Cutaneous Seeding of Glioblastoma: A Case Report and Literature Review.

ABSTRACT: We present the case of a 61-year-old male patient with a history of intracranial IDH-wildtype glioblastoma with an isolated cutaneous metastasis within the previous surgical site scar. The cytomorphology of the cutaneous deposits was reminiscent of metastatic melanoma, which is a differential diagnostic pitfall. The tumor molecular characteristics are described, as these have become essential diagnostic criteria for many central nervous system tumors, along with a discussion of the role of immunohistochemical markers and potential pitfalls in the differential diagnosis of melanoma and poorly differentiated carcinoma. We discuss the biology of metastatic glioblastoma and provide a focused literature review of previous glioblastomas with tumor cell seeding within prior surgical scars.

NUT Expression Is of Diagnostic Utility in the Distinction of Digital Papillary Carcinoma From Poroid Hidradenoma.

ABSTRACT: The distinction between digital papillary adenocarcinoma (DPAC) and benign cutaneous adnexal tumors is clinically important and can be challenging. Poroid hidradenoma frequently occurs at acral sites and can show a number of histological features, which overlap with digital papillary adenocarcinoma. Recent work has shown that YAP1-NUTM1 fusions are frequent in poroid hidradenoma and are associated with nuclear protein in testis (NUT) expression by immunohistochemistry. We evaluated the expression of NUT-1 by immunohistochemistry in 4 cases of DPAC and 4 cases of poroid hidradenoma. Three of 4 cases of poroid hidradenoma showed strong NUT-1 expression, with no staining in any of the cases of DPAC. These results suggest that NUT-1 immunohistochemistry may be a useful additional tool in evaluating this differential diagnosis.

Idiopathic Lichenoid and Granulomatous Vulvitis: A Distinct Clinicopathological Entity.

ABSTRACT: The combination of lichenoid and granulomatous inflammation is uncommon in vulval biopsies. We present a series of 5 patients with lichenoid and granulomatous vulvitis, presenting with clinical changes resembling lichen sclerosus. Despite detailed clinicopathological investigation and follow-up, there was no apparent association with an underlying recognized cause. All 5 cases occurred in postmenopausal women and displayed a distinctive histological pattern of superficial band-like inflammation with granulomas "anchored" to the dermoepidermal junction. There was no evidence of deeper granulomatous inflammation. Despite repeated biopsies over 2 years in 2 patients, neither developed typical histological features of lichen sclerosus. We postulate that idiopathic lichenoid and granulomatous vulvitis may represent a distinct clinicopathologically defined vulvar dermatosis.

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.

Skin Biopsy in Pediatric Oncology/Hematopoietic Stem Cell Transplantation Patients.

ABSTRACT: The aim of this study was to review the dermatopathological findings in skin biopsy specimens from pediatric oncology and hematopoietic stem cell transplantation patients over a 20-year period. Three hundred fifty-two skin biopsies from 240 patients were reviewed, and the findings were grouped into 6 categories: index neoplasms, nonindex neoplasms, infections, graft-versus-host disease, other treatment complications, and others. Among the index neoplasms identified on skin biopsy, the most common conditions were Langerhans cell histiocytosis (14 patients) and melanoma (7 patients), with other hematological malignancies and an array of soft-tissue tumors accounting for the bulk of the remainder. Neoplastic conditions common in general dermatopathological practice such as basal cell carcinoma and squamous cell carcinoma were uncommon, each being identified in only 1 patient younger than the age of 18, although basal cell carcinomas developing subsequently in young adult life were identified in 7 patients. Infections were common, with infectious agents or viral cytopathic effects (not including human papillomavirus) identified in 34 biopsies. A significant proportion (74%) represented invasive fungal infections, which are of very significant clinical importance. Biopsies performed for a clinical suspicion of graft-versus-host seldom showed histological features to suggest an alternative diagnosis, with only a single case suggesting a diagnosis of toxic erythema of chemotherapy identified.

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.

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.

Histiocytoid Melanoma.

While most melanomas display well-characterised and readily recognised architectural and cytomorphological features, unusual variants can create diagnostic difficulties. Variants which mimic benign or reactive processes are particularly problematic. We report 5 cases of melanoma characterised by a subtle microscopic appearance reminiscent of a benign dermal histiocytic infiltrate, which we refer to as "histiocytoid melanoma." These lesions are characterised clinically by ill-defined areas of cutaneous pigmentation, which in several cases reached large proportions. Microscopically, there is a subtle interstitial pattern of infiltration by predominantly single cells with a histiocytoid morphology, often resembling melanophages. Immunohistochemical confirmation was typically required, with the cells showing positive labelling for Sox-10 as well as Melan-A. In several examples, the proliferation extended to clinically uninvolved surgical margins, necessitating multiple excisions, and many of our patients have experienced locoregional recurrence. However, none have developed distant metastases or died of melanoma. While uncommon, this subtle variant is important to recognise in order to ensure adequate histological clearance is obtained.

