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.

Adequacy of cytology and small biopsy samples obtained with rapid onsite evaluation (ROSE) for predictive biomarker testing in non-small cell lung cancer.

Complete biomarker workup of non-small cell lung cancer (NSCLC) specimens is essential for appropriate and timely clinical management decisions. This can be challenging to achieve from small cytology and histology specimens, with increasing numbers of molecular and immunohistochemical biomarkers required. We conducted a 5 year retrospective audit of cases at our institution to assess the diagnostic and biomarker testing adequacy rates, particularly those specimens obtained with rapid onsite evaluation (ROSE), performed by a cytopathologist and a cytology scientist or pathology trainee, including all endobronchial ultrasound guided transbronchial needle aspirations (EBUS-TBNA), CT guided lung fine needle aspirations (FNA) and CT guided lung core biopsies. A total of 5,354 cases were identified, of which 92.2% had sufficient material for diagnosis. Of the 1506 cases identified with a recorded diagnosis of lung adenocarcinoma or NSCLC, not otherwise specified, 1001 (66.5%) had biomarker testing requested. Sufficient material was available in 89.5% of cases for a complete biomarker workup which included EGFR and KRAS mutational testing (all cases), ALK, ROS1 and PD-L1 immunohistochemistry (all cases), and ALK and ROS1 FISH (as required). For EGFR and KRAS mutational testing across both cytology and histology specimens, 99% of cases were sufficient. Of the samples in which a complete biomarker workup was unable to be performed, approximately half were only insufficient due to inadequate numbers of tumour cells for PD-L1 immunohistochemistry. Excluding PD-L1 IHC, 952 (95.1%) of samples obtained with ROSE were sufficient for the remainder of the testing requirements. Next generation sequencing using a 33 gene custom AmpliSeq panel was achieved in up to 72% of cases. In conclusion, small cytology and histology specimens obtained with ROSE are suitable for predictive biomarker testing in NSCLC, although attention needs to be paid to obtaining sufficient cells (>100) for PD-L1 immunohistochemistry.

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.

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.

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.

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.

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.

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.

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.

Detection of Low-level EGFR c.2369 C > T (p.Thr790Met) Resistance Mutation in Pre-treatment Non-small Cell Lung Carcinomas Harboring Activating EGFR Mutations and Correlation with Clinical Outcomes.

Increasing evidence points to the presence of low-level de novo T790M mutations in patients with non-small cell lung carcinoma (NSCLC) harboring activating EGFR mutations. We utilized digital PCR (dPCR), a highly sensitive gene mutation detection method, to detect pre-treatment T790M mutations in NSCLC tumor samples and correlated the T790M status with clinical features and patient outcomes. DNA extracted from pre-treatment NSCLC tumor tissue with known activating EGFR mutations, diagnosed between October 2010 and May 2017 at PathWest laboratory, was used to perform targeted dPCR for quantitative detection of T790M mutations. T790M was detected in 42 of 109 pre-treatment samples (38.5%). Median variant allele frequency was 0.14% (range 0.02-28.5%). Overall response rate to first generation EGFR tyrosine kinase inhibitors (TKI) was 67% regardless of T790M status. The median progression free survival was 10.7 (IQR 5.6-19.9) versus 6.7 (IQR 3.5-20.8) months in T790M negative and positive patients respectively. T790M positivity correlated with increased rate of early disease progression. It also correlated with increased mortality (HR 3.1 95%CI 1.2-8.1, p = 0.022) in patients who did not respond to TKI treatment. We detected a significant rate of low-level pre-treatment T790M mutations in NSCLC using highly sensitive dPCR. Low-level pre-treatment T790M did not impact treatment response rate or overall survival, but was associated with increased rate of early progression on TKI therapy.

Large nested melanoma: a clinicopathological, morphometric and cytogenetic study of 12 cases.

A group of melanomas characterised by predominant growth as large nests within the epidermis has been described. These cases present a diagnostic challenge, as many traditional architectural criteria for the recognition of melanoma are absent. We report the clinical, histological, immunohistochemical, morphometric and cytogenetic features of a series of 12 cases of large nested melanoma. In this series, large nested melanoma accounted for 0.2% of cases of melanoma. The majority occurred on the trunk of middle aged patients with absent or minimal solar elastosis and 42% were associated with a component of benign intradermal melanocytic naevus, speaking to classification of these melanomas as falling within the spectrum of lesions developing in skin with low cumulative sun damage. In 67% of cases invasive melanoma was present. Criteria such as asymmetry, variation in nest size and intraepidermal nests with an underlying rim of junctional keratinocytes appear to be highly specific, and are strongly predictive of typical cytogenetic abnormalities of melanoma, which were identified in 92% of cases. Conversely, in addition to features which are definitionally absent or limited, features such as solar elastosis and cytological atypia do not appear to be particularly helpful in recognition of this variant.