorectal mucosal melanoma is often performed according to the American Joint Commission on Cancer (AJCC) guidelines for cutaneous melanoma, as an anorectal melanoma-specific staging system does not exist. However, it remains unknown whether prognostic factors derived for cutaneous melanoma also stratify risk in anorectal melanoma. We retrospectively determined correlations between clinicopathological parameters and disease-specific survival in 160 patients. Patients were grouped by clinical stage at presentation (localized disease, regional or distant metastases). Cox proportional hazards regression models determined associations with disease-specific survival. We also summarized the somatic mutations identified in a subset of tumors analyzed for hotspot mutations in cancer-associated gene panels. Most of the patients were white (82%) and female (61%). The median age was 62 years. With a median follow-up of 1.63 years, median disease-specific survival was 1.75 years, and 121 patients (76%) died of anorectal melanoma. Patients presenting with regional (34%) or distant metastases (24%) had significantly shorter disease-specific survival compared to those with disease localized to the anorectum (42%). Of the 71 anorectal melanoma tumors analyzed for hotspot genetic alterations, somatic mutations involving the KIT gene (24%) were most common followed by NRAS (19%). Increasing primary tumor thickness, lymphovascular invasion, and absence of regression also correlated with shorter disease-specific survival. Primary tumor parameters correlated with shorter disease-specific survival in patients presenting with localized disease (tumor thickness) or regional metastases (tumor thickness, absence of regression, and lymphovascular invasion), but not in patients presenting with distant metastases. Grouping of patients according to a schema based on modifications of the 8th edition AJCC cutaneous melanoma staging system stratified survival in anorectal melanoma. Our findings support stage-specific associations between primary tumor parameters and disease-specific survival in anorectal melanoma. Moreover, the AJCC cutaneous melanoma staging system and minor modifications of it predicted survival among anorectal melanoma patients.

Linear IgA bullous dermatosis is a rare autoimmune vesiculobullous disease characterized by linear deposition of IgA along the basement membrane zone. It is classically idiopathic, but may also arise secondary to drug exposure. A heterogeneous spectrum of clinical features has been described, including a rare, morbid variant mimicking toxic epidermal necrolysis. Herein, we present a case of vancomycin-induced linear IgA bullous dermatosis that manifested clinically as toxic epidermal necrolysis and resolved with dapsone therapy.

Digital papillary adenocarcinoma is a rare malignant tumor of the sweat glands, most commonly encountered in adult males. Only few pediatric cases have been reported, with an apparent predominance of females and none on the ankle. We report a case of a 15-year-old girl with a slowly growing, non-tender mass on the right ankle presenting with difficulty in walking; clinically believed to be a keloid. Excision of the mass revealed a glandular neoplasm with largely eccrine and focally apocrine differentiation. Histologic features do not reliably predict biologic behavior. Because of the existing confusion over the nomenclature, we propose that such tumors be called 'papillary adnexal neoplasms of distal extremities'.

Background Assessment of histologic and immunohistochemical maturation (with HMB-45 and anti-Ki-67) may be helpful in differentiating benign melanocytic nevi (BMN) from malignant melanoma. Recently, we reported loss of maturation and aberrant immunohistochemical findings in melanocytic nevi after liquid nitrogen cryotherapy (Adeniran et al, J Am Acad Dermatol 2009;61:341-5). Herein we report a similar phenomenon identified in traumatized melanocytic nevi (TMN). Objective We sought to evaluate the histologic and immunohistochemical findings in early and late stages of traumatized nevi. Methods Twenty-four cases of TMN were retrieved from the pathology archives. These were then assessed by two pathologists (T.L. and A.H.D.) using HMB-45 and MIB-1 (for Ki-67) antibodies. Results TMN showed some of the following findings: epidermal changes (parakeratosis, ulceration, serum crust, flattening of the epidermis) and dermal changes including fibrosis and the presence of melanophages. In some cases, there was architectural disorder of the overlying melanocytes, with crowding in the basal layer, but without significant pagetoid spread. Occasionally, the dermal scar contained larger, more epithelioid-appearing melanocytes than those beneath the scar. Fifty-four percent of TMN lacked obvious immunohistochemical maturation with HMB-45, since nevus cells within the scar or directly beneath it were strongly labeled. None of the TMN showed appreciable labeling for Ki-67. Limitations The exact clinical duration between trauma and biopsy could not be determined. Conclusion Loss of maturation with HMB-45 in TMN can be a diagnostic pitfall in challenging cases. Concurrent evaluation of MIB-1 expression, along with the characteristic histologic features of trauma, should allow the correct diagnosis to be reached.

