Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin.

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

Varied Presentations of Pediatric Lipoblastoma: Case Series and Review of the Literature.

Lipoblastoma is a rare neoplasm of embryonal adipose tissue most often encountered on the trunk and extremities of children. It commonly presents as a painless subcutaneous soft tissue mass, but there are other unique clinical presentations that are important to recognize. The differential is broad and includes sarcoma, vascular tumor, myofibroma, and other fibromatoses. We present three varied, distinct cases of pediatric lipoblastoma and review the literature on this condition.

Atypical Spitzoid Neoplasms in Childhood: A Molecular and Outcome Study.

The natural history of atypical Spitz neoplasms remains poorly understood, resulting in significant patient and clinician anxiety. We sought to better characterize outcomes that correlated with molecular features by performing a prospective cohort study of pediatric atypical spitzoid neoplasms in which fluorescence in situ hybridization studies were obtained for diagnosis. Cases with sufficient tissue underwent additional retrospective assessment for translocations in ALK, NTRK1, BRAF, RET, and ROS1. Among 246 total patients assessed, 13% had a positive fluorescence in situ hybridization result. Follow-up data was available in 85 patients. Two patients had a recurrence of whom 1 had distant metastasis. Both patients had homozygous deletions in 9p21. Homozygous deletions in 9p21 significantly correlated with recurrence of disease (P = 0.027). Fifteen (36%) of 42 cases were found to have a kinase fusion protein. However, the presence of kinase fusions was nonprognostic of recurrence (P > 0.99). This study was limited by the availability and length of follow-up data and the number of adverse outcomes. The majority of atypical spitzoid neoplasms in childhood have indolent behavior. Although the subgroup of patients with homozygous deletions in 9p21 is at higher risk for aggressive clinical behavior, their prognosis seems considerably better than similarly staged conventional melanoma.

A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms.

Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET. Features with the highest discriminatory value included diameter of the lesion, dermal architecture, and certain cytomorphologic features. Specifically, cases with a large diameter (≥9 mm) and wedge-shaped, plexiform dermal architecture of nests of large, spindle-shaped cells were most likely to have an ALK fusion. NTRK1-fused cases were most likely of the fusions to have Kamino bodies and were typically arranged in smaller nests with smaller predominantly spindle-shaped cells, occasionally forming rosettes. BRAF fusion cases were the only fusion subtype to have a predominance of epithelioid cells, were less organized in nests, and commonly had a sheet-like growth pattern or dysplastic Spitz architecture. BRAF fusion cases were most likely to have high-grade nuclear atypia, to be diagnosed as spitzoid melanoma, to have a positive result by melanoma fluorescence in situ hybridization assay, and to develop copy number gains in the kinase domain of the fusion protein. On the basis of experience from this cohort, BRAF-fused cases appear most likely to progress to melanoma.

Primary Cutaneous Mammary Analog Secretory Carcinoma With ETV6-NTRK3 Translocation.

Mammary analog secretory carcinoma (MASC) is a recently described tumor of the salivary glands named for its morphological and molecular similarity to secretory carcinoma of the breast. Many primary carcinomas arising from the adnexal glands also share similar morphology to those arising from the breast. Brandt et al first described primary cutaneous MASC in 2009 and since then only 2 other cases have been reported. Herein, we describe a long-standing mass on the arm of an otherwise healthy 40-year-old female. Histologic examination revealed a circumscribed but unencapsulated, nodular tumor composed of bland epithelial cells arranged in solid and microcystic growth patterns. The cells showed vacuolated cytoplasm and round to oval nuclei with vesicular chromatin. Intraluminal homogenous eosinophilic secretions were present. Mitotic figures were not identified. The tumor cells stained positive for CK8/18, CK7, and S100 but were negative for other markers performed, including estrogen receptor, progesterone receptor, HER2/neu, paired box 8 (PAX8), and thyroid transcription factor 1 (TTF1). As the patient clinically had no other masses or known carcinomas, a diagnosis of primary cutaneous MASC was rendered. The ETV6-NTRK3 fusion transcript was subsequently detected by reverse transcriptase polymerase chain reaction amplification, further supporting the diagnosis. We present this case to review the histologic features of MASC and highlight the importance of recognizing this lesion not only as a possible cutaneous metastasis but also as a primary cutaneous tumor.

