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The immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and the programmed death protein 1 (PD-1)/PD-L1 pathway have recently shown promising therapeutic results in patients with metastatic melanoma. Dermatologic side effects of these agents occur in ∼30-40% of cases. Here, we report the development of a biclonal cutaneous T-cell lymphoproliferative disorder in a patient being treated with ipilimumab (a CTLA-4 inhibitor) for metastatic melanoma. Nivolumab (a PD-1 inhibitor) had also been administered to him previously. An 8 mm reddish papule appeared on the skin of the left forearm. A biopsy of that lesion showed an atypical population of predominantly CD4-positive, CD30-positive T-cells that also expressed PD-1 and PD-L1 immunohistochemically. PCR studies for T-cell receptor rearrangements showed the presence of two distinct clonal T-cell populations. The lesion was completely excised and the patient had no local recurrences. There was also no subsequent evidence of a systemic lymphoproliferative process. Although the development of a lymphoid skin lesion in our patient may have only been coincidentally related to his treatment, immunostimulatory drugs could theoretically cause clonal expansion of a population of lymphocytes that leads to a lymphoproliferative disorder.

Intranodal spindle cell lesions on biopsy are problematic for a surgical pathologist, often requiring an extensive immunohistochemical evaluation with variable and frequently unsatisfactory results. In the absence of a history of malignancy, the differential diagnosis of a spindle cell tumor must include both a primary nodal proliferation and a metastatic process. Particularly challenging are those lesions that share morphologic and immunohistochemical features; spindle cell melanomas (SCM) and interdigitating dendritic cell sarcomas (IDCS) belong to this category. At present, electron microscopy is the only method proposed to distinguish between the 2 entities; however, this method is often unavailable and impractical. In this study, we assessed the comparative immunophenotypes of 18 cases of SCM and 8 cases of IDCS, with particular emphasis on the expression of MUM-1, β-catenin, SOX-10, MiTF, and p75. Our results showed nearly equivalent staining patterns and profiles; 12% and 17% of IDCS and SCM were labeled for MUM-1, 75% and 83% stained for β-catenin, 0% and 24% expressed MiTF, and 100% and 94% labeled for p75, respectively. All cases of IDCS and SCM displayed strong nuclear reactivity for SOX-10. On the basis of our study and pertinent literature, the morphologic and immmunophenotypic features of SCM and IDCS appear to be virtually indistinguishable from one another, raising the question as to whether these 2 entities represent a pathobiologically similar or even identical process.

Metastatic melanoma (MM) has the potential to involve virtually any anatomical site, and it also has a wide spectrum of histological appearances. General clinicopathologic data pertaining to MM are presented in this review, together with a discussion of its differential diagnosis and therapy. "Biological" agents used in the treatment of melanoma are considered, along with the pathological features of the complications that they may cause., (Copyright © 2016. Published by Elsevier Inc.)

Melanoma of the skin is the fifth leading new cancer diagnosis, having accounted for almost 77,000 cases and more than 9000 deaths in the United States in 2013. Although cutaneous neoplasms of this type are relatively common, their mucosal counterparts are not. Mucosal melanomas comprise approximately 1.3% of all melanocytic malignancies. Although they are rare, these lesions present at an advanced stage with more adverse prognoses. In addition, at a molecular level, they have proven to be distinct entities because they possess genetic mutations not usually seen in their cutaneous counterparts. Conversely, a sizable proportion of mucosal melanomas lack the gene aberrations seen in cutaneous melanomas. Such findings indicate different pathways in tumorigenesis for the two subtypes. Because melanomas arising from the mucosae are not often encountered, very little has been published on staging guidelines and prognostic factors. This causes dilemmas for both patients and physicians. Further work is necessary to define staging systems for all mucosal locations, so that accurate prognoses can be assigned to such lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cutaneous melanoma continues to increase in frequency, for unknown reasons, and it can pose considerable diagnostic challenges to clinician and pathologists alike. This review considers current concepts pertaining to that tumor, including those concerning epidemiology, clinical diagnosis, histologic findings, adjunctive diagnostic studies, and prognosis., (Copyright © 2016. Published by Elsevier Inc.)

As cutaneous melanomas manifest a wide spectrum of clinical and pathologic presentations, several other lesions enter into their differential diagnosis. This article considers those entities, including melanocytic hyperplasia, cellular nodules in congenital nevi, atypical lentiginous melanocytic proliferations, "special site" nevi, epithelioid histiocytoma, neurothekeoma, cellular schwannoma, and proliferating scars., (Copyright © 2016. Published by Elsevier Inc.)

