Cutaneous Malignant Melanoma With Rhabdomyosarcomatous Dedifferentiation: an Immunohistological and Molecular Case Study With Literature Review.

ABSTRACT: Cutaneous malignant melanoma can show a wide range of cytomorphological variability, in particular exhibiting a rhabdoid appearance is not uncommon in melanoma cells; however, the phenomenon of "dedifferentiation" with loss of melanocytic immunohistochemical properties and expression of skeletal muscle immunomarkers is exceedingly rare. Owing to the rarity of such melanomas, their clinicopathological features and molecular profile remain largely unknown. In this report, we describe the clinical, immunomorphological, and molecular features of melanomas with rhabdomyosarcomatous dedifferentiation by presenting a new case and exploring the literature for the previously reported cases.

Metastatic Melanoma to a Neurofibroma.

ABSTRACT: We present an extraordinary case of metastatic cutaneous melanoma to a pre-existing neurofibroma in a 75-year-old man with a history of primary invasive melanoma in an anatomically close vicinity. Histological examination of the metastatic melanoma showed a well-circumscribed intradermal nodule of frankly malignant epithelioid melanocytes without an intraepidermal component, surrounded and sharply demarcated from a diffuse spindle cell proliferation with morphological features of a neurofibroma. The spindle cell component showed bland cytologic features, with no mitotic activity or lymphocytic inflammation and no features of malignancy. By immunohistochemistry, both components expressed S100, while HMB45 positivity and complete loss of p16 were only observed in the epithelioid cells. The morphologically distinct areas were analyzed by fluorescent in situ hybridization, which demonstrated an abnormal profile (gain of RREB1 and homozygous loss of CDKN2A) in the epithelioid nodule; however, no abnormalities were detected in the spindle cell component. Next-generation sequencing showed somatic NRAS and PTEN mutations in the melanoma cells only. The overall molecular findings supported the immunomorphological diagnosis of metastatic melanoma within a neurofibroma over the potential differential diagnosis of melanoma with a neurofibroma-like spindle/desmoplastic component.

An Atypical Deep Penetrating Nevus With Mutations in Beta Catenin , BRAFV600E , and IDH1R132C in an 8-Year-Old Boy.

ABSTRACT: Deep penetrating nevus (DPN) is a pigmented melanocytic tumor which typically displays a wedge-shaped deep penetrating architecture. Some cases show a coexisting component resembling conventional melanocytic nevus. These morphological attributes are correlated with the acquisition of genomic alterations in the Wnt pathway on a background of underlying activating MAPK pathway mutations. Lesions with features of DPN, but displaying expansile architecture, sheet-like arrangement of cells, cytological atypia, and/or more than rare mitotic activity have been described as "atypical deep penetrating nevus" or "deep penetrating melanocytoma." The molecular correlates of these atypical morphological features are not well-established. In this case report, we describe a tumor in an 8-year-old boy with histological features of atypical DPN showing somatic BRAFV600E , beta catenin , and IDH1R132C mutations. The combination of abnormalities in MAPK and Wnt pathways with IDH1 mutations seems to be a reproducible feature in a subset of atypical DPNs. Whether this "three-hit" combination is associated with a significant risk of adverse outcome remains to be established.

Merkel Cell Carcinosarcoma With a Bland Sarcomatous Component.

ABSTRACT: Merkel cell carcinoma with a sarcomatous component is very rare, with only 12 cases reported in the literature, often with overtly malignant myoid differentiation. We report a case of metastatic Merkel cell carcinosarcoma presenting in a lymph node 6 months after a diagnosis of cutaneous Merkel cell carcinoma with conventional histologic features. The metastatic lesion showed a unique biphasic appearance with admixed populations of neuroendocrine epithelial cells and fascicles of mitotically active spindle cells with mild cytological atypia. In addition to the immunomorphological features, a common molecular profile between the epithelial and mesenchymal components further supported the notion of carcinosarcoma in this case. To the best of our knowledge, a bland sarcomatous component has not been previously described in Merkel cell carcinosarcoma, which can be easily overlooked as a reactive stromal reaction microscopically.

Primary orbital melanoma arising in an atypical diffuse (plaque-like) blue naevus/melanocytosis: a case report and review of literature.