CD8+ mycosis fungoides clinically masquerading as alopecia areata.

A 33-year-old female with a 7-year history of CD8-positive hypopigmented mycosis fungoides (MF) involving the trunk and extremities presented with a large well-defined alopecic patch on her frontal scalp. Clinically, this area resembled alopecia areata (AA) and was without hypopigmentation or erythema. A scalp biopsy revealed a non-scarring inflammatory alopecia and a superficial band-like atypical lymphoid infiltrate with prominent epidermotropism. Atypical, predominately CD8-positive lymphocytes were seen surrounding and infiltrating the bulb portion of several hair follicles. Treatments for her MF lesions have included topical bexarotene, topical corticosteroids and phototherapy. Her alopecia has been treated with high potency topical corticosteroids and multiple intralesional triamcinolone injections with very minimal hair regrowth to date. Alopecia due to cutaneous lymphoma is an uncommon phenomenon but can occur in erythrodermic MF or Sezary syndrome. AA-like changes have most often been reported in conventional patch/plaque stage MF and folliculotropic MF. In these cases, the atypical lymphoid infiltrate is comprised predominately of CD4-positive lymphocytes. This is a rare report of a CD8-positive MF causing AA-like changes. This case highlights the importance of a scalp biopsy in patients with a history of cutaneous lymphoma presenting with alopecia in order to evaluate the nature of their hair loss.

Evaluation of dermoscopic features for distinguishing melanoma from special site nevi of the breast.

BACKGROUND: Nevi of special sites display aberrant clinical and histologic features that can be difficult to distinguish from melanoma, leading to unnecessarily high rates of excision with poor cosmetic or functional results. Dermoscopy can improve clinical assessment of melanocytic lesions by visualizing morphologic structures beyond the epidermis. OBJECTIVE: We sought to assess the value of specific dermoscopic features for diagnosing melanocytic neoplasms arising on the breast area in females. METHODS: In this retrospective cohort study, we collected clinical and dermoscopic information for 104 nevi and 13 melanomas removed from the breast, chest, and areola, and evaluated the diagnostic performance of each dermoscopic feature. RESULTS: Melanomas from the breast area were larger (P = .0175) than nevi and occurred in older women (P = .0117). Irregular blotches, nonuniform radial streaks, blue-gray veil, and regression were highly specific for melanoma, whereas atypical network and irregular dots and globules had low to moderate specificity. LIMITATIONS: This study was retrospective with a small sample size. CONCLUSION: Compared to melanocytic neoplasms from other sites, atypical network and irregular dots and globules were poor indicators for breast melanoma. Irregular blotches, nonuniform radial streaks, blue-gray veil, and regression were highly specific and should heighten clinical suspicion for melanoma arising on the breast.

Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi.

Genital melanomas (GM) are the second most common cancer of the female external genitalia and may be confused with atypical genital nevi (AGN), which exhibit atypical histological features but have benign behavior. In this study, we compared the clinical, histological, and molecular features of 19 GM and 25 AGN. We described chromosomal copy number aberrations and the mutational status of 50 oncogenes and tumor suppressor genes in both groups. Our study showed that a pigmented lesion occurring in mucosal tissue, particularly in postmenopausal women, was more likely to be a melanoma than a nevus. GM had high levels of chromosomal instability, with many copy number aberrations. Furthermore, we found a completely nonoverlapping pattern of oncogenic mutations when comparing GM and AGN. In GM, we report somatic mutations in KIT and TP53. Conversely, AGN had frequent BRAF V600E mutations, which were not seen in any of the GM. Our results show that GM and AGN have distinct clinical and molecular changes and that GM have a different mutational pattern compared with AGN.

The utility of dermoscopy-guided histologic sectioning for the diagnosis of melanocytic lesions: A case-control study.

