PRAME-negativity in sclerosing nevi with pseudomelanomatous features supports classification as an indolent lesion.

BACKGROUND: Some dysplastic nevi, termed sclerosing nevi with pseudomelanomatous features, may have florid fibroplasia associated with features that cause melanoma to be a prominent consideration in the differential diagnosis. PRAME (PReferentially expressed Antigen in MElanoma) immunohistochemistry (IHC) has been shown to be a useful marker in the distinction of melanoma and nevus. PRAME expression in such sclerosing nevi with pseudomelanomatous features has not been evaluated to our knowledge. METHODS: Thirty-two sclerosing nevi with pseudomelanomatous features were stained with PRAME IHC, with positive labeling defined as staining of >75% of the cytomorphologically atypical lesional cells. RESULTS: All 32 cases had variable cytologic atypia, bridging of elongated rete, fibroplasia, and a vertically oriented trizonal appearance. Some cases (23/32) had centrally located flattening of the rete ridge pattern bilaterally flanked by fibroplasia associated with elongated rete. PRAME labeling was negative (<1% labeling) in 28/32 cases. Four cases, also interpreted as having negative labeling with PRAME, showed only weak nuclear positivity of <50% of the melanocytes within the pseudomelanomatous foci. p16 staining was positive in 28/28 lesions. CONCLUSIONS: Rare sclerosing nevi with pseudomelanomatous features (4/32; ~13%) had weak PRAME labeling of 25%-50% of atypical foci. Twenty-eight of 32 lesions had virtually no labeling with PRAME. PRAME results support classifying sclerosing nevi with pseudomelanomatous features as indolent lesions.

Acute Epstein-Barr virus infection resembling cutaneous T-cell lymphoma.

Primary, acute Epstein-Barr virus (EBV) infection is associated with a variety of cutaneous eruptions, including the viral exanthem of infectious mononucleosis and erythema multiforme. Latent, chronic EBV infection can rarely result in development of lymphoproliferative disorders with cutaneous manifestations; however, these disorders do not arise from primary infection. In this report, we present a case of primary, acute EBV infection presenting with histopathologic features closely mimicking aggressive cytotoxic cutaneous T-cell lymphoma.

More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations.

BACKGROUND: Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. OBJECTIVE: We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. METHODS: We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. RESULTS: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. LIMITATIONS: This clinical review was retrospective. CONCLUSION: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy.

BACKGROUND: Bullous disorders associated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established. OBJECTIVE: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy. METHODS: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018. RESULTS: We identified 9 of 853 patients who developed bullous eruptions (∼1%) that were treated with an-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression. LIMITATIONS: This was a retrospective study from a single tertiary care center. CONCLUSIONS: Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents.

Squamous proliferations on the legs of women: Qualitative examination of histopathology, TP53 sequencing, and implications for diagnosis in a series of 30 cases.

BACKGROUND: Women with multiple squamous cell carcinomas (SCCs) of the legs have a striking clinical phenotype. Numerous tumors can develop in a short period of time. OBJECTIVE: Because histopathologic findings can vary in women with multiple SCC lesions, from keratoacanthoma-like to well-differentiated SCC, we hypothesized that TP53 variants might shed light on the appropriate classification. METHODS: We sequenced TP53 in 30 SCCs from 6 women who had multiple SCCs on their legs during a 21-month time frame. RESULTS: Histopathologic analysis showed 16 of the 30 lesions did not have prominent cytologic atypia and were distinguished by having expanded follicle-like structures composed of large, glassy, eosinophilic keratinocytes; these lesions resembled keratoacanthoma and were categorized as keratoacanthoma-like squamous proliferations (KASPs). The 14 remaining tumors had more prominent cytologic atypia and remained classified as SCC. Twenty of 30 tumors (including the KASPs) from the 6 different patients lacked detectable TP53 mutations. Ten of the 14 tumors that remained classified as SCC had detectable TP53 mutations. LIMITATIONS: This is a small series. CONCLUSION: These findings suggest that some cutaneous squamous proliferations on the legs of women with multiple lesions lack prominent cytologic atypia as well as TP53 mutations and might be more akin to keratoacanthoma than SCC or might represent a reactive phenomenon.