Distinction between radial growth phase (RGP) and vertical growth phase (VGP) in cutaneous melanomas is prognostically significant. Despite established morphological criteria, molecular markers to separate RGP and VGP have not been well established. The goal of this study was to investigate associations of p16, WT1, and Fli-1 with RGP-to-VGP progression, by immunohistochemistry. The p16 is a tumor suppressor, whereas WT1 and Fli-1 are transcriptional activators. The authors hypothesized that entry into VGP would be associated with decreased p16 and increased WT1 and Fli-1. Paraffin sections from 18 RGP and 15 VGP melanomas were immunostained with well-characterized antibodies to p16, WT1, and Fli-1. Melanoma growth phases were determined using precodified morphological attributes. In RGP melanomas, p16 was expressed in 15 of 18 (83%), WT1 in 17 of 17 (100%), and Fli-1 at least focally in 6 of 18 (33%). The deep dermal component of VGP melanomas stained positively for Fli-1 in 9 of 14 (64%), strongly for WT1 in 10 of 14 (71%), and strongly for p16 in only 2 of 15 (13%). Observed patterns of WT1 immunopositivity did not support the authors' hypothesis; it is not likely to be a good indicator of VGP. On the other hand, Fli-1 staining trended toward more positive deep tumor compartment staining and p16 to weaker staining in the deep compartment. At present, application of histological criteria remains the best method for assignment of growth phase in melanomas; however, p16 and possibly Fli-1 immunostains may serve as useful adjuncts in morphologically indeterminate cases.

Melanocytic nevus rests in lymph nodes are a known diagnostic challenge, especially in patients with a history of melanoma. Reticulin and NM23 have been studied in this context. The pattern of reticulin staining in melanomas surrounds groups/nests of melanocytes but individual cells in benign nevi. NM23, a metastasis-suppressor gene, has an association with metastatic potential in melanomas and some carcinomas. Twenty-eight cases (14 cases of metastatic melanoma to lymph nodes and 14 cases of lymph node nevus rests, all confirmed with Melan-A staining) were stained with reticulin and NM23. The pattern of reticulin staining was reported as surrounding groups if staining was noted in approximately 5-10 melanocytes in greater than 50% of the lesion but was otherwise reported as surrounding individual melanocytes. Cytoplasmic staining was considered to represent reactivity for NM23. Reticulin staining around groups of melanocytes was identified in all 14 cases of metastatic melanoma. Regarding nodal nevus rest cases, 12 of 14 cases (86%) demonstrated staining around individual melanocytes, whereas in 2 cases, reticulin surrounded melanocytic groups. NM23 staining was equivocal in all cases. Reticulin staining reliably invests groups of melanocytes in cases of metastatic melanoma, whereas in nodal nevus rests, it predominantly surrounds individual melanocytes. NM23 demonstrated no discriminatory value in this analysis. In cases in which a collection of melanocytes is present within a lymph node, reticulin deposition around individual melanocytes supports a diagnosis of lymph nodal nevus rest.

Background: Atypical fibroxanthoma (AFX) is a pleomorphic spindle cell lesion of the skin; it is considered in the differential diagnosis with spindle cell malignant melanoma (MM) and sarcomatoid carcinoma/spindle cell squamous cell carcinoma (SCC). An optimum approach has yet to fully emerge with respect to the immunohistochemical discrimination of these lesions., Methods: Departmental archives from 1978 onwards were searched for clinicopathologically confirmed cases of AFX, MM and SCC. Immunostains for CD10, CD99 and p63 were performed in each case. Scored staining results were analyzed using Fisher's Exact Test., Results: Twenty-seven of 31 cases of AFX were positive for CD10, as compared with 3 of 22 SCCs and 0 of 20 MMs. CD10 positivity was preferentially associated with the diagnosis of AFX (p < 0.001). p63 reactivity was observed in 15/22 cases of SCCs, 5/31 AFXs and 1/20 MMs. CD99 reactivity was observed in 3/31 cases of AFX, 2/22 SCCs and 3/20 MMs., Conclusion: CD10 positivity is relatively specific in this context for the diagnosis of AFX. Its utility is enhanced when only strong, diffuse membranocytoplasmic staining is considered as a positive result. In contrast to prior reports, p63 was not found to be highly sensitive for SCC. Similarly, CD99 showed no preferential staining of any single diagnostic group of lesions.