Cutaneous leishmaniasis is rarely seen in the United States. Four Cuban immigrants traveled along the same route at different times from Cuba to Ecuador, then northward, including through the Darién Jungle in Panama. These patients had chronic ulcerative non-healing skin lesions and were given a diagnosis of leishmaniasis.

PURPOSE To report the clinical and histopathologic features in 6 patients with cutaneous melanoma metastatic to the eyelid and periocular skin. METHODS Clinical records and radiographic features of all consecutive patients treated by the principal investigator between January 2005 and October 2007 with the diagnosis of cutaneous melanoma metastatic to the eyelid and periocular skin. RESULTS Six patients ranged in age from 26 to 84 years old (median, 55 years). Five patients had their metastatic lesion in the upper eyelid and 1 in the lower eyelid. The mean survival after the diagnosis of melanoma metastatic to the eyelid was 5.3 months. All patients had metastases at other sites detected prior to the diagnosis of the eyelid metastasis. The mean interval from initial primary tumor diagnosis to metastasis to the eyelid was 121 months. In all 6 patients, palliative surgical resection of the metastatic eyelid lesions was carried out. CONCLUSIONS Melanoma metastatic to the eyelid is not uncommon in advanced stage cutaneous melanoma. Palliative surgical management of these metastatic lesions should be considered to improve the patient's quality of life.

Using immunohistochemistry with anti-D2-40 for the detection of lymphovascular invasion (LVI-IHC) in 74 cases of invasive melanoma, we found LVI in 23% (16/74) of the tumors. Data on sentinel lymph node (SLN) biopsy were available for 36 patients. Sixty-seven percent (6/9) of patients with LVI-IHC and 19% (5/27) without LVI-IHC had positive SLN. Follow-up data were available for 60 patients. Data on recurrence/metastasis were available for 60 patients. Twenty-five percent (15/60) had LVI with immunohistochemistry. Fifty-three percent (8/15) of these patients had “distant” metastasis or regional recurrence compared with 11% (5/45) in those without LVI-IHC. Overall and disease-specific survival was shorter for patients with LVI. In both the univariate and multivariate Cox proportional hazards regression models, LVI-IHC in addition to ulceration was statistically significant with respect to overall survival. Specifically, in the reduced multivariate model, compared with patients with no LVI, patients with intratumoral LVI had a hazard ratio (HR) of 5.4 (95% CI 1.6–18.4), while patients with peritumoral LVI had a HR of 3.8 (95% CI 0.7–20.9). In addition, patients with ulceration had an increased hazard of 4.4 (95% CI 1.2–16.8). For the first time, we herein show a positive correlation with LVI in melanoma detected with immunohistochemistry and distant metastasis, overall survival and disease-free survival.

Clusterin expression is common in systemic and cutaneous anaplastic large cell lymphoma (ALCL). Mycosis fungoides (MF) in large cell transformation can resemble ALCL. In this study, we immunohistochemically assessed for clusterin in 97 skin biopsy specimens, including 70 MF cases and 27 other cutaneous neoplasms including ALCL, peripheral T-cell lymphoma unspecified (PTCL), and lymphomatoid papulosis (LyP). Clusterin was positive in 36 (51%) of 70 cases of MF and correlated with clinical stage in 68 cases: 3 of 21 stage I, 11 of 20 stage II, and 23 of 27 stage III/IV. Clusterin expression also correlated with type of skin lesion (3/19 patch, 13/28 plaque, and 20/23 tumor/erythroderma) and number of large cells (6/30 small cell, 12/18 with increased large cells, and 18/22 with large cell transformation). Clusterin expression was not specific for MF as it also was positive in 3 of 3 cases of LyP, 2 of 2 systemic ALCL cases involving skin, 7 of 16 cutaneous ALCLs, and 1 of 6 PTCLs.

Epithelioid cell histiocytoma (ECH) is a variant of dermatofibroma that presents typically as a solitary nodule. We report a case of a 20-year-old male who presented with a bleeding nodular lesion on the left arm followed a month later by a nodule on the right nostril. Both lesions had epithelioid cells in the dermis, with focal Factor 13a and CD68 immunoreactivity. The left arm lesion, in addition, showed staghorn vasculature as well. Both lesions were interpreted as ECH. The patient had an unremarkable medical history. To the best of our knowledge, multiple ECHs have not been reported in the literature. An appropriate diagnosis of ECH is important as the differential diagnosis usually includes melanocytic lesions.

