Melanoma and Glioblastoma-Not a Serendipitous Association.

Recently, we came across a patient with malignant melanoma and primary glioblastoma. Given this, we parsed the literature to ascertain the relationship, if any, between these 2 malignancies. We begin with a brief overview of melanoma and glioma in isolation followed by a chronologic overview of case reports and epidemiologic studies documenting both neoplasms. This is followed by studies detailing genetic abnormalities common to both malignancies with a view to identifying unifying genetic targets for therapeutic strategies as well as to explore the possibility of a putative association and an inherited cancer susceptibility trait. From a scientific perspective, we believe we have provided evidence favoring an association between melanoma and glioma. Future studies that include documentation of additional cases, as well as a detailed molecular analyses, will lend credence to our hypothesis that the co-occurrence of these 2 conditions is likely not serendipitous.

Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.

Expression of an oncogene in a primary cell can, paradoxically, block proliferation by inducing senescence or apoptosis through pathways that remain to be elucidated. Here we perform genome-wide RNA-interference screening to identify 17 genes required for an activated BRAF oncogene (BRAFV600E) to block proliferation of human primary fibroblasts and melanocytes. Surprisingly, we find a secreted protein, IGFBP7, has a central role in BRAFV600E-mediated senescence and apoptosis. Expression of BRAFV600E in primary cells leads to synthesis and secretion of IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling and induce senescence and apoptosis. Apoptosis results from IGFBP7-mediated upregulation of BNIP3L, a proapoptotic BCL2 family protein. Recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAFV600E-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses growth of BRAFV600E-positive tumors in xenografted mice. Immunohistochemical analysis of human skin, nevi, and melanoma samples implicates loss of IGFBP7 expression as a critical step in melanoma genesis.

Nodular lymphangitis related to methicillin-resistant staphylococcus aureus infection.

Nodular lymphangitis, also known as lymphocutaneous syndrome or sporotrichoid lymphangitis, presents with inflammatory nodules along the lymphatic vessels, typically involving the upper or lower extremities. Although the most common cause of nodular lymphangitis is infection due to Sporothrix schenckii, Nocardia brasiliensis, Mycobacterium marinum, or Leishmania braziliensis, it is important for clinicians to be aware of methicillin-resistant Staphylococcus aureus as a rare cause of nodular lymphangitis and perform gram stain, bacterial culture, and antibiotic sensitivity profiles when appropriate. History of recent travel or exposures, incubation time, presence of systemic symptoms, and presence of ulceration, suppuration, or drainage can serve as diagnostic clues, but microbiological tissue cultures and histopathologic studies confirm the diagnosis. Herein, we present a case of nodular lymphangitis caused by methicillin-resistant Staphylococcus aureus (MRSA); tissue culture and antibiotic sensitivities were used to guide treatment.

Reforms, Errors, and Dermatopathology Malpractice: Then and Now: A Comprehensive Retrospective.

Medical malpractice occurs when a hospital, doctor, or other health care professional, through a negligent act or omission, causes an injury to a patient. The negligence might be the result of errors in diagnosis, treatment, aftercare, or health management. To be considered medical malpractice under the law, the claim must violate the standard of care, the injury must be caused by the negligence and, last but most certainly not least, the injury must result in significant damages. This review is an overview of medicolegal issues specific to the practice of Dermatopathology with the caveat that most are likely pertinent to other specialties of pathology as well. The safety of patients remains the priority in pathology as it does in any medical undertaking, and this is no different in the practice of Dermatopathology. The review is broadly divided in 2 parts-we begin with an overview of tort reforms, advocated by physicians to reduce costs associated with malpractice defense. In the second part we address practical issues specific to the practice of pathology and dermatopathology. These include among others, errors-related to the biopsy type, inadequacy of clinical information regarding the lesion that is biopsied, role of interstate dermatopathology as well as examples of select entities commonly misdiagnosed in dermatopathology. In the last decade, artificial intelligence (AI) has moved to the forefront of technology. While research into the uses of AI in pathology is promising, the use of AI in diagnostic practice is still somewhat uncommon. Given that AI is not fully integrated routinely as a diagnostic adjunct, its' impact on pathology-specific medicolegal issues cannot, as yet at least, be defined. Restriction of medical malpractice is of particular relevance in the COVID-19 era, a period that is anything but normal. The response of states with specific pandemic-related guidelines is addressed with the caveat that this particular issue is only covered in select states. Furthermore, given that the COVID pandemic is only a year old, while it does not appear to have had an immediate impact on pathology-specific medicolegal matters, it is possible that the role of COVID on this issue, if any at all, will and can only be fully defined a few years down the line.