BACKGROUND: Primary orbital melanoma is a rare disease and can occasionally develop from a pre-existing neoplasm of the blue naevus family of melanocytic lesions. CASE PRESENTATION: Herein we report a rare case of primary orbital melanoma arising from an unusual atypical diffuse (plaque-like) blue naevus/melanocytosis. A 27 year old man presented with mild pain and swelling of the left eye. Magnetic Resonance Imaging revealed a left lateral episcleral orbital mass and an incisional biopsy confirmed the diagnosis of malignant melanoma. Skin-sparing total left orbital exenteration was performed. Histopathological examination of the exenteration specimen revealed a primary orbital melanoma arising in a pre-existing blue naevus like melanocytosis. We demonstrate the evidence for histological progression, characterise the molecular profile of this tumour and discuss the related literature. CONCLUSIONS: This case emphasises the importance of a meticulous clinicopathological correlation in recognising such a tumour as a primary orbital melanoma rather than a metastasis, which is managed differently.

Spitz Melanoma of Childhood With A Novel Promoter Hijacking Anaplastic Lymphoma Kinase (C2orf42-ALK) Rearrangement.

ABSTRACT: We present the case of a prepubescent man of African descent who developed a spitzoid melanocytic proliferation showing evidence of a novel promoter hijacking ALK-C2orf42 rearrangement, with atypical histology, clinically apparent metastatic disease, and abnormal cytogenetic findings, representing a rare genuine case of "Spitz melanoma of childhood." As our understanding of the distinct molecular biology of different tumors traditionally grouped as spitzoid melanocytic lesions evolves, it is becoming increasingly apparent that this group encompasses morphologically and genetically distinct entities. Accurate classification with detailed molecular analysis and prolonged clinical follow-up is essential to allow meaningful conclusions regarding prognostication and prediction of response to therapy.

Mitotically Active Nevus and Nevoid Melanoma: A Clinicopathological and Molecular Study.

ABSTRACT: The distinction between nevoid melanoma and a mitotically active nevus can be challenging at the microscopic level. In this study, we performed cytogenetic testing on a cohort of 25 mitotically active melanocytic proliferations resembling common melanocytic nevus from 25 patients. Based on cytogenetic findings, the lesions were classified as "nevoid melanoma" (n = 13) or "mitotically active nevus" (n = 12). Subsequently, we compared the clinicopathological features between these 2 groups. Nevoid melanomas occurred in older patients (P = 0.007); however, there were no significant differences in gender, size, or anatomical distribution between the 2 groups. Histologically, deep/marginal mitoses (P = 0.006), lack of maturation with depth (P = 0.036), and pseudo-maturation (P = 0.006) were significantly more common in nevoid melanomas. Immunohistochemically, complete loss of p16 was an important divisive feature (P = 0.0004), seen in 70% of nevoid melanomas, and highly correlated with loss of CDKN2A gene (chromosome 9p21). Our findings suggest that such reproducible immunomorphological differences can be of value in distinguishing nevoid melanoma from mitotically active nevus. Nevoid melanomas demonstrated a spectrum of chromosomal aberrations similar to those seen in common subtypes of melanoma, which can serve as a powerful adjunct diagnostic tool in morphologically challenging lesions.

Correlation of FISH and PRAME Immunohistochemistry in Ambiguous Superficial Cutaneous Melanocytic Proliferations.

ABSTRACT: Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated repressor of retinoic acid signaling which is expressed in melanoma and has emerged as a potential biomarker for malignant behavior in melanocytic neoplasms. Although ancillary molecular techniques such as fluorescence in situ hybridization (FISH) are established techniques in the diagnosis of problematic cutaneous melanocytic proliferations, they are expensive, time-consuming, and require appropriate infrastructure, which places them out of reach of some laboratories. The advent of readily available commercial antibodies to PRAME has the potential to provide a more accessible alternative. The aim of this study was to determine whether immunohistochemistry for PRAME could serve as a surrogate for FISH analysis in a subgroup of challenging superficial melanocytic proliferations. Cases which had previously been submitted for FISH analysis were stained for PRAME and interpreted by a panel of at least 3 dermatopathologists is a blinded fashion. Of a study set of 55 cases, 42 (76%) showed a pattern of PRAME immunostaining which was concordant with the cytogenetic interpretation, with an unweighted kappa of 0.42 (representing mild-to-moderate agreement). Thus, although there was a correlation between positive immunohistochemistry for PRAME and abnormal findings on FISH analysis, in our view, the concordance was not sufficient to enable PRAME immunohistochemistry to act as a surrogate for FISH testing. Our findings reiterate the principle that interpretation of problematic superficial melanocytic proliferations requires a synthesis of all the available data, including clinical scenario, morphological features, immunohistochemistry, and ancillary molecular investigations.

Eczematous graft-vs-host disease: A report of three cases and review of the literature.