According to most authors, dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) represent the adult and juvenile forms, respectively, of the same disease entity, as evidenced by similar morphology, an identical chromosomal translocation, and CD34 positivity. It has been shown that DFSP and nuchal-type fibroma (NTF) (which is also CD34-positive) are related lesions, and that there might possibly be a continuum between the two. In addition, NTF exhibits CD99 positivity. It was therefore, hypothesized that both DFSP and GCF would show similar immunopositivity for CD99. Archives of pathology at several institutions were searched for DFSP and GCF tissue blocks. A total of 29 DFSP and 5 GCF were analyzed by immunohistochemistry for expression of CD99. Twenty-three of 29 DFSP (79%) and 2 of 5 GCP (40%) expressed CD99. Comparison of CD99 and CD34 showed that the non-tumoral periphery of DFSP was less probable to be CD99 positive, but this finding was not statistically significant.

Cutaneous sebaceous neoplasia is known to exhibit a high degree of DNA mismatch repair (MMR) deficiency leading to microsatellite instability and these tumors can be markers of the Muir-Torre syndrome and internal malignancy. Other tumors, such as colonic carcinoma, show tendencies toward particular histologic features and sites of involvement correlating with MMR deficiency. There are few comprehensive studies of unselected cutaneous sebaceous neoplasms. To address this gap in knowledge, we examined 94 sebaceous neoplasms from 92 patients and 17 sebaceous hyperplasia controls using immunohistochemistry for MLH1, MSH2, and MSH6. Our results indicate that MMR deficiency is significantly associated with anatomic location (more frequently in the trunk and extremities as compared with head and neck), tumor type (more often in adenoma compared with carcinoma within the head and neck region), and architecture (keratoacanthomalike). No correlation between cystic change and MMR deficiency was noted. Cutaneous sebaceous neoplasia has tendencies toward certain tumor types and anatomic distribution based on MMR status analogous to that seen in colonic carcinomas and other tumors. These may be helpful indicators for further workup for the Muir-Torre syndrome.

Basal cell carcinoma is the most common malignancy in Caucasian individuals. Metastatic basal cell carcinoma is extremely rare (with a rate estimated as 0.03%). Actin has been detected in aggressive forms of basal cell carcinoma, but their expression in metastatic lesions is not known. We compared the expression of actin and actin-related cytoskeletal proteins in relatively less aggressive basal cell carcinoma (nodular), aggressive basal cell carcinoma (infiltrative/morpheaform), and metastatic basal cell carcinoma. We studied 12 cases of nodular basal cell carcinoma, 10 cases of infiltrative basal cell carcinoma, and 10 cases of metastatic basal cell carcinoma with immunohistochemistry for alpha-smooth muscle actin, calponin, myosin, and E-cadherin. Expression was interpreted as positive when at least 5% of the tumor exhibited at least weak expression. Five of the ten patients with metastatic basal cell carcinoma had an antecedent history of radiotherapy. Actin was present in 3 of 12 (25%) of the nodular, all 10 of the infiltrative, and 3 of 10 of the metastatic basal cell carcinomas (P

Renal cell carcinoma marker (RCC-Ma) is a monoclonal antibody against a normal renal proximal tubule antigen. RCC-Ma expression is relatively specific for primary clear cell renal cell carcinoma. Its expression in cutaneous metastasis of renal cell carcinoma (MRCC) and other cutaneous clear cell lesions has not been studied.One hundred and thirty-seven cutaneous clear cell lesions including eight xanthomas, 32 xanthelasmas, 25 xanthogranulomas, seven balloon cell nevi, six clear cell hidradenomas, 29 sebaceous adenomas, six sebaceous epitheliomas, eight sebaceous carcinomas, and 16 MRCC were examined using immunohistochemistry for the expression of RCC-Ma.RCC-Ma was expressed in 10 of 16 (62.5%) MRCC, all with greater than 20% of cell labeling. Of these, 4 of 10 (40%) labeled with a membranous pattern and 6 of 10 (60%) labeled with both a membranous and a cytoplasmic pattern. RCC expression was not seen in any of the other clear cell lesions (p0.001). Furthermore, lack of expression in each of the other diagnostic groups was significant when each group was compared with the MRCCs (p0.01 at least for each group).Our study demonstrates that RCC may be a valuable component of a panel of immunohistochemical markers when evaluating cutaneous clear cell lesions.