Congenital nevi versus metastatic melanoma in a newborn to a mother with malignant melanoma - diagnosis supported by sex chromosome analysis and Imaging Mass Spectrometry.

A 37-year-old pregnant woman presented with a 2-cm irregular reddish nodule on her left upper arm during pregnancy. A biopsy from the lesion showed a 2.2-mm thick malignant melanoma with intravascular invasion, 25 mitosis/mm(2) and no ulceration. Following induction of labor, the patient underwent re-excision with sentinel lymph node biopsy. This showed no residual melanoma and no lymph node metastasis. The newborn boy had multiple pigmented lesions on the trunk, some of which were large and irregular. Two were biopsied and histologic examination showed dense dermal proliferation of medium sized melanocytes with multiple mitotic figures and no maturation with their descent into the dermis, raising suspicion of transplacental metastases. Examination of the placenta failed to show metastatic lesions. Multiplex polymerase chain reaction (PCR)-based genotyping, including testing for amelogenin locus for sex chromosome determination, demonstrated the presence of Y chromosome material in the melanocytes of the newborn's lesions excluding maternal origin. A diagnosis of congenital nevi was rendered. Subsequently, Imaging Mass Spectrometric analysis of the mother's lesion showed proteomic signature expression indicative of malignant melanoma, whereas the two lesions in the newborn showed changes indicative of nevi. This case demonstrates the utility of genotyping and Mass Spectrometry analysis in this challenging clinical scenario.

Cytokeratin 20 expression in basaloid follicular hamartoma and infundibulocystic basal cell carcinoma.

BACKGROUND: Tumors with similar or identical histopathologic features have been termed basaloid follicular hamartoma (BFH) or infundibulocystic basal cell carcinoma (BCC). BCC typically lacks immunoreactivity with cytokeratin 20 (CK20) and pleckstrin homology-like domain, family A, member 1 protein (PHLDA1). AIM: A series of BFH and infundibulocystic BCC were investigated to determine the pattern of CK20 and PHLDA1 labeling in these lesions. MATERIALS AND METHODS: Thirty-six samples of BFH (n = 14) and infundibulocystic BCC (n = 22) were collected. CK20 and PHLDA1 staining was performed and evaluated. RESULTS: All the lesions were small (average of 3 mm), well circumscribed, and composed of basaloid to squamoid cells arranged in islands resembling ramifying rootlets with interspersed horn cysts. CK20-positive cells were present in all 36 cases (average, 22/mm(2)), throughout the tumor, including deeper portions, irrespective of original diagnosis. Six of thirty cases (20%; 5 infundibulocystic BCC, 1 BFH) were focally PHLDA1 positive. CONCLUSIONS: Findings on hematoxylin and eosin staining and those of CK20 staining in BFH and infundibulocystic BCC were similar, and in most cases were indistinguishable. The CK20 labeling was similar to that of trichoepithelioma. The findings add a degree of support to the argument that BFH and infundibulocystic BCC represent the same lesion and, further, a benign one.

p40 is a more specific marker than p63 for cutaneous poorly differentiated squamous cell carcinoma.

BACKGROUND: Poorly differentiated squamous cell carcinoma (SCC) of the skin may pose a diagnostic challenge for pathologists. p40 is a recently introduced antibody that recognizes specific p63 protein isoforms and has shown superior results labeling non-cutaneous SCC. We hypothesize that p40 may improve diagnostic accuracy of poorly differentiated SCC. METHODS: Twelve cases of poorly differentiated SCC were stained with p63, p40 and cytokeratin MNF116. Control cases included nine atypical fibroxanthoma (AFX), five cutaneous leiomyosarcoma (LMS) and three giant cell tumors of soft tissue (GCTST). RESULTS: All 12 cases labeled with p63 and p40 and 11/12 were positive with MNF116. Whereas p40 labeled fewer cells, it showed exclusive nuclear staining, with no staining of cytoplasm or of background cells, in contrast to p63. Six of nine AFX and 2 of 3 GCTST showed scattered nuclear staining with p63 but were negative with p40. Additionally, one LMS showed focal staining with MNF116 but was negative with p40. CONCLUSION: For the diagnosis of cutaneous poorly differentiated SCC, p40 appears equally sensitive to MNF116 and p63. While labeling fewer cells, p40 labels without confounding staining of tumor cytoplasm or background cells. More importantly, p40 appears to be more specific for SCC than p63 and MNF116, each of which occasionally labels non-squamous tumors.