The mucosal surfaces represent the third most common site of origin for melanoma, after the skin and ocular uveal tract. However, anorectal mucosal melanoma is a rare neoplasm, usually occurring in the sixth and seventh decades of life. It may often be confused clinically with other pathologic entities, such as prolapsed rectal polyps and hemorrhoids. The prognosis of anorectal melanoma is poor; this is at least in part attributable to the relatively large size that such tumors have frequently achieved at presentation, as well as their rich vascular network. In particular, anorectal melanoma in children and adolescents is extraordinarily uncommon. The authors herein report 2 examples of that tumor in 11-year-old and 19-year-old patients; one was alive and tumor-free after 6 years, whereas the other died with osseous and hepatic metastasis at the same time point. The authors emphasize the need for differential diagnostic inclusion of melanocytic malignancies when considering anorectal masses in pediatric individuals. Systematic collation and evaluation of pediatric melanomas of the anus and rectum are needed, to better define the biologic attributes of those neoplasms., (Copyright 2010. Published by Elsevier Inc.)

The histopathologic distinction between pigmented actinic keratosis (PAK) and atypical junctional melanocytic proliferations (AJMP) is a common problem, and it is one with meaningful clinical significance. Previous publications have suggested that Melanocyte Antigen Related to T-cells-1 (MART-1)--a melanocytic marker related to host immune response--was not useful in making this interpretative separation. To revisit that assertion, the authors selected 68 specimens that concerned the diagnosis of PAK vs. AJMP. The degree of morphologic difficulty attached to each case was rated semiquantitatively using a three-tiered scale, and interpretative problems were caused by cytologic similarity between atypical keratinocytes and aberrant melanocytes, obscuring lichenoid inflammation, subepidermal fibrosis, and an absence of clearly defined cell nests at the dermoepidermal junction. Each biopsy sample was immunostained for MART-1 (using antibody clone A103) with azure-B counterstaining; the principal criterion for a diagnosis of AJMP was that of confluent cellular positivity over at least 1 high-power (x400) microscopic field, in conjunction with nested cell growth. The specimens were then re-examined diagnostically. Immunostaining definitely improved interpretative certitude in 65 examples (96% effectiveness); the final diagnosis was that of PAK for 21 lesions and AJMP for 47. Three specimens--all of which represented AJMP--did not benefit by MART-1 staining. It is concluded that MART-1 immunostaining with azure-B counterstaining is a useful adjunct in the interpretation of problematic intra-epidermal pigmented lesions.

Context: Selected cutaneous neoplasms share features with benign counterparts or have subtle morphologic features that could be overlooked by the pathologist., Objective: To present clues to the diagnosis of potentially deceptive malignancies, including desmoplastic malignant melanoma, nevoid malignant melanoma, subcutaneous lymphoma, metastatic breast carcinoma, and epithelioid sarcoma., Data Sources: Published literature and personal experience., Conclusions: Knowledge of commonly misdiagnosed cutaneous neoplasms will help the general surgical pathologist avoid these potential pitfalls in neoplastic dermatopathology.

Cutaneous melanocytic proliferations are diverse morphologically, and their behavioral attributes may be difficult to discern with certainty. As a consequence, diagnostic anatomic pathologists regularly encounter problems in the interpretation of such lesions. This review considers several selected issues in that subject area, including proliferative congenital nevi, architecturally disordered (dysplastic) nevi, morphologic variants of Spitz nevus, atypical lentiginous melanocytic proliferations, nevoid melanoma, diagnostically deceptive histologic variants of melanoma, "epidermotropic" metastases of melanoma, and the relationship of melanoma microstages to tumor growth phases.

Through careful clinicopathologic correlation, we identified 37 metastatic melanomas in the skin, all of which had intraepidermal components. These were compared with 43 microscopically similar primary melanomas with a predetermined panel of immunostains in general use in surgical pathology, including bcl-2 protein, mutant p53 protein, Ki-67 (MIB-1), proliferating cell nuclear antigen (PCNA), alpha-isoform actin, and CD117 (c-kit protein). There was no significant difference in bcl-2 or alpha-isoform actin staining patterns of primary vs secondary cutaneous melanomas. The expression of Ki-67 generally was higher in metastatic melanomas than in primary lesions, and the same was true of mutant p53 protein labeling; however, some overlap was observed. CD117 staining was retained in 65% of metastatic melanomas (24/37) when they originated from ocular primary tumors; nevertheless, that marker was lost in virtually all of the other metastatic melanocytic neoplasms, whereas primary melanomas demonstrated consistent reactivity for c-kit protein. Although they are not definitive, these trends in immunoreactivity could facilitate the process of distinguishing the multiple primary melanoma syndrome from melanomatous metastases to the skin. That undertaking is best approached with circumspection, because clinicopathologic discriminators for this diagnostic separation are still imperfect.

