Genomic and Transcriptomic Underpinnings of Melanoma Genesis, Progression, and Metastasis.

Melanoma is a deadly skin cancer with rapidly increasing incidence worldwide. The discovery of the genetic drivers of melanomagenesis in the last decade has led the World Health Organization to reclassify melanoma subtypes by their molecular pathways rather than traditional clinical and histopathologic features. Despite this significant advance, the genomic and transcriptomic drivers of metastatic progression are less well characterized. This review describes the known molecular pathways of cutaneous and uveal melanoma progression, highlights recently identified pathways and mediators of metastasis, and touches on the influence of the tumor microenvironment on metastatic progression and treatment resistance. While targeted therapies and immune checkpoint blockade have significantly aided in the treatment of advanced disease, acquired drug resistance remains an unfortunately common problem, and there is still a great need to identify potential prognostic markers and novel therapeutic targets to aid in such cases.

Hypercellular Encapsulated Neuroma Imitating Desmoplastic Melanoma.

Palisaded encapsulated neuromas (PENs) are benign cutaneous nerve sheath proliferations that typically occur as flesh-colored papules solitarily on the head and neck in adults, with a slight predilection for females. Histopathologically, they are partially or completely encapsulated intradermal nodules with Schwann cells and axons in fascicles separated by clefts. Although these features are often characteristic, the hypercellular variant of PEN can pose a diagnostic challenge in distinguishing between other cellular neural and melanocytic lesions. We herein report a case of hypercellular PEN, which showed striking similarity to desmoplastic melanoma.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy, and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience, and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate" and 52 (25%) "rarely appropriate" and 43 (20%) having "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision to order specific tests rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-the AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Panniculitis in a patient with pathologic complete response to talimogene laherparepvec treatment for recurrent, in-transit melanoma.

Talimogene laherparepvec (T-VEC) is a novel intralesional oncolytic genetically modified herpes simplex virus type 1 vector for the treatment of unresectable cutaneous, subcutaneous, and nodal melanoma. Although immunological therapies such as T-VEC offer therapeutic promise, they carry a risk of immune-related adverse events (irAEs), the full spectrum of which is incompletely understood. We report a 63-year-old previously healthy man with cutaneous melanoma of the right ankle and progressive right lower extremity in-transit metastases despite systemic therapy with immunomodulatory and molecularly targeted treatments. T-VEC treatment resulted in a complete pathologic response on scouting biopsies. Biopsy of the right lateral calf showed lobular and septal panniculitis with lymphoplasmacytic infiltrate and lipophages. Gomori methenamine silver (GMS) stain and acid-fast bacilli (AFB) stains were negative, and no polarizable foreign material was noted. T-VEC was discontinued due to complete pathologic response and, in part, concern for development of irAEs including this panniculitis and an early concomitant autoimmune colitis. This case highlights a previously unreported irAE with this novel treatment for advanced cases of melanoma.

Appropriate use criteria in dermatopathology: Initial recommendations from the American Society of Dermatopathology.

BACKGROUND: Appropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision-making. OBJECTIVES: The American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology. METHODS: The RAND/UCLA appropriateness methodology, which combines evidence-based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology. RESULTS: With the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered "usually appropriate," 52 (25%) "rarely appropriate" and 43 (20%) "uncertain appropriateness." LIMITATIONS: The methodology requires a focus on appropriateness without comparison between tests and irrespective of cost. CONCLUSIONS: The ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness-AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed "uncertain appropriateness" and where consensus was not reached may benefit from further research.

Seborrheic Keratosis With Prominent Clear Cell Changes-A Rare But Important Diagnostic Variant.

Seborrheic keratoses, although exceedingly common, occasionally have morphologic similarities to other lesions that complicate a typically straightforward diagnosis. The authors present a case of a 69-year-old man with a left shoulder lesion that displayed characteristic clinical and microscopic features of seborrheic keratosis on biopsy. However, diffuse and prominent clear cells were also noted. These stained strongly with Periodic acid-Schiff and were diastase sensitive, suggestive of glycogen accumulation and possible trichilemmal differentiation. This case is presented to demonstrate a unique and striking example of clear cell change within a seborrheic keratosis and to briefly review the published literature on this finding, which is rarely reported and demands close examination to exclude more aggressive neoplasms.