Graft-vs-host disease (GVHD) is the most common complication following hematopoietic cell transplantation, which affects skin frequently. Acute and chronic forms of GVHD manifest commonly as maculopapular to morbilliform eruptions and sclerotic or lichen-planus-like lesions, respectively; however, atypical presentations such as eczema-like GVHD may occur at times. We describe three cases of GVHD with diverse and polymorphous cutaneous eruptions including pompholyx-like and vasculitis-like rash as well as erythematous plaques and papulosquamous eruptions, with skin biopsy showing unifying histopathological findings with concurrent changes of spongiotic dermatitis and vacuolar interface reaction with apoptotic keratinocytes. In addition, the clinical and pathological features of previously reported cases of eczema-like GVHD are reviewed. It is emphasized that the course of the disease can be variable and successful management often involves a combination of multiple therapeutic modalities including immunosuppression with or without ultraviolet therapy. These cases highlight the importance of meticulous clinicopathological correlation with careful exclusion of mimicking conditions to arrive at the correct diagnosis.

Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein-1 (BAP1)-deficient cutaneous tumors are common in patients with BAP1 tumor predisposition syndrome, frequently presenting before other associated neoplasms, and can serve as an early marker to identify individuals with this disease. The typical lesions are dermal based and composed of a combination of larger epithelioid melanocytes with abundant glassy cytoplasm and smaller cells resembling those of a conventional nevus. There is often a component of interspersed lymphocytes. However, BAP1-deficient melanocytic tumors can show a spectrum of histologic appearances, ranging from lesions with pure epithelioid, pure conventional nevus, or rhabdoid cells and tumors with an intraepidermal component. To demonstrate such morphologic variation, we present a case of a 50-year-old woman with multiple histologically diverse BAP1-deficient melanocytic tumors and germline BAP1 mutation, identified after a diagnosis of pleural mesothelioma. We also discuss the pathogenesis and potential histopathological and clinical indications of germline versus sporadic etiology in the assessment of BAP1-deficient melanocytic tumors.

Programmed death ligand-1 expression in non-small cell lung cancer in a Western Australian population and correlation with clinicopathologic features.

Immune checkpoint inhibition is an important therapeutic option in patients with non-small cell lung cancer. Programmed cell death ligand-1 (PD-L1) expression may serve as a predictive marker for anti-PD-1/PD-L1 therapies. The relationship between non-small cell lung cancer PD-L1 expression and clinicopathological characteristics remains unclear and there is no population level Australian data. We report the results of PD-L1 testing in patients with non-small cell lung cancer diagnosed at major Western Australian public hospitals served by a single state Pathology provider. We analyzed PD-L1 expression by immunohistochemistry in 241 non-small cell lung cancer specimens using the 22C3 clone on a Dako autostainer platform. Tumor cell PD-L1 expression was scored as Tumor Proportion Score and categorized using pre-specified subsets of 1%, 1-49% and ≥ 50% for correlation with clinicopathologic features. PD-L1 Tumor Proportion Score was 1% in 65 (27%) cases, 1-49% in 100 (41%) cases and ≥ 50% in 76 (32%) cases. PD-L1-positive rate was 92% in squamous cell carcinomas and 67% in adenocarcinomas. PD-L1 Tumor Proportion Score was higher in squamous cell carcinomas (p = 0.004) and lower in adenocarcinomas (p = 0.003). Of the 196 non-squamous carcinomas, 35% had rat sarcoma viral oncogene homolog (RAS) mutations, 13% had epidermal growth factor receptor (EGFR) mutations, 2% had anaplastic lymphoma kinase (ALK) translocations and 2% had ROS1 translocations. Tumor Proportion Score ≥ 50% was seen in 34% (23/68), 28% (7/25) and 25% (1/4) of RAS, EGFR mutant, and ALK translocated carcinomas, respectively. There was no significant correlation between PD-L1 expression and molecular or genetic abnormalities, or other parameters including age, gender, stage, and smoking status. In our patient cohort, PD-L1 Tumor Proportion Score was significantly higher in squamous cell carcinomas and lower in adenocarcinomas. The overall prevalence of Tumor Proportion Score ≥ 50% is consistent with that reported in clinical trials.

Polypoid Compound Melanocytic Proliferations: A Clinicopathological Study.