Background: Although various studies have stressed the role of phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-PI3K-AKT pathway in the progression of melanocytic lesions, little is known about the expression pattern of PI3K in these lesions. Objective: To investigate the expression pattern of PI3K in benign and dysplastic nevi, primary melanomas, and metastatic melanomas and the role of PTEN and PI3K in melanocytic tumor progression. Methods: Tissue microarrays were constructed using formalin-fixed, paraffin-embedded archival tissue blocks from 89 melanocytic lesions: 17 benign nevi, 18 dysplastic nevi, 23 primary melanomas, and 31 metastatic melanomas. Expression of PTEN and PI3K (p85 and p110 subunits) was evaluated immunohistochemically, and the number of cells and labeling intensity were assessed semiquantitatively. Results: Both benign and dysplastic nevi showed strong cytoplasmic staining with PTEN, which was subsequently less in melanomas and completely lost in the metastatic lesions. Eleven of 17 (64%) benign nevi, seven of 10 (70%) dysplastic nevi, four of 23 (17%) primaries, and one of 31 (3%) visceral or lymph node metastasis showed strong positivity. Loss of PTEN expression from benign and dysplastic nevi to melanoma was statistically significant (p = 0.001). Although few cells showed reactivity for phosphoinositide 3-kinase (PI3 kinase)-p85 subunit, strong positivity was not detected in the cytoplasm of benign, malignant, or metastatic lesions, except for a single visceral metastasis. Three of 13 (23%) nevi showed positivity for the p110 subunit. No positivity was observed in the dysplastic nevi. Two of 22 (9%) melanomas, one of 14 (7%) visceral metastasis, and three of 12 (25%) lymph node metastasis showed strong positivity. There was no statistical difference in PI3 kinase expression in benign and malignant melanocytic lesions (p = 0.2). Conclusion: PI3K is not overexpressed in melanocytic lesions.

We assessed the feasibility of using high-frequency ultrasound biomicroscopy (UBM) in estimating thickness of conjunctival melanomas preoperatively. Three patients underwent UBM prior to excision of conjunctival melanoma between February 2003 and March 2006. Conjunctival tumor thickness was estimated via UBM in each case and compared with the estimated histopathologic tumor thickness (Breslow thickness). Patient 1 had an estimated thickness of 1.99 mm via UBM versus a Breslow thickness measurement of 1.5 mm based on the surgical specimen. Patient 2 had a UBM thickness measurement of 2.4 mm and a Breslow thickness of 2.23 mm based on the surgical specimen. In patient 3, both UBM thickness and Breslow thickness were 2.3 mm. The use of high-frequency UBM is feasible for the estimation of tumor thickness for conjunctival melanomas. UBM may serve as an additional diagnostic tool for estimating tumor thickness before surgical resection of conjunctival melanoma. © 2007 Wiley Periodicals, Inc. J Clin Ultrasound, 2007

We report the association of common variable immunodeficiency syndrome with epidermodysplasia verruciformis (EV) manifesting as flat warts and squamous cell carcinomas in a 21-year-old Hispanic woman. Human papillomavirus (HPV) typing by polymerase chain reaction using an EV-HPV primer system, cloning, and sequencing detected HPV-8 and HPV-23 DNAs in the biopsy sample. Our case is the second reported case of common variable immunodeficiency syndrome associated with EV.

We have reported a high prevalence of hypothyroidism in the cutaneous melanoma population, suggesting that the pathologic hormonal environment of hypothyroidism promotes melanoma growth. The objective of this study was to test the hypothesis that TSH, which circulates at elevated levels in hypothyroid individuals, stimulates the growth of melanoma cells. Our results show that TSH receptors (TSHR) are expressed by virtually all cutaneous melanocytic lesions, including benign nevi, dysplastic nevi, and melanomas, with higher expression found in malignant and pre-malignant lesions. The finding of TSHR expression by human tumors is confirmed in cultured melanoma cells and melanocytes, in which TSHR expression is demonstrated by immunofluorescent staining, western blotting, and reverse transcriptase-PCR. Melanoma TSHR are functional, as evidenced by the ability of TSH to induce the formation of cAMP and to activate the mitogen-activated protein kinase (MAPK) pathway. Cultured melanoma cells, but not melanocytes, are induced to proliferate at a physiologically relevant concentration of TSH. Taken together, these data support the hypothesis that TSH is a growth factor for human melanoma. Our findings have broad clinical implications for the prevention of melanoma and the management of established disease.

Angiosarcoma is a rare, aggressive, malignant endothelial neoplasm with a variable clinical presentation. The authors describe a case of angiosarcoma involving the eyelid that was complicated by a superimposed Enterobacter infection. Following positive cultures for E. aerogenes and multiple biopsies suspicious but not definitive for angiosarcoma, a final biopsy was consistent with angiosarcoma.

Immunodeficiency-related lymphoproliferative disorders (IR-LPD) may occur in the setting of immunosuppressive therapy with methotrexate and TNF-α antagonists. As far as we are aware, this is the first report of an Epstein-Barr virus-associated B-cell lymphoproliferative disorder, secondary to methotrexate therapy in a patient with mycosis fungoides/Sézary syndrome.