Ki-67 labeling of paraffin sections has been correlated with the number of cells in non-G(o) phases of the replicative cell cycle, and this immunohistochemical technique has been applied to the evaluation of a variety of human neoplasms. Similarly, immunolabeling for p53 protein has been used to detect mutations in the corresponding gene, as a reflection of possible cellular transformation in the same context. Both of these techniques were applied to 253 melanocytic tumors of the skin to assess their possible utility in the diagnosis and subcategorization of such lesions. They included 76 banal (common) nevi (CN), 39 Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth (SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in radial growth (LMMs), and 23 melanomas arising in association with preexisting compound nevi (MCN). One hundred cells were counted randomly in each tumor, and dark, exclusively nuclear reactivity was scored as positive labeling; results were recorded as percentages. Negligible Ki-67 and p53 labeling was seen in CN and SN, at a level that was similar to that obtained in cases of LMM and MCN. The largest proportion of Ki-67-positive and p53-positive cells was observed in NMMs, followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles that were similar to those of melanocytic nevi, and MCN did so as well. The prototypical malignant melanocytic tumor representing the vertical growth phase-nodular melanoma--demonstrated a statistically significant difference from all other lesions in this study with respect to Ki-67 index (P = .008, chi2) and p53 reactivity (P < .000001, chi2). Subsequent concurrent use of a Ki-67 threshold index of 10% and a p53 index of 5% correctly indicated the presence of vertical growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other types were colabeled at the same levels of reactivity for the two markers (P < .00001, chi2). Thus, although the distinction between benign and malignant melanocytic tumors could and should not be based on immunohistology for Ki-67 and p53, these results suggest that the latter determinants may, in fact, be used as an adjunct to morphology in the recognition of the vertical growth phase in cutaneous malignant melanomas.

The authors propose the addition of malignant melanoma to the list of extrarenal neoplasms that may be predominantly composed of polygonal cells with the cytologic features of "rhabdoid" tumor. A review of 313 metastatic melanomas disclosed 49 examples with rhabdoid features, from which 31 had sufficient material for further pathologic and immunohistologic characterization. A control group of 46 nonrhabdoid metastatic melanomas was examined in parallel fashion. In 39% of cases, rhabdoid melanomas manifested relative deletion of S100 protein compared with the control tumors. However, there were no differences in staining with HMB-45. Vimentin immunoreactivity was concentrated in the paranuclear cytoplasm of rhabdoid melanoma cells. However, ultrastructural studies of these cases failed to show corresponding whorls of intermediate filaments and instead demonstrated paracrystalline paranuclear inclusions in profiles of rough endoplasmic reticulum. It is concluded that metastatic rhabdoid melanoma exhibits significant morphologic similarity to other rhabdoid tumors at a light-microscopic level. However, it usually retains enough melanocytic attributes to allow for accurate diagnostic recognition. Probably because patients with metastatic melanoma have an extremely poor prognosis overall, no worsening of biologic behavior was associated with rhabdoid cytomorphologic findings in this tumor type when compared with the control cases.

Cutaneous sarcomas and sarcoma-like lesions pose special problems for pathologists. These lesions manifest a great deal of clinical and histological overlap, and they may be virtually impossible to separate from one another on conventional microscopy. Spindle-cell squamous carcinoma (SCSC), sarcomatoid malignant melanoma (SCMM), and fibrohistiocytic tumors, such as "atypical fibroxanthoma" (AFX) and superficial malignant fibrous histiocytoma (SMFH), comprise the group of neoplasms in this category that pose the greatest diagnostic difficulty. All may or may not show attachments between dermal tumor cells and the overlying epidermis; all may be composed of varying proportions of fusiform and pleomorphic cells; and all may demonstrate the presence of "divergent" differentiation into bone, cartilage, or myogenous tissues. Electron microscopy and immunohistology usually are required to identify these tumors with certainty. The usefulness in doing so is supported by differing biological behaviors in this context. SCMM shows the greatest tendency for recurrence and metastasis, followed in relative order by SMFH, SCSC, and AFX.