GLI1-amplifications expand the spectrum of soft tissue neoplasms defined by GLI1 gene fusions.

GLI1 fusions involving ACTB, MALAT1, and PTCH1 genes have been recently reported in a subset of malignant soft tissue tumors with characteristic monomorphic nested epithelioid morphology and frequent S100 positivity. However, we encountered a group of morphologically similar soft tissue tumors lacking the canonical GLI1 gene fusions and sought to investigate their genetic abnormalities. A combined approach including RNA sequencing, targeted exome sequencing and FISH methodologies were used to identify potential novel genetic abnormalities. Ten patients (five females, five males) with an age range of 4-65 years (median 32.5) were identified. Tumors were located in the soft tissues of the limbs, trunk and head and neck, with one each in the tongue and lung. Histologically, tumors revealed ovoid to epithelioid cells arranged in a distinctive nested-trabecular pattern, separated by thin septa and a delicate vascular network. Two cases showed areas of increased nuclear pleomorphism and focal fascicular spindle cell growth. Four tumors showed a high mitotic count (≥15/10 HPFs), with necrosis seen in three of them. Lymphovascular invasion was noted in two cases. No consistent immunoprofile was detected, with positivity for CD56 (six cases), S100 (four cases), SMA (two cases), and pan-CK (one case). FISH showed GLI1 (12q13.3) gene amplification in all 10 cases, with co-amplification of CDK4 (12q14.1) in nine (90%) and MDM2 (12q15) in eight (80%) cases. Targeted exome sequencing performed in three cases confirmed the GLI1, CDK4, and MDM2 co-amplification. Only one case showed the presence of both GLI1 break-apart and amplification, although no gene partner was detected. Our findings suggest that GLI1 amplification, often associated with co-amplifications of CDK4 and MDM2 genes, may represent an alternative genetic mechanism of GLI1 oncogenic activation akin to GLI1 fusions, defining the pathogenesis of an emerging group of malignant soft tissue tumors with a distinctive nested growth pattern and variable immunoprofile.

Histological Features of Flagellate Erythema.

Flagellate erythema is a distinctive eruption characterized by "whip-like" linear or curvilinear streaks and plaques, occurring mainly on the trunk. It has classically been described in 2 disparate clinical settings: chemotherapy with bleomycin and ingestion of mushrooms (most commonly Shiitake mushrooms). Most of the literature comprises single case reports, often with minimal histological description of rather nonspecific features. We describe in detail the histological features of 3 cases of flagellate erythema (2 related to bleomycin therapy and one related to ingestion of mushrooms) and review the findings described in the literature to define the spectrum of histological changes encountered in this eruption. Our 3 cases showed mild epidermal changes, with spongiosis and variable interface inflammation. All 3 showed a relatively prominent dermal lymphohistiocytic infiltrate, with features suggestive of a lymphocytic vasculopathy extending to at least the mid-reticular dermis. Eosinophils were a prominent component of the inflammatory infiltrate in 2 cases. Our review of the literature identified a total of 45 publications, representing reports of 46 patients, containing histological information. As well as bleomycin- and mushroom-related cases, similar eruptions have been reported in the context of connective tissue disease and other drugs. Although cases related to connective tissue disease show features of the underlying condition, cases secondary to drugs or mushrooms predominantly show features compatible with common patterns of exanthematous/morbilliform drug reaction. In particular, subtle spongiosis and/or interface dermatitis combined with a dermal lymphocytic infiltrate that includes increased numbers of eosinophils is a common finding. Features of a lymphocytic vasculopathy may be seen in a subset of these cases.

The RCPA Quality Assurance Program in Dermatopathology: A Retrospective Review.

AIMS: To review the Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program Dermatopathology module from 2005 to 2016 to assess diagnostic performance, changes over time, and areas of diagnostic difficulty. METHODS: The computerized records of the RCPA Dermatopathology subspecialist module were reviewed. Cases were categorized into groups including nonneoplastic disorders, neoplasms, and cases with multiple diagnoses. The performance of participants over time in each of these categories and in more specific areas (including melanocytic and adnexal neoplasms) was assessed. Cases which showed high rates of discordant responses were specifically reviewed. RESULTS: One hundred sixteen cases circulated over 10 years were evaluated. The overall concordance rate was 77%, with a major discordance rate of 7%. There was a slightly higher concordance rate for neoplasms compared with nonneoplastic lesions (80% vs. 74%). Specific areas associated with lower concordance rates included classification of adnexal tumors and identification of multiple pathologies. A spindle cell nevus of Reed yielded a 40% discordance rate, with most misclassifications indicating melanoma. CONCLUSIONS: The RCPA quality assurance program module has circulated a wide range of common and uncommon cases to participants over the 12 years studied, highlighting a low but important rate of major discordant responses. Melanocytic lesions, hematolymphoid infiltrates, adnexal tumors, and identification of multiple pathologies are identified as areas worthy of particular attention in quality improvement activities.