Cognitive bias in pathology, as exemplified in dermatopathology.

Cognitive bias refers to human thinking patterns, as well as pitfalls, that are reproducible. Importantly, cognitive bias is not intentionally discriminatory and is necessary to properly interpret the world around us, including microscopic slides. Thus, it is a useful exercise to examine cognitive bias in pathology, as exemplified in dermatopathology.

The melanoma 'epidemic': lessons from prostate cancer.

The rise in malignant melanoma incidence has been termed "epidemic". Closer scrutiny of epidemiologic data suggests overdiagnosis as the true cause of the dramatic rise in melanoma incidence. In epidemiologic terms, "overdiagnosis" describes lesions that are histologically malignant but biologically benign. Overdiagnosis is not unique to melanoma screening but is prevalent in screening for cancers of other organs, including the thyroid and prostate glands.

An incompletely penetrant novel mutation in COL7A1 causes epidermolysis bullosa pruriginosa and dominant dystrophic epidermolysis bullosa phenotypes in an extended kindred.

Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of dystrophic epidermolysis bullosa (DEB) characterized by intense pruritus, nodular or lichenoid lesions, and violaceous linear scarring, most prominently on the extensor extremities. Remarkably, identical mutations in COL7A1, which encodes an anchoring fibril protein present at the dermal-epidermal junction, can cause both DEB and EBP with either autosomal dominant or recessive inheritance. We present one family with both dystrophic and pruriginosa phenotypes of epidermolysis bullosa. The proband is a 19-year-old Caucasian woman who initially presented in childhood with lichenoid papules affecting her extensor limbs and intense pruritus consistent with EBP. Her maternal grandmother saw a dermatologist for similar skin lesions that developed without any known triggers at age 47 and mostly resolved spontaneously after approximately 10 years. The proband's younger brother developed a small crop of pruritic papules on his elbows, dorsal hands, knees, and ankles at age 13. Her second cousin once removed, however, reported a mild blistering disease without pruritus consistent with DEB. Genetic sequencing of the kindred revealed a single dominant novel intron 47 splice site donor G>A mutation, c.4668 + 1 G>A, which we predict leads to exon skipping. Incomplete penetrance is confirmed in her clinically unaffected mother, who carries the same dominant mutation. The wide diversity of clinical phenotypes with one underlying genotype demonstrates that COL7A1 mutations are incompletely penetrant and strongly suggests that other genetic and environmental factors influence clinical presentation.

"Clark/dysplastic" nevi with florid fibroplasia associated with pseudomelanomatous features.

BACKGROUND: Melanocytic nevi may exhibit histologic features in common with cutaneous melanoma, creating diagnostic difficulties. OBJECTIVE: We sought to assess the clinical behavior of melanocytic nevi with pseudomelanomatous features in association with dermal fibrosis. METHODS: Forty-two melanocytic nevi with pronounced fibrosis and associated pseudomelanomatous changes were collected and studied clinically and histologically. RESULTS: The fibrosis was centrally located and laminated in appearance. It imparted a trizonal appearance: a junctional component with prominent single cells and/or irregular nests, underlying fibrosis, and a mature dermal component. No recurrence or metastases were evident over an average follow-up period of 2 years. LIMITATIONS: The follow-up period was short. CONCLUSIONS: The central location and laminated appearance of the fibrosis suggest that this may represent the extreme end of a spectrum of fibroplastic changes in "Clark/dysplastic" nevi. Adjacent features of "Clark/dysplastic" nevi and limitation of pseudomelanomatous features to the perifibrotic focus are important in accurately identifying these lesions. Although melanocytic nevi with exaggerated fibroplasia may show foci with melanoma-like features, they do not appear to exhibit aggressive clinical behavior.