BACKGROUND: Dermoscopy allows for visualization of morphologic structures beyond the epidermis, including features that may indicate early malignant transformation. However, dermoscopic features are rarely considered during routine histologic sectioning, and areas of clinical concern may be missed during microscopic evaluation. OBJECTIVE: We assessed the diagnostic impact of a dermoscopy-guided micropunch score for the evaluation of melanocytic lesions. METHODS: In this case-control study, we evaluated 150 scored melanocytic lesions. Original tissue specimens were reprocessed to create a control group, in which a new score was introduced elsewhere in the lesion to guide an alternative plane of section. Slides were reviewed in a randomized, double-blinded manner to assess histologic features and render a diagnosis. Dermoscopy was also reviewed. RESULTS: The proportion of cases with a higher grade in the original, dermoscopy-guided section was statistically significant. Four invasive melanomas were exclusively identified using the scoring protocol. The presence of regression structures, negative pigment network, radial streaming or pseudopods, and irregular blotches were highly specific for a higher diagnostic grade. LIMITATIONS: This study is retrospective and reprocessing tissue does not perfectly mimic routine sectioning. CONCLUSION: Dermoscopy can identify important, histologically high-grade areas, and this information can be used to optimize the sectioning of melanocytic neoplasms.

A comparative study of proliferative activity and tumor stage of pregnancy-associated melanoma (PAM) and non-PAM in gestational age women.

BACKGROUND: The influence of pregnancy on the development, progression, and prognosis of melanoma is controversial. OBJECTIVE: We sought to compare clinical characteristics, histologic features, and proliferative activity in pregnancy-associated melanoma (PAM) and melanoma in nonpregnant women of reproductive age (non-PAM). METHODS: In this retrospective cohort study, we reviewed medical records and pathology reports from women given a diagnosis of melanoma between 2006 and 2015. We also examined tumor proliferation rates using mitotic count and 2 immunohistochemical markers of proliferation, phosphohistone H3 and Ki-67. RESULTS: In 50 PAM and 122 non-PAM cases, a diagnosis of melanoma in situ was associated with PAM. Among invasive melanomas, there was no difference in proliferative activity between groups. Pregnancy status was also not associated with age at diagnosis, tumor site, Breslow depth, Clark level, ulceration, or overall stage. LIMITATIONS: This was a retrospective study with a small sample size of mostly patients with early-stage melanoma. CONCLUSIONS: In our study of primarily early-stage melanoma, pregnancy did not have a significant impact on tumor proliferation. Particularly for patients given a diagnosis of stage I melanoma who are undergoing close surveillance, a history of PAM should not outweigh traditional factors, such as advanced maternal age, in planning future pregnancies.

Morphologic clues and utility of fluorescence in situ hybridization for the diagnosis of nevoid melanoma.

BACKGROUND: Nevoid melanomas include melanomas with a low power silhouette similar to melanocytic nevi. However, at higher power magnification, nevoid melanoma may have severe nuclear atypia and dermal mitoses. METHODS: We performed a clinical, pathological and molecular study on a series of 58 examples of nevoid melanoma, excluding cases with spitzoid morphology. RESULTS: We identified distinct morphologic patterns: 'classic' nevoid melanoma, superficial spreading melanomas with nevoid invasive melanoma, lentigo maligna with nevoid invasive melanoma and deep penetrating nevus-like nevoid melanoma. Fluorescence in situ hybridization (FISH) was positive in 74% of cases. Copy number gains in 8q24 were common in amelanotic nevoid melanoma. The median follow-up was 28 months (range 140). At last follow-up, 37 patients had no evidence of disease, 3 were alive with metastases and 6 died from metastatic melanoma. Of these six patients who died, four had a sentinel lymph node biopsy (SLNB) performed, which was negative in all four. CONCLUSIONS: We describe distinct clues to the diagnosis of nevoid melanoma including occult intraepidermal atypia, and expansile nesting resulting in asymmetric silhouette or dermal papillae expansion. We also describe that nevoid melanoma have infrequent SLNB involvement in aggressive cases, and have frequent 8q24 gains rather than 9p21 deletions. Our results suggest that nevoid melanoma are distinct from spitzoid melanomas and should be distinguished.