Nevi can show a polypoid appearance both clinically and histologically. Anecdotally, polypoid compound melanocytic nevus may exhibit a spectrum of junctional architectural and cytologic atypia, at times creating a diagnostic challenge by mimicking the radial growth phase of melanoma. To investigate this issue, we prospectively reviewed 40 polypoid compound melanocytic proliferations without overt malignant features. The lesions frequently occurred in young female patients and were predominantly from the trunk and intertriginous areas. Commonly observed atypical features included asymmetry (30%), shouldering (47.5%), poor circumscription (37.5%), and deep extension of melanocytes along the adnexal structures (67.5%). Severe cytologic junctional atypia (22.5%), dermal mitoses (10%), and pagetoid spread of melanocytes (5%) were less commonly seen. All lesions showed a reassuring dermal component with negligible cytologic atypia and maturation with depth. Overall, 7 lesions could not be readily classified as benign nevus; 5 of these in which a benign diagnosis was strongly favored were classified as atypical polypoid compound melanocytic nevi, whereas 2 lesions with diffuse severe junctional cytologic atypia and dermal mitoses were classified as ambiguous melanocytic proliferations. Atypical/ambiguous lesions were significantly larger and predominantly located in the axilla and groin. On molecular studies, none of the lesions tested showed the molecular profile of melanoma. We confirmed that polypoid compound melanocytic nevus can exhibit a variable degree of junctional atypia, likely related to frequent episodes of trauma and regeneration resulting in melanocytic proliferation. Pathologists should be aware of this phenomenon to avoid overdiagnosis.

Dysplastic/Clark naevus in the era of molecular pathology.

Dysplastic naevus has been a controversial entity since its first description by Clark in 1978. Despite a recent paradigm shift from the initially proposed notion that dysplastic naevus is a precursor to melanoma, its management has been increasingly more aggressive in the last decade. The latter is due to an unresolved uncertainty regarding its biological nature which necessitates further clarification. Recent molecular genetics, epigenetic and transcriptomic discoveries have revealed that a subset of dysplastic naevi exhibits a genomic profile which is intermediate between that of benign naevus and melanoma. This group of lesions often shows somatic mutations in non-V600E BRAF, NRAS and TERT and hemizygous deletion of CDKN2A gene as well as upregulation of genes involved in proliferation, cell adhesion and migration, and epidermal and follicular keratinocyte-related genes. These new genomic insights suggest that a proportion of dysplastic naevi have a greater propensity to evolve to melanoma; however, the clinical and histopathological features of this proposed intermediate category are still to be elucidated by further research.

Pathological Sampling of Basal Cell Carcinoma Re-excision Specimens: How Much is Enough?

Basal cell carcinoma (BCC) is the most common cutaneous malignancy, comprising approximately 75%-80% of all skin cancers. Surgical excision is the most common first line treatment modality, with the intent of obtaining clear margins. If the initial excision is incomplete or inadequate, a re-excision will often be performed in an attempt to achieve histological clearance. The pathological examination of these specimens requires a balance between the need for adequate assessment and efficient use of laboratory resources. In this study, we sought to systematically compare different approaches to the pathological sampling of these specimens in the hope of providing an evidential basis for a rational approach. Seventy-four BCC re-excision specimens were entirely sampled and retrospectively examined to determine the rate of detection of residual BCC which would have been achieved using different sampling methodologies. Residual BCC was identified in 37 specimens (50%). Limited transverse sections through the centre of the ellipse resulted in a sensitivity for detection of residual BCC of 78% (or 85% if only "significant" residual tumor is considered). By including the entire scar or the remainder of the specimen except the polar pieces, the sensitivity improved to 95% and 97%, respectively. Only one case showed residual tumor in the apical sections alone, with tumor extending to the new surgical margin in that case. We hope that this data may help laboratories develop sampling protocols appropriate to their own cost-benefit analyses and patient populations.

Giant proliferating pilomatricoma; report of a rare entity.

Proliferating pilomatricoma is a benign tumour and a rare variant of pilomatricoma that has the potential for local recurrence if incompletely excised. We report a case of giant proliferating pilomatricoma on the forearm of a 66-year-old woman. This tumour was unusually large and the presence of ulceration and rapid growth raised clinical suspicion of malignancy. The identification of shadow or ghost cells is a good clue to matrical differentiation, which can be confirmed by ß-catenin immunostaining.

Bowen disease is not synonymous with intraepidermal squamous cell carcinoma.

The terms 'Bowen disease' and 'intraepidermal squamous cell carcinoma' are sometimes considered synonymous. In this paper we present historical, clinical, histological and molecular evidence that this is incorrect. The term Bowen disease should be reserved for a subset of intraepidermal squamous cell carcinoma with a distinctive and reproducible morphological pattern, described in detail by Bowen in 1912. One other common subset of intraepidermal squamous cell carcinoma represents progression of actinic keratosis. In some cases the separation of these two common patterns of intraepidermal squamous cell carcinoma can be challenging and there are patterns of intraepidermal squamous cell carcinoma which appear to represent other distinct pathways. However, there is emerging biological evidence to support this distinction and reason to suspect that the types of invasive squamous cell carcinoma which arise from these different pathways may show important clinical and biological differences, particularly in the era of targeted and immunomodulatory therapy for advanced disease.