The melanoma 'epidemic', a dermatopathologist's perspective.

Over the past several decades, the rise in melanoma incidence has been termed "epidemic." However, detailed analysis of mortality data suggests that the true incidence of melanoma has not increased dramatically. Dermatopathologists, who hold a key position in the diagnosis of melanoma, should have unique insight into this quandary. Factors contributing to the apparent melanoma epidemic likely include intense screening, sampling of earlier lesions, medical-legal pressures, imperfect diagnostic methodology, and lack of a usable gold standard. Consequences of the apparent melanoma epidemic are also explored herein.

Quantitative comparison of MiTF, Melan-A, HMB-45 and Mel-5 in solar lentigines and melanoma in situ.

BACKGROUND: It is often challenging to reliably assess the number of lesional melanocytes in intraepidermal melanocytic proliferations involving sun-damaged skin. Therefore, dermatopathologists routinely use immunostains to help differentiate melanocytes from surrounding keratinocytes. METHODS: Forty-three cases of solar lentigo or melanoma in situ (of the lentigo maligna type) were retrospectively chosen (20 melanomas in situ and 23 solar lentigo). Microphthalmia transcription factor (MiTF), HMB-45, Melan-A and Mel-5 immunostains were performed with an Azure blue counterstain, and the mean melanocyte counts were calculated within a 1-mm segment of epidermis. RESULTS: In solar lentigines, the mean melanocyte counts were 27 (MiTF), 23 (HMB-45 and Mel-5) and 41 (Melan-A), as compared to hematoxylin and eosin (H&E) (25). In melanoma in situ, the mean melanocyte counts were 112 (MiTF), 149 (Melan-A), 111 (HMB-45) and 80 (Mel-5), as compared to H&E (109). CONCLUSIONS: These results show that Melan-A significantly overestimates the density of melanocytes within dermatoheliotic skin. Compared to other tested stains, nuclear staining MiTF allowed greater distinction of melanocytes from keratinocytes with melanized cytoplasm. These findings indicate that MiTF is a superior marker for quantification of melanocytes in the evaluation of subtle intraepidermal melanocytic proliferations and in the differential diagnosis of solar lentigo.

Cutaneous Involvement in Plasma Cell Myeloma.

OBJECTIVES: Plasma cell myeloma (PCM) involving skin is rare and occurs in 1% to 4% of patients with PCM. We evaluated the clinicopathologic features, cytogenetic findings and clinical follow-up in a series of PCM cases with cutaneous involvement. METHODS: Cases of PCM with cutaneous involvement were retrospectively reviewed with clinical data. RESULTS: Skin involvement in PCM occurred in older individuals (mean, 75 years) and was more frequent in men (7/10 patients). All cases showed bone marrow involvement preceding the cutaneous lesions. Histopathologically, the infiltrate was plasmacytic (n = 5) or primitive or plasmablastic (n = 4), and 1 case showed predominantly lymphoplasmacytic features with cyclin D1 immunoreactivity and CCND1 gene rearrangement. Concurrent amyloid deposition was seen in one biopsy, and another case demonstrated coexisting squamous cell carcinoma. The most common immunophenotype was CD138+, CD20-, and CD56+ with light chain restriction. Cytogenetic analysis (available for 7 cases) showed multiple hyperdiploid abnormalities. Follow-up was available for 8 cases (mean, 42 months; range, 11-156 months) and showed short-term disease-related death in 7 of 8 patients. CONCLUSIONS: Cutaneous involvement in PCM demonstrates a diverse cytomorphologic spectrum with plasmacytic, plasmablastic, or lymphoplasmacytic features and may show concurrent amyloid deposition or neoplasms such as squamous cell carcinoma. Cutaneous involvement typically occurs late in the course of the disease and likely portends poor outcome.

Mohs micrographic surgery histopathology concordance.