Combined cutaneous tumors with a melanoma component: A clinical, histologic, and molecular study.

BACKGROUND: The histogenesis and clinical behavior of combined cutaneous tumors (CCTs) in which the mesenchymal component consists of melanoma remain unclear. OBJECTIVE: We sought to characterize the clinical, histologic, and molecular findings in CCTs with an epithelial and a melanoma component. METHODS: We retrospectively reviewed the records from 2 institutions for CCTs. Fluorescence in situ hybridization was performed to assess chromosomal copy number alterations in both components. RESULTS: Sixteen CCTs were included. The most common subtype was the squamomelanocytic tumor (11), followed by the basomelanocytic tumor (3) and the trichoblastomelanoma (2). CCTs were more common in men (87%), on the head and neck (57%), and had extensive solar elastosis (81%). The median follow-up was 25 months (range, 8-167 months). One case had an adverse outcome. Fluorescence in situ hybridization revealed chromosomal alterations in approximately 55% of the cases. Five cases showed chromosomal gains only in the melanocytic component. One case showed 11q13 gains in both the epithelial and melanocytic components. LIMITATIONS: Our study is retrospective and the sample is small. CONCLUSIONS: The low incidence of adverse outcomes suggests that CCT may be more indolent than noncombined tumors. 11q13 amplification in both components supports the theory of dual differentiation from a common progenitor cell.

Large cell acanthoma: a variant of solar lentigo with cellular hypertrophy.

BACKGROUND: Large cell acanthoma (LCA) is an epidermal proliferation of enlarged keratinocytes. There is a lack of consensus on whether it represents a unique neoplasm or not. To determine whether it is a variant of solar lentigo, we compared macroscopic, microscopic and immunophenotypic attributes of LCA with conventional solar lentigo, seborrheic keratosis, actinic keratosis and Bowen disease. METHODS: We constructed tissue microarrays containing multiple cores of LCA, solar lentigo, seborrheic keratosis, actinic keratosis and Bowen disease. Tissue microarray sections were blindly analyzed for microscopic morphologic variables. Corresponding ex vivo dermoscopic images from the original cases were blindly analyzed for macroscopic morphologic variables. Immunostained sections from the tissue microarray were tested for keratin 10, keratin 5/6, Bcl-2 and Ki-67 expression by image analysis. RESULTS: There were no significant differences in the studied morphologic attributes between LCA and solar lentigo. All other tumor classes showed at least one significant morphologic difference with LCA. LCA and solar lentigo showed different keratin 10 and Bcl-2 signal intensities. CONCLUSIONS: LCA is best considered a variant of solar lentigo with cellular hypertrophy. The differences in immunophenotype and cell size could be because of differences in cell kinetics.

Progressive nodular histiocytosis with normal karyotypic analysis.

Non-Langerhans cell histiocytoses (NLH) comprise a spectrum of diseases that includes sinus histiocytosis with massive lymphadenopathy, hemophagocytic lymphohistiocytosis, xanthogranuloma, and reticulohistiocytoma. Progressive nodular histiocytosis (PNH) is a rare NLH that microscopically mimics juvenile xanthogranuloma but presents with disseminated persistent and progressive papulonodules in adults. Herein, we describe a case of PNH presenting as diffuse, progressively enlarging papules, nodules, and pedunculated tumors in a 38-year-old male. The diagnosis is supported microscopically by the morphologic and immunohistochemical findings. Whereas conventional cytogenetic analysis of Langerhans cell histiocytosis and juvenile xanthogranuloma has previously been described, there are no reports of the karyotype of PNH. In our patient, conventional cytogenetic analysis of the tumor revealed a normal karyotype. Although these results may represent the overgrowth of normal stromal cells rather than lesional cells, we believe this to be an important finding, indicating karyotypic analysis will not allow for distinction between PCH and other NLH or Langerhans cell histiocytoses.