Loss of Conventional Melanocytic Markers in Malignant Melanoma and Lymph Node Metastasis; an Uncommon but Dangerous Pitfall.

Although malignant melanomas exhibit a wide range of immunophenotypes, concurrent loss of all 3 conventional melanocytic markers (S-100, Melan-A, and HMB-45) is relatively rare. We report a case of primary malignant melanoma with lymph node metastasis, both exhibiting loss of immunoreactivity for conventional melanocytic markers, while aberrantly expressing epithelial antigenicity (pancytokeratin, CAM 5.2).

Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases.

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

Prior knowledge of the clinical picture does not introduce bias in the histopathologic diagnosis of melanocytic skin lesions.

A common debate among dermatopathologists is that prior knowledge of the clinical picture of melanocytic skin neoplasms may introduce a potential bias in the histopathologic examination. Histologic slides from 99 melanocytic skin neoplasms were circulated among 10 clinical dermatologists, all of them formally trained and board-certified dermatopathologists: 5 dermatopathologists had clinical images available after a 'blind' examination (Group 1); the other 5 had clinical images available before microscopic examination (Group 2). Data from the two groups were compared regarding 'consensus' (a diagnosis in agreement by ≥4 dermatopathologists/group), chance-corrected interobserver agreement (Fleiss' k) and level of diagnostic confidence (LDC: a 1-5 arbitrary scale indicating 'increasing reliability' of any given diagnosis). Compared with Group 1 dermatopathologists, Group 2 achieved a lower number of consensus (84 vs. 90) but a higher k value (0.74 vs. 0.69) and a greater mean LDC value (4.57 vs. 4.32). The same consensus was achieved by the two groups in 81/99 cases. Spitzoid neoplasms were most frequently controversial for both groups. The histopathologic interpretation of melanocytic neoplasms seems to be not biased by the knowledge of the clinical picture before histopathologic examination.

Squamous cell carcinoma with perineural and intraneural invasion associated with hyalinized tumor nodules: a diagnostic pitfall and review of the literature.

Cutaneous squamous cell carcinoma with perineural invasion (PNI) is an important inconspicuous finding. We report a case of a common tumor with an uncommon finding. A 57-year-old white man presented with paresthesias and a new lesion at the site of a previously resected squamous cell carcinoma. At the time of case review, present deep in the dermis, were large hyalinized tumor nodules. These nodules could have easily have been dismissed as sclerotic tumor nodules or fibrotic in-transit metastases. With the clinical history in mind, these nodules were further investigated by immunohistochemistry and reviewed in conjunction with the Mohs frozen section slides. These nodules were subsequently diagnosed as significant peri- and intraneural invasion. This extremely unusual presentation of PNI is a potential diagnostic pitfall that is potentially under-recognized by dermatopathologists but crucial for determining patient management.

Cutaneous epithelioid melanocytic neurofibroma arising in a patient with neurofibromatosis-1.

Tumors expressing both melanocytic and neural features can pose a diagnostic challenge to the dermatopathologist and provoke questions regarding their lineage. We report a case of a tumor arising on the right cheek of a 9-year-old boy with neurofibromatosis type 1 (NF-1). This neoplasm featured nests of non-pigmented epithelioid cells arising within a neurofibroma. The entire tumor stained strongly with S100, whereas the epithelioid population stained with MART-1, HMB-45 and MiTF. The neoplasm shows only scattered Ki-67 positivity. This tumor represents a neurofibroma with portions that have undergone melanocytic differentiation (melanocytic neurofibroma). This exceedingly rare tumor represents a distinct entity from neurotized melanocytic nevi, combined melanocytic nevi or pigmented neurofibromas and provides further evidence that melanocytes arise indirectly from ventromedial neural crest-derived Schwann cell precursors.

Cutaneous angiosarcoma clinically presenting as progressive solid facial edema in a 43-year-old male.