To the editor:We thank Dr. Zidar and Dr. Gale for their timely and detailedcomments on our paper [1]. Indeed, epithelial-mesenchymaltransition (EMT) is a multifaceted process driven by an intri-cate network of molecular mechanisms which to date remainincompletelyunderstood,duetotheextraordinarycomplexityoftheirregulation[2].Theseprocessesincludechangesincelladhesionandshape,geneexpression,andextensivecross-talkbetween signaling pathways that create complex biochemicalnetworks [2, 3], of which the final result in cancer is the de-velopment of mesenchymal-like cells with enhanced capacityfor invasion, migration, and dissemination [3].Even though some authors have proposed that phenotypicmodulation in tumor progression is a reflection of genomicinstabilityratherthananEMT-drivenprocess[4],westronglybelievethatthereiscompellingevidencesuggestingakeyroleof EMTin the biology of tumor progression.As we proposedin our paper, primary carcinosarcomas of the skin are rarebiphenotypiccutaneoustumorswhichsimultaneouslyexpressboth epithelial and mesenchymal elements, suggesting that intheirdevelopmentanEMTprocessmightbeinvolved[5].Weexplored this possibility by assessing loss of E-cadherin ex-pression and upregulation of vimentin expression, a patternthat is considered to be the hallmark of EMTchanges in epi-thelial cells [5]. However, we do agree that more stringentcriteria should be applied when assessing EMT-suggestivehistological patterns.As Zidar and Gale state, among the multiple criteria thatshouldbeassessed,thepresenceofspindlecellmorphologyisa sine qua non. Although different epithelial morphotypes ofcutaneous carcinosarcoma exist (squamous cell or basal cellderived), the presence of a spindle cell component is obliga-tory and a feature of all cases we studied. In all cases westudied, β-catenin and E-cadherin were expressed in the cy-toplasmic membrane of benign epithelium, while tumor cellsshowed decreased E-cadherin membranous expression along

Mycosis fungoides is an indolent, epidermotropic, cutaneous T-cell lymphoma of helper/memory T cells that presents as heterogeneous, papulosquamous patches, plaques, and tumors. We present a patient with mycosis fungoides and infection with Coccidioides immitis of the skin, which has not been previously reported.

Pleomorphic fibromas represent dome-shaped or polypoid cutaneous lesions characterized by a paucicellular and densely fibrotic background punctuated by scattered atypical to pleomorphic spindle and multinucleated giant cells. Some of these tumors will have incorporated adipose tissue, although these adipocytic areas lack distinct cytologic atypia and may represent entrapped normal periadnexal or subcutaneous adipose tissue. Nonetheless, owing to the similarity of some of the morphologic features of pleomorphic fibroma with cutaneous atypical lipomatous tumor, diagnostic confusion can ensue. The potential diagnostic challenges are further highlighted by a recent report of a lesion with histopathologic features of both. In response, we studied the presence of 12q15/ MDM2 amplification by fluorescence in situ hybridization and MDM2 expression by immunohistochemistry in a series of 15 pleomorphic fibromas to investigate whether these two entities share a common pathogenic origin. One case of cutaneous atypical lipomatous tumor was used as positive control for 12q15 amplification. All 15 cases were negative for MDM2 by immunohistochemistry with no demonstrable 12q15/MDM2 amplification by fluorescence in situ hybridization. Therefore, these two entities are best regarded as pathogenetically distinct. MDM2 immunohistochemistry or fluorescence in situ hybridization studies can be used to differentiate between the two if needed.

Simple lipomas of the eyelid are rare. We present a case of a 61-year-old man, who presented with 6 months of a slowly worsening blepharoptosis. On examination, that patient was noted to have a palpable, soft mass in the medial left upper eyelid. Histopathological examination of the mass revealed mature adipose tissue most consistent with lipoma. Simple lipomas of the eyelid are very unusual but should be considered in the differential diagnosis of patients presenting with mechanical ptosis.

Leuprolide acetate represents a gonadotropin-releasing hormone agonist, used as part of the treatment of prostate cancer. We report an unusual case of disseminated urticarial rash following leuprolide injection in a 67-year-old man that histopathologically and immunohistochemically resembled mycosis-fungoides, including the presence of follicular mucinosis and eosinophils in the follicles. This histopathologic pattern has not been previously described as a drug reaction pattern due to leuprolide, and it underscores the importance of correlation with the clinical impression to arrive at a correct diagnosis.

This article discusses the key features of nevoid melanoma. Gross features, microscopic features, immunohistochemistry, differential diagnosis, diagnosis, prognosis, and treatment are also discussed.