Acantholytic Dyskeratosis Post-COVID Vaccination.

ABSTRACT: Acantholytic dyskeratosis mimicking Grover disease as a cutaneous manifestation of a side effect to the Moderna (mRNA-1273) COVID vaccine is rare with only one documented case in the literature to date. Herein, we present a case of an eruptive, erythematous, vesiculopapular rash developing in a patient after the Moderna vaccine. Histopathology of a representative biopsy [x2, done 8 weeks apart] of the rash revealed similar histopathologic findings of patchy suprabasal acantholysis with dyskeratotic keratinocytes and an underlying inflammatory infiltrate of lymphocytes and neutrophils. Direct immunofluorescence was negative. In contrast to the only case previously reported in the literature, a confounding feature in our case, was that patient had a medical history significant for Grover disease, which had been successfully treated with complete resolution and seemed to be in remission. Given the temporal relationship of the onset of the rash to vaccine administration, the changes were likely vaccine-related with the caveat that, in light of the medical history, the differential diagnosis includes reactivation of Grover disease by the vaccine as a trigger factor.

Total Margin-Controlled Excision is Superior to Standard Excision for Keratinocyte Carcinoma on the Nose: A Veterans Affairs Nested Cohort Study.

BACKGROUND: Keratinocyte carcinoma (KC), including basal and squamous cell carcinoma, is the most common human malignancy. Limited real-world data have compared surgical outcome or cost between total margin-controlled excision (TMCE) and standard excision (SE), the two most common treatments for invasive KC. We compared reconstruction, margin status, and cost between TMCE and SE for KC on the nose at a Veterans Affairs (VA) healthcare system. METHODS: Randomly selected primary KCs on the nose ≤3 cm that were confined to soft tissue, without nerve or lymphovascular invasion, and treated with SE or TMCE between 2000 and 2010, were assessed. Utilization of flap or graft reconstruction and margin status following all surgical attempts were recorded. Costs were based on Current Procedural Terminology codes standardized to 2019 Medicare payments. RESULTS: Overall, 148 cases were included in each treatment group. Baseline characteristics were similar between groups, although SE tumor median diameter was 1 mm larger. SE was associated with increased utilization of flap or graft reconstruction (odds ratio 2.05, 95% confidence interval 1.16-3.59, p = 0.01). Positive margins were present in 24% of SEs initially and remained positive after the final recorded excision in 9% of cases. No positive final margins were noted in TMCE cases. SE cost per tumor was significantly higher than TMCE ($429.03 ± 143.55; p = 0.003). CONCLUSIONS: Surgical management of KC with SE is associated with increased reconstruction complexity, a significant risk of positive margins, and higher cost compared with TMCE. The 23% risk of positive margins supports National Comprehensive Cancer Network guidelines for the treatment of high-risk KC with TMCE, unless delayed reconstruction is employed.

Glioblastoma and malignant melanoma: Serendipitous or anticipated association?

We describe a patient who had primary glioblastoma (GB) and malignant melanoma (MM). A 78-year-old man presented with several weeks to months of history of gait disturbance, confusion, memory disturbance, and worsening speech. Imaging studies performed on admission revealed a large frontotemporal lobe mass associated with the surrounding zone of vasogenic edema. Given the patient's medical history of incomplete biopsy of a midback tumor performed three weeks before, the presumptive clinical diagnosis was metastatic MM. Pathological examination of frozen sections of fragmented specimens obtained at stereotactic biopsy performed on admission revealed a high-grade malignant neoplasm characterized by discohesive cells in a blue myxoid background and abundant foci of tumor necrosis. Given these features, in conjunction with the abovementioned pathological report, the frozen section diagnosis by the neuropathologist was "neoplasm identified, favor melanoma." Due to the paucity of lesional tissue, a limited immunohistochemistry performed on the permanent sections revealed positive staining of lesional cells for Sox10 alone using a multiplex MART1/Sox10 immunostain and S-100 protein, an immunohistochemical profile supporting the presumptive frozen section diagnosis. A tumor debulk procedure, performed two weeks later, revealed histopathologic features most compatible with GB, IDH wild-type. Thus, additional immunohistochemistry on the permanent sections revealed positive staining of glial fibrillary acidic protein (GFAP), Sox10, and S-100 protein as well as negative staining of gp100, a complex carbohydrate matrix protein in embryonic melanosomes, using a specific antibody HMB45. The concomitant occurrence of MM and GB in our patient underscores the association between these two entities. Our literature review suggests that the sporadic co-occurrence of these two conditions is likely not serendipitous.