Cutaneous angiosarcoma of the head and neck is a rare, highly malignant neoplasm; prognosis is heavily influenced by tumor size, resectability, and stage at initial diagnosis. Most patients present with one to several erythematous to violaceous patches, plaques, or nodules. However, the clinical presentation is highly variable and leads to delayed diagnosis. We report cutaneous angiosarcoma in a 43-year-old man who presented with an 11-month history of progressive solid (non-pitting) edema involving his entire face, scalp, eyelids, and neck without characteristic clinical features of cutaneous angiosarcoma. A skin biopsy had shown non-specific findings consistent with solid facial edema or rosacea. Various etiologies were considered but there was no significant improvement after directed medical therapy. Repeat skin biopsies revealed angiosarcoma involving the dermis and sub-cutis. Computed tomography (CT) of the chest showed multiple lung nodules bilaterally and a lytic lesion in the T6 vertebra consistent with metastases. He was treated with single agent chemotherapy (paclitaxel), and had a partial response that restored his ability to open both eyes spontaneously; However, his edema has recently progressed 7 months after diagnosis. This is a rare example of cutaneous angiosarcoma presenting as progressive solid facial edema, which underscores the diverse range of clinical manifestations associated with this neoplasm.

p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility.

OBJECTIVES: To determine the clinical utility of p63 expression, which has been identified in several cohorts as a predictor of poorer prognosis in Merkel cell carcinoma (MCC). METHODS: Immunohistochemistry was used to determine p63 expression on MCC tumors from 128 patients. RESULTS: Of the patients, 33% had detectable p63 expression. p63 Positivity was associated with an increased risk of death from MCC (hazard ratio, 2.05; P = .02) in a multivariate Cox regression model considering stage at presentation, age at diagnosis, and sex. Although p63 expression correlated with diminished survival in this largest cohort reported thus far, the effect was weaker than that observed in prior studies. Indeed, within a given stage, p63 status did not predict survival in a clinically or statistically significant manner. CONCLUSIONS: It remains unclear whether this test should be integrated into routine MCC patient management.

Langerhans cell sarcoma in a patient with hairy cell leukemia: common clonal origin indicated by identical immunoglobulin gene rearrangements.

Histiocytic/dendritic cell sarcomas are rare tumors, a few of which have been reported in association with B-cell lymphoma/leukemia. Isolated reports have documented identical immunoglobulin gene rearrangements suggesting a common clonal origin for both the sarcoma and the B-cell neoplasm from individual patients. We report a case of a 75-year-old male with hairy cell leukemia who subsequently developed Langerhans cell sarcoma 1 year after his primary diagnosis of leukemia. The bone marrow biopsy containing hairy cell leukemia and skin biopsies of Langerhans cell sarcoma were evaluated by routine histology, immunohistochemistry, flow cytometric immunophenotyping and PCR-based gene rearrangement studies of the immunoglobulin heavy chain and kappa genes. The hairy cell leukemia showed characteristic morphologic, immunohistochemical and flow cytometric features. The Langerhans cell sarcoma showed pleomorphic cytology, a high mitotic rate and characteristic immunohistochemical staining for Langerin, S100 and CD1a. There was no evidence of B-cell differentiation or a background B-cell infiltrate based on the absence of immunoreactivity with antibodies to multiple B-cell markers. Identical immunoglobulin gene rearrangements were identified in both the hairy cell leukemia and Langerhans cell sarcoma specimens. Despite the phenotypic dissimilarity of the two neoplasms, identical immunoglobulin gene rearrangements indicate a common origin.

Analysis of Tp53 codon 72 polymorphisms, Tp53 mutations, and HPV infection in cutaneous squamous cell carcinomas.

BACKGROUND: Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas. METHODS: We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism). RESULTS: We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R. CONCLUSIONS: These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.

Plexiform melanocytic schwannoma: a mimic of melanoma.

We present a unique dermal tumor for which we propose the term plexiform melanocytic schwanomma. The proliferation consisted of lobules of epithelioid and spindled cells with S100, Melan-A and HMB-45 positivity but without obvious melanin pigmentation. The nuclei were moderately pleomorphic in some areas, and in a few areas the mitotic index was elevated. Schwannian differentiation was inferred from the presence of areas with nuclear palisading resembling Verocay bodies, from plexiform architecture and from the presence of a thin rim of EMA positivity around the tumor. Array-based comparative genomic hybridization showed genomic losses that overlap with those seen in sporadic schwanomma. The differential diagnosis included melanoma, melanotic schwannoma and cutaneous melanocytoneuroma, and we compare and contrast our case with these entities.