Melanocytic nevi can undergo clinical and histopathologic changes during pregnancy, as well as after various forms of surgical and nonsurgical trauma. We report the case of a 9-month postpartum 29-year-old female who presented to her dermatologist with a clinically worrisome nevus. This nevus had been treated with liquid nitrogen by her primary care physician 6 months prior to presentation. Histopathologic evaluation revealed a crowded proliferation of atypical melanocytes at the dermal-epidermal junction overlying a scar. The dermal component contained scattered mitotic figures. A combined MART-1, tyrosinase and Ki-67 immunohistochemical study showed foci of increased melanocytic proliferation. These atypical features were interpreted as associated with both the prior cryotherapy, as well as her recent pregnancy. Knowledge of the clinical context in evaluating difficult melanocytic lesions is essential.

Metastatic melanoma represents one of the most common types of cutaneous metastases. In up to 5% of patients, metastatic melanoma can be the first manifestation of the disease. For the most part, the histologic diagnosis of metastatic melanoma poses little diagnostic difficulty; however, some metastases may adopt unusual or unfamiliar appearances mimicking other benign and malignant conditions. We present a study of 192 cases of cutaneous metastatic melanomas with special emphasis on their spectrum of morphologic features. The patients were 115 men and 77 women, 23-91 years of age (mean 57 years). Most tumors were located on the proximal legs, scalp, and arms and ranged from 0.8 to 3.0 cm. One hundred ten cases showed the classic morphologic appearance of melanoma (well-circumscribed epithelioid dermal/subcutaneous nodule), 82 cases showed unusual histologic appearances that mimicked other benign and malignant neoplasms. In 16 patients (8.3%), there was no evidence of primary melanoma and the cutaneous metastasis was the only manifestation of the disease. The histologic diagnosis of cutaneous metastatic melanoma can pose difficulties for diagnosis, especially in the face of an unknown primary neoplasm. Unusual features observed in this series included examples of cutaneous metastatic melanoma that closely simulated metastatic carcinoma, dermatofibroma, leiomyosarcoma, angiosarcoma, nevoid melanoma, halo nevus, blue nevi, and atypical fibroxanthoma. Several cases also showed rhabdoid, balloon cell, and alveolar features. Immunohistochemical stains plus careful clinical history helped to establish the correct diagnosis. Our series illustrates that the differential diagnosis of cutaneous metastatic melanoma can be broad and difficult. To the best of our knowledge, this is the largest series of cutaneous metastatic melanomas reported in the literature.

Background: Little is known about the significance of severe architectural disorder in small melanocytic lesions with features of dysplastic nevi (DN). Methods: Using previously reported criteria, 355 consecutive DN were scored for architectural disorder and cytologic atypia. The DN were classified according to their size as small (equal or less than 3 mm) or large (greater than 3 mm). Results: Of these 136 (38.3%) DN were classified as small. Grades of architectural disorder and cytologic atypia were equally distributed in small and large DN. Forty lesions were diagnosed as dysplastic nevi with severe architectural disorder (DNSAD). Thirteen DNSAD were small; of these, 84.6% were junctional. DN showing only mild to moderate architectural disorder were found to be predominantly compound. DN with severe cytologic atypia were mainly large (8/10 cases) with no particular type (junctional or compound) predominance. Seven cases displayed both severe architectural disorder and severe cytologic atypia; only one of these cases (a junctional lesion) measured less than 3 mm. Conclusions: Small melanocytic lesions displaying severe architectural disorder are mainly junctional and tend to show only mild cytologic atypia. Caution is needed when interpreting the degree of architectural disorder in these small melanocytic lesions, in order to avoid overdiagnosis of melanoma. Torres-Cabala CA, Plaza CA, Hafeez Diwan A, Prieto VG. Severe architectural disorder is a potential pitfall in the diagnosis of small melanocytic lesions.