Differing biologic behaviors of desmoplastic melanoma subtypes: Insights based on histopathologic, immunohistochemical, and genetic analyses.

Desmoplastic melanoma (DM) is an uncommon variant of melanoma that can be challenging to diagnose. Phenotypic variations in terms of the proportion of spindled cells and fibromucinous stroma have led to the subclassification of pure (>90% spindled cells) and mixed (<90% spindled cells admixed with epithelioid cells) histopathologic DM subtypes. This subclassification is not just semantic; several studies have underscored differences in clinical and prognostic behaviors of the subtypes. In this review, we parse the literature on DM subtypes with an emphasis on histopathologic, immunohistochemical, and genetic data to ascertain whether these factors influence and/or affect their differing biological behaviors. Demographics regarding age, location, and clinical behavior of the subtypes are detailed, as is the impact of dermoscopy as a diagnostic adjunct. Despite the plethora of markers used, our findings suggest that few differentiate between the DM subtypes. Differential expression of PD-L1 suggests that patients with the mixed subtype are likely better candidates for anti-PD/PD-L1 therapy. Significant differences between the subtypes in terms of neurofibromin expression and the frequency of TERT promoter mutations suggest that the subtypes have distinct genetic drivers. Thus, immunohistochemical and genetic analyses imply that these likely affect the biological behaviors of the DM subtypes.

Poikilodermatous plaque-like hemangioma: A benign vasoformative entity with reproducible histopathologic and clinical features.

Poikilodermatous plaque-like hemangioma (PPLH) is a recently described benign vasoformative entity with only 16 cases reported to date. We present an additional case of a 90-year-old male who presented with a 2-year history of a relatively large, asymptomatic, atrophic plaque on his left buttock. The lesion was initially smaller and grew before stabilizing in size. The patient denied preceding trauma or injury at this site as well as the presence or history of any similar lesions elsewhere. Physical examination revealed a reniform atrophic pink plaque with peripheral hyperpigmentation and overlying cigarette paper wrinkling. Given this appearance, scar or post-inflammatory changes were favored clinically, but lack of preceding trauma raised clinical concerns for poikilodermatous mycosis fungoides. Given the location and appearance, a broad shave biopsy was performed to rule out mycosis fungoides. Histopathologic examination revealed an increased density of superficial endothelial-cell-lined vessels, telangiectasias with sludging and congestion of superficial dermal vessels and loss of elastic tissue fibers in the lesional area. These findings, in the context of the clinical history, were consistent with this newly described hemangioma. We present this case to increase awareness amongst dermatopathologists of the reproducible clinical and histopathologic findings of this new benign vasoformative entity.

Adherence to the National Comprehensive Cancer Network Criteria of Complete Circumferential Peripheral and Deep Margin Assessment in Treatment of High-Risk Basal and Squamous Cell Carcinoma.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) has established guidelines for the treatment of keratinocyte carcinomas (KCs). Complete circumferential peripheral and deep margin assessment (CCPDMA) is recommended for "high-risk" tumors that cannot be closed primarily. If flap or grafts are needed and CCPDMA was not used, it is recommended that reconstruction be delayed until achieving clear margins. OBJECTIVE: To measure provider utilization rates of the NCCN guidelines for high-risk KCs and assess barriers that are limiting adherence. MATERIALS AND METHODS: A ten-item questionnaire was distributed to NCCN nonmelanoma skin cancer panel members and physicians participating in KC treatment at academic institutions. RESULTS: Response rate was 49% (57/116). Responses were categorized by practice area: Mohs surgery, pathology, and other specialties: General Dermatology, Otolaryngology, Plastic Surgery, Surgical Oncology, Radiation Oncology, and Oral and Maxillofacial Surgery. Mohs surgeons were most likely to use CCPDMA for tumors meeting NCCN criteria with 14/15 using this technique in a majority of their cases, versus 2/6 pathologists and 10/16 specialists from other fields. Reasons cited for not using CCPDMA included deference to pathologists to determine the appropriate method for margin assessment and logistical difficulty. CONCLUSION: Further efforts are needed to increase adherence to NCCN's guidelines regarding CCPDMA in KCs.

SOX-10 and S100 Negative Desmoplastic Melanoma: Apropos a Diagnostically Challenging Case.