BACKGROUND: The low recurrence rate and tissue-sparing benefit associated with Mohs micrographic surgery (MMS) requires accurate interpretation of frozen sections by the MMS surgeon. OBJECTIVE: We sought to assess concordance between dermatopathologists and MMS surgeons when reporting cutaneous malignancy in the MMS setting. METHODS: This study is a retrospective analysis of 1156 slides submitted during 10 years as part of a pre-existing randomized, blinded, quality assurance protocol. Slides were read by one of 5 dermatopathologists and represent cases from 3 MMS surgeons and 5 MMS fellows. Agreement or disagreement was recorded. RESULTS: Of the 1156 slides, 32 slides (2.8%) were disparate. Aside from differences regarding intraepidermal neoplasia, the concordance rate was 99.7%. LIMITATIONS: This study represents data collected at a single institution in the United States alone. CONCLUSION: There was statistically significant concordance between MMS surgeons and dermatopathologists in frozen section interpretation in the MMS setting. Discordance was primarily related to the interpretation of in situ malignancy.

Melanocytic nevi with features of Spitz nevi and Clark's/dysplastic nevi ("Spark's" nevi).

BACKGROUND: Nevi with cytologic characteristics of Spitz nevus and architectural features of Clark's/dysplastic nevus are not well recognized in the literature. METHODS: Twenty-seven nevi with characteristics of Spitz nevus and Clark's/dysplastic nevus are reviewed. RESULTS: The patients' mean age was 33 years, and 17/27(63%) patients were female. Lesions were most frequent on the trunk and lower extremities. Histopathologically, these nevi were composed of large, monomorphous spindled and/or epithelioid melanocytes. Spindle cells were often oriented parallel to the epidermis, with fused rete and lamellar fibroplasias. Lateral extension of the junctional component was a feature of compound lesions. An average of 10 years of clinical follow up in 12 patients revealed no recurrence or metastasis. CONCLUSIONS: Recognition of this type of nevus is important to avoid confusion with malignant melanoma.

Promontory sign--present in patch and plaque stage of angiosarcoma!

Kaposi sarcoma is characterized by a proliferation of irregular jagged vascular channels, which partly surround preexisting blood vessels in some areas. This characteristic appearance of a small vessel protruding into an abnormal vascular space has been termed "promontory sign". Cutaneous angiosarcoma (AS) is a malignant vascular neoplasm comprised of a meshwork of anastomosing irregular dilated vessels between collagen bundles and around skin appendages, lined by atypical endothelial cells. The presence of promontory sign has not been described as a histologic finding in AS. We retrieved all cases of cutaneous AS from the files of Yale Dermatopathology Laboratory between 1990 and 2007. Sixty-six biopsies from 15 patients (7 men and 8 women) were reviewed. The lesions were divided histologically in a patch, plaque, or tumor stage according to the depth of invasion of malignant cells. Forty of the 66 biopsies were from a patch or plaque stage of AS. The remaining 26 biopsies were from tumor stage of AS. In 13 of 40 biopsies (32.5%) of patch and plaque lesions of AS, promontory sign was identified, seen primarily in the upper reticular dermis. These biopsies were taken from 11 patients (6 men and 5 women), ranging in age from 36 to 86 years (median 69). Promontory sign was not found in any of the 26 biopsies of tumor stage AS. The presence of promontory sign has not been emphasized in lesions other than Kaposi sarcoma, but seems to be a feature that is not uncommon in patch/plaque stage AS.

Squamous cell carcinomas with single cell infiltration: a potential diagnostic pitfall and the utility of MNF116 and p63.

Numerous variants of squamous cell carcinoma (SCC) have been described. We recently encountered four examples of SCC composed primarily of single, atypical cells that were cytokeratin (CK) MNF116-positive and p63-positive. One case was particularly difficult to diagnose as the single cells were obscured by a dense inflammatory infiltrate. We have also noted similar single cell infiltration toward the periphery of four additional cases of more typical SCC. These foci resemble the single tumor cells that may infiltrate at the borders of spindle cell and desmoplastic SCCs. CK MNF116 and p63 were useful in identifying each of these neoplasms. This single--cell pattern of SCC can easily be misdiagnosed, and CK MNF116 and/or p63 are diagnostically helpful in recognizing it.