Neurothekeoma is a term introduced by Gallager and Helwig describing a superficial tumor of purported nerve sheath derivation, with cellular and myxoid types. Recently, it has been suggested that the cellular type does not have nerve sheath differentiation. This subtype represents an uncommon neoplasm and sometimes can be problematic to diagnose because it can be easily mistaken for melanoma. We studied the immunohistochemical features of 31 cases of cellular neurothekeomas to evaluate their immunoprofile. Immunohistochemical studies were performed in all 31 cases with formalin-fixed paraffin-embedded tissue sections with antibodies against S100 protein, S100A6, and melanoma antigen recognized by T-cells (MART-1). In addition, 8 cases were evaluated for HMB-45 antigen, keratin (with a pankeratin cocktail), epithelial membrane (EMA), and smooth muscle antigen (SMA). The lesions were from 8 men and 23 women aged 6-64 years (mean 35 years). Four tumors were located on the nose; 4 scalp; 4 finger; 3 thigh; 2 shoulder; 2 wrist; 2 hand; and 1 each on pelvis, cheek, toe, chest, eyebrow, forearm, penis, axilla, mouth, and leg. All tumors were positive for S100A6 (100%) and negative for cytokeratin, HMB-45 antigen, MART-1, and EMA (100%); 29 cases were negative for S100 protein (93.5%; the 2 positive cases had only scattered cells labeled), and only 2 cases were focally positive for SMA (7.5%). Therefore, the combination of strong immunoreactivity for S100A6, in nested dermal spindle cell proliferations, and lack of S100 protein or keratin, supports a diagnosis of cellular neurothekeoma.

Introduction: The term spitzoid melanoma (SM) is reserved for a rare group of tumors with striking resemblance to Spitz nevus, often developing in children diagnosed in retrospect after the development of metastases. Objectives: To determine the biological significance of SM and to analyze the effectiveness of adjuvant diagnostic techniques. Materials and methods: A retrospective, observational study of 38 cases of SM in patients younger than 18 years. Histological type, Clark level and Breslow thickness, radial and vertical growth phase, mitotic count/mm2, ulceration, regression, vascular and perineural invasion, satellitosis, cytology and associated nevi were reviewed. An immunohistochemical analysis with HMB45 and Ki67 was performed in 10 cases. These features were correlated to patient’s stage and outcome. Results: Analysis of histological and immunohistochemical features should allow accurate diagnosis in most cases. Given the low mortality rate, no conclusions about the prognostic significance of histological parameters of the primary tumor could be established. Conclusion: We report the largest series of SM from a unique center. Although these patients may have a better prognosis than adults, some patients with SM develop metastasis and die, particularly after age 11 years. Therefore, we recommend using the same treatments as in adults.

We have previously shown thryotropin-releasing hormone expression in nevi and melanoma. Thryotropin-releasing hormone regulation by leptin has been shown in the hypothalamus. The present study was therefore undertaken to evaluate leptin and leptin receptor in nevi and melanoma. Leptin receptor expression as assessed using an anti-leptin receptor antibody showed uniform expression throughout the lesion in 14 of 17 melanomas; 3 melanomas lacked leptin receptor immunoreactivity. In contrast, out of 15 nevi, 10 showed weak to moderate leptin receptor immunoreactivity, with positivity present only in the superficial dermal component. Thus, maturation was present in nevi but not in melanoma with the anti-leptin receptor antibody (P

Two patients with atypical histologic and immunohistochemical findings in nevi after cryotherapy are reported. Patient 1, a 32-year-old white woman, presented to our cancer center with two changing moles that had been treated with liquid nitrogen therapy by her primary care provider. After cryotherapy, these two lesions showed paradoxical loss of maturation, with aberrant expression of HMB-45 in the dermal component, thereby mimicking melanoma. Although the overall Ki-67 labeling was low, focally there was no diminution in Ki-67 immunoreactivity with descent into the dermis. Patient 2, a 39-year-old white man, had a nevus treated with liquid nitrogen by his primary care physician and presented to us with a changing mole. Histologically, there was loss of maturation and aberrant HMB-45 expression. These features may pose a diagnostic dilemma, and highlight the importance of clinicopathologic correlation in arriving at the correct diagnosis.

PurposeWe and others have demonstrated that additional positive lymph nodes (LNs) are identified in only 8% to 33% of patients with melanoma who have positive sentinel LNs (SLNs) and undergo complete therapeutic LN dissection (cTLND). We sought to determine predictors of additional regional LN involvement in patients with positive SLNs.Patients and MethodsPatients with clinically node-negative melanoma who underwent SLN biopsy (1991 to 2003) and had positive SLNs were identified. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs.ResultsOverall, 359 (16.3%) of the 2,203 patients identified had a positive SLN. Positive non-SLNs were identified in 48 (14.0%) of the 343 patients with positive SLNs who underwent cTLND. On univariate analysis, several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness more than 2 mm, age older than 50 years, and Clark level higher than III were predictive of positive non-SLNs; primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs; tumor thickness more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement.ConclusionIn melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group at low risk for positive non-SLNs and be spared the potential morbidity of a cTLND.