Unusual Case of Combined Gliomeningeal Heterotopia on the Nose of an Infant.

Nasal glial heterotopia ("nasal glioma") and cutaneous heterotopic meningeal nodules ("primary cutaneous meningioma") are rare congenital lesions characterized by the presence of heterotopic mature cerebral tissues. Nasal glial heterotopia occurs predominantly in the nasal area and typically does not contain meningothelial elements, whereas heterotopic meningeal nodules occur predominantly on the scalp and do not contain glial elements. In this article, we report an unusual case of cutaneous heterotopia on the nose of an infant composed of both glial and meningothelial elements. The glial component was characterized by irregular islands of predominantly astrocytic cells, on a fibrillary background. The meningothelial component was characterized by bland ovoid cells with focal intranuclear inclusions forming whorled arrangements, with associated psammomatous calcification. To our knowledge, this is the first time such a lesion has been documented. It has also provided us with an opportunity to review the literature regarding heterotopic deposits of both glial and meningothelial tissues.

Pseudomelanomas Following Stevens-Johnson Syndrome.

In this report, we present a novel case of pseudomelanoma, similar to that seen in a recurrent/traumatized nevus, in pre-existing nevi in a 36-year-old man a few months after recovering from an episode of severe Stevens-Johnson syndrome. The mechanism responsible for the atypical transformation of these nevi is likely the release of cytokines and growth factors in the microenvironment during the repair/regeneration process. It is important to be aware of this phenomenon, and specific inquiry about potential recent blistering skin disorder in addition to the other causes of trauma should be made when dealing with cases of pseudomelanoma to avoid misdiagnosis.

Metastatic Cellular Blue Nevus: A Rare Case With Metastasis Beyond Regional Nodes.

In this study, we present a rare case of a 35-year-old man with a long-standing blue-black lesion on his left hand with subsequent infraclavicular and axillary lymph node tumor deposits. The hand lesion and lymph nodes were excised revealing histological, immunohistochemical, and molecular findings consistent with cellular blue nevus. Despite nonregional lymph node involvement, there has been no progression at 12-months follow-up. This is an index case of a cellular blue nevus with metastasis to both regional and nonregional lymph nodes. The lack of atypical/malignant features in this lesion makes the metastatic behavior extraordinary, and hence the prognosis of lesions of this type is indeterminate.

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.

The "Umbrella Sign": A Useful Clue in the Diagnosis of Melanocytic Lesions in Sun Damaged Skin.

As ultraviolet radiation is an important aetiological agent in melanoma development, the presence of solar elastosis is an important factor in the assessment of any melanocytic lesion. However, melanocytic naevi are also seen in chronically sun damaged skin, particularly in regions with high levels of ultraviolet exposure and fair skinned populations. It has previously been noted that the relationship of a melanocytic proliferation to elastic fibers in the dermis can be of discriminatory value in the separation of melanoma from melanocytic naevus, in particular, it has been proposed that naevi act as a "sunscreen," which may result in a histological clue that the authors colloquially refer to in practice as "the umbrella sign." The aim of this study was to evaluate the patterns of solar elastosis within and beneath melanocytic proliferations developing in sun damaged skin and to determine the utility of the "umbrella sign" in diagnostic practice. We assessed 81 melanocytic proliferations in sun damaged skin for the presence of an umbrella sign, that was present in 49/53 melanocytic naevi (92%) compared with only 2/28 melanomas (7%, P < 0.05). In addition, entrapped elastotic fibers displaying distinct purple discolouration were identified in 16 melanocytic naevi. This finding was not identified in any of the melanomas. The umbrella sign appears to be a useful clue in the distinction of melanoma from melanocytic naevus in sun damaged skin, although as with all histological features in melanocytic pathology, it requires interpretation within a multifactorial assessment cognizant of potential diagnostic pitfalls.

Malignant Melanocytic Matricoma: A Report of 2 Cases and Review of the Literature.

BACKGROUND: To describe 2 cases of melanocytic matricoma with malignant histological features and systematically review previously reported cases of malignant melanocytic matricoma. METHODS: Two cases of malignant melanocytic matricoma were identified from the practice of the authors. Additional 3 cases were identified in the literature. The clinical and pathological features of these 5 cases are described. RESULTS: Malignant melanocytic matricoma occurs predominantly in sun-damaged skin of elderly individuals. The tumor is composed of atypical epithelial cells with brisk mitotic activity showing evidence of matrical keratinization and widespread positivity with beta-catenin. There is an admixed cytologically bland dendritic melanocytic component. To date, local recurrence has occurred in one case, but no cases of disseminated disease or death have been reported. CONCLUSIONS: Recognition of this rare tumor and separation from a range of diagnostic mimics is important to ensure adequate treatment by local excision and to allow further cases to be identified to better define the biological potential of this lesion.