A review was conducted of 335 malignant melanomas to identify variant morphologic patterns that might be confused with other tumors. In all, 27 predominantly amelanotic neoplasms with unusual histologic features were selected for additional study. These included nine with an adenoid or pseudopapillary pattern, seven small cell neoplasms, five with prominent myxoid stroma, four with a hemangiopericytoma-like appearance, and two composed of neoplastic cells with a signet-ring configuration. A diagnosis of melanoma was confirmed in all cases by Fontana-Masson strains for melanin pigment, electron microscopic examination, or the results of immunohistochemical analyses for cytokeratin, vimentin, S-100 protein, and the HMB-45 antigen. One tumor was associated with a congenital hairy melanocytic nevus, five were vulvovaginal lesions, four arose in the sinonasal tract, and one occurred in the rectum. Four of the specified microscopic patterns were observed in both primary and secondary neoplasms; the two signet-ring cell melanomas were recurrent lesions. The authors conclude that malignant melanomas may assume the histologic guise of adenocarcinomas, small cell carcinomas, and sarcomas, in a variety of tissue sites. Special studies designed to detect melanocytic differentiation are therefore appropriate in diverse differential diagnostic settings.

The efficacy of two new monoclonal antibodies with cell lineage-restricted reactivity (HMB-45 [melanocytes] and anti-synaptophysin [neuroepithelial cells]) was compared with that of "traditional" antibody panels in the delineation of malignant melanoma (MM) of the sinonasal region, nasopharyngeal carcinoma (NPC), and olfactory neuroblastoma (ONBL). HMB-45 recognized all of eight melanomas and stained one of five neuroblastomas, but failed to label any of 12 cases of NPC. All examples of ONBL were stained by anti-synaptophysin; other tumors were nonreactive with this reagent. A panel of antibodies to cytokeratin, vimentin, epithelial membrane antigen, and S100 protein was also effective in discriminating between MM, NPC and ONBL. These results suggest that HMB-45 and anti-synaptophysin are comparable in utility to more extended antibody panels in the diagnosis of sinonasal malignancies, but only if used in combination with one another.

This study compares the immunoprofiles of 25 cutaneous and mucosal melanomas with those of 400 poorly differentiated carcinomas, using a polyclonal antiserum to S100 and murine monoclonal antibodies to keratin (KER) and epithelial membrane antigen (EMA). All malignant melanomas expressed S100 but lacked reactivity for KER and EMA. Conversely, all of 49 carcinomas (12%) that displayed S100 also exhibited positivity for both epithelial markers. The latter group of tumors included 17 carcinomas of the breast, 16 eccrine sweat gland carcinomas, five high-grade salivary glandular adenocarcinomas, four lung cancers, three pancreatic ductal carcinomas, two serous ovarian carcinomas, one clear cell adenocarcinoma of the bladder, and one uterine cervical squamous carcinoma. None of 32 epithelial neoplasms that lacked both KER and EMA (19 testicular seminomas, four hepatocellular carcinomas, eight adrenocortical carcinomas, and one Merkel's cell carcinoma) contained S100 protein. These results suggest that S100 protein is relatively nonspecific as a single immunodeterminant in the diagnostic separation of melanoma and anaplastic carcinoma. The concomitant use of stains for EMA and KER, however, obviates this problem. Finally, since it is somewhat restricted in distribution, S100 reactivity in a known carcinoma may be of some use in predicting possible primary sources for a metastasis of unknown origin.

Antibodies to S-100 protein have been used widely as markers of malignant melanoma, despite abundant evidence that they are non-specific for this neoplasm. Hence, alternatives to these reagents are desirable in diagnostic dermatopathology. We evaluated the characteristics of a new monoclonal antibody (HMB-45) which does have putative specificity for melanoma, and compared it with a polyclonal anti-S-100 reagent in immunohistochemical staining of 67 melanomas of the skin and 133 non-melanomatous cutaneous neoplasms. All specimens were formalin-fixed and paraffin-embedded, and were studied with the avidin-biotin-peroxidase complex technique. HMB-45 labelled 62 of 67 melanomas, while anti-S-100 recognized all tumors of this type. On the other hand, S-100 also was expressed by 15 of the non-melanocytic neoplasms, all 133 of which were HMB-45-negative. The only cases of melanoma that were missed by the latter reagent were of the spindle-cell type. Hence, HMB-45 was 100% specific and 93% sensitive, relative to a diagnosis of malignant melanoma in paraffin sections. Epithelioid and small-cell neoplasms are reliably recognized by this antibody, but it would appear that spindle-cell melanomas must be detected by other immunohistochemical means.