Background Keratoacanthomas, as well as an actinic keratosis progressing to squamous cell cancer, have been reported in patients who were treated with sorafenib, a multikinase inhibitor known to suppress the actions of Raf kinase and vascular endothelial growth factor receptor. Observations We describe a 70-year-old white woman with metastatic renal cell carcinoma who was treated with a combination of sorafenib and tipifarnib (a farnesyltransferase inhibitor). She had no history of skin cancer. However, within 3 months after starting this therapy, she developed 3 erythematous nodules on her legs. Pathologic examination showed deeply invasive, well-differentiated squamous cell carcinomas. The tumors were excised, and sorafenib-tipifarnib treatment was discontinued. No new lesions have developed to date. Conclusions Targeted agents, such as sorafenib and tipifarnib, are increasingly being used in the management of visceral malignant neoplasms. A temporal relationship was observed between the initiation of the targeted treatments and the emergence of these cutaneous cancers. Further study of the mechanisms responsible for the rapid appearance of squamous cell cancers in this setting may provide insights into the pathogenesis of skin tumors.

Appropriate classification of melanocytic lesions in the eyelid region is important to avoid unnecessary surgery. Here we report 3 cases of cellular blue nevi in the lower eyelid, and make recommendations about approaching these challenging lesions. In each case, a diagnosis of cellular blue nevus was made using the following features: low mitotic rate, absence of necrosis, low Ki-67 reactivity, and mostly uniform HMB45 labeling. Furthermore, in each case there was either a prior diagnosis of melanoma or features worrisome for an atypical melanocytic lesion. For melanocytic lesions of the eyelid with histologic features suggestive of cellular blue nevus, the correct diagnosis may mean a more conservative surgical resection and less likelihood of ocular tissue sacrifice and disfigurement.

An 86-year-old white male presented with an erythematous, painless, slowly growing, and firm left thigh nodule. Histologic examination revealed a dermal proliferation of monomorphous cells arranged in trabeculae, nests, and sheets with an infiltrative growth pattern. The cells had a high nuclear-cytoplasmic ratio, finely granular nuclear chromatin, and nuclear molding. Numerous mitotic figures, apoptotic cells, and individual cell necrosis were present; lymphovascular invasion was identified. The tumor was attached, demonstrating pagetoid intraepithelial migration, to a follicular cyst lined by squamous epithelium, lacking a granular cell layer and filled with compact keratinous content, diagnostic of trichilemmal cyst. Immunohistochemical study revealed that tumor cells expressed pan-cytokeratin (CK), chromogranin, synaptophysin, neuron-specific enolase, and CK20 (dotlike staining pattern), thus supporting the diagnosis of Merkel cell carcinoma. The association of Merkel cell carcinoma with a cyst is an exceptionally rare occurrence. As a result of the prominent involvement of the cyst wall by tumor cells, we favor that in this case carcinoma arose in the trichilemmal cyst rather than being a collision tumor. This hypothesis is also supported by the recent observation that Merkel cells are frequently present within normal hair follicles, especially in the isthmic portion that corresponds with the area of origin of the trichilemmal cyst.

A 44-year-old man was referred for a right chest nodule of 3 months duration. A 'benign' nodule had been excised from this location 8 years prior. On examination, palpable nodes were noted in the right axilla. Radiographic studies were significant only for right axillary lymphadenopathy. Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor. Features of a clear cell hidradenoma were noted focally. Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu. Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2. A wide local excision and axillary node dissection was performed. Metastatic tumor involved nine of 28 nodes. Interphase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis. The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic. We believe this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor. In analogy to breast carcinoma, these findings suggest the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.

Purpose: Most studies accept a multistep pathogenic process in melanoma that may include the phases of benign nevi and dysplastic nevi, melanoma, and metastatic melanoma. Dysregulation of cellular proliferation and apoptosis is probably involved in melanoma progression and response to therapy. We have studied the expression of galectin-3, a β-galactoside-binding protein involved in apoptosis, angiogenesis, and cell proliferation, in a large series of melanocytic lesions, and correlated the expression with clinical and histologic features. Experimental Design: Tissue microarray blocks of 94 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic or nuclear expression of galectin-3. Results: Primary and metastatic melanomas expressed galectin-3 at a significantly higher level than nevi in both cytoplasm and nuclei (P < 0.0073). There was a significant association between anatomic source (as indirect indication of level of sun-exposure) and cytoplasmic and nuclear expression. Lymph node and visceral metastases had a higher level of expression than s.c. lesions (P < 0.004). Interestingly, there was an almost significant finding of worse survival in those patients with lesions showing higher levels of cytoplasmic than nuclear galectin-3 expression (log-rank test, P = 0.06). Conclusions: Melanocytes accumulate galectin-3 with tumor progression, particularly in the nucleus. The strong association of cytoplasmic and nuclear expression in lesions of sun-exposed areas suggests an involvement of UV light in activation of galectin-3.