An 83-year-old man presented with a tumor of the neck, clinically consistent with an epidermal inclusion cyst. Excisional biopsy revealed a deeply infiltrating spindled cell tumor. Immunohistochemical markers for S100, SOX-10, Melan-A, HMB-45, and NK1/C3 were negative. Based on the presence of an area of lentigo maligna and the histologic pattern of the spindle cell component, a diagnosis of desmoplastic melanoma was made despite the absence of immunophenotypic evidence for melanocytic differentiation. To the best of our knowledge, the complete lack of both S100 and SOX-10 makes this tumor an unprecedented case. To avoid ruling out the diagnosis of desmoplastic melanoma prematurely, physicians should be made aware of this possible immunohistochemical profile.

Immunohistochemistry as a Genetic Surrogate in Dermatopathology: Pearls and Pitfalls.

Immunohistochemistry (IHC) is routinely performed in most laboratories, and other than purchase of commercially available antibodies, requires no additional equipment or reagents. As such, IHC is an accessible and relatively inexpensive test and one that can be performed quite quickly. This is in sharp contrast to genomic or mutational testing methodologies that are routinely "send out" tests as they require specialized equipment and reagents as well as individuals with expertise in the performance of the tests and analysis of the results, resulting in a prolonged turn-round-time and enhanced associated costs. However, many open questions remain in a rapidly changing therapeutic and scientific landscape with most obvious one being what exactly is the utility of "good old fashioned" IHC in the age of targeted therapy? For molecular applications, is a negative immunohistochemical result enough as a stand-alone diagnostic or predictive product? Is a positive immunohistochemical result perhaps more suitable for a role in screening for molecular alterations rather than a definitive testing modality? This review is an attempt to answer those very questions. We elucidate the broad range of entities in which IHC is currently used as a molecular surrogate and underscore pearls and pitfalls associated with each. Special attention is given to entities for which targeted therapies are currently available and to entities in which molecular data is of clinical utility as a prognosticator.

PD-L1 Detection-Pearls and Pitfalls Associated With Current Methodologies Focusing on Entities Relevant to Dermatopathology.

PD-L1 is a transmembrane glycoprotein with an extracellular as well as an intracellular cytoplasmic domain. Physiologically, it plays a pivotal role in regulating T-cell activation and tolerance. Many tumor cells have exploited this regulatory mechanism by overexpressing PD-L1 in an effort to escape immunologic surveillance. In this review, we parse the literature regarding the prognostic value of tumoral PD-L1 expression before discussing the various methodologies as well as the pearls and pitfalls associated with each for predicting response to anti-PD-1/PD-L1 therapies. Special attention is given to cutaneous entities in which PD-L1 expression has been documented with an emphasis on cutaneous malignancies that have seen the broadest applications of anti-PD-L1/PD-1 therapies. Currently, immunohistochemistry is the method that is most commonly used for detection of PD-L1. However, with the wide array of immunohistochemistry protocols and staining platforms available in the market, there seems to be different cutoffs not just for different entities but also for the same entity. This review is an attempt to address the need for standardization and validation of existing protocols for PD-L1 detection.

Necrotizing Granulomas in a Patient With Psoriasis and Sarcoidosis After Adalimumab-Medication-Induced Reaction or Reactivation of Latent Disease?

In this report, we describe a case of a patient with a clinical history of systemic sarcoidosis and psoriasis who developed biopsy-confirmed perforating and necrotizing cutaneous granulomas after 12 months of treatment with adalimumab, a tumor necrosis factor-alpha-inhibiting, anti-inflammatory, biologic medication, prescribed for the patient's psoriasis. Although rare reports of a "sarcoidosis-like" reaction associated with select tumor necrosis factor-alpha agents exist, to the best of our knowledge, perforating and necrotizing cutaneous granulomas after treatment with adalimumab has not been previously reported. Given the patient's history of systemic sarcoidosis, the differential diagnosis includes reactivation of latent sarcoidosis with adalimumab as a trigger.

Tumoral PD-L1 expression in desmoplastic melanoma is associated with depth of invasion, tumor-infiltrating CD8 cytotoxic lymphocytes and the mixed cytomorphological variant.

Recently, patients with metastatic desmoplastic melanoma (DM) have been shown to respond more favorably to anti-PD1/PD-L1 therapy than other melanoma subtypes. Given this, we evaluated PD-L1/2 expression in primary DM samples and correlated these with subtype, CD8+ lymphocyte status, histopathological prognosticators, and select genetic alterations. Eighty-six (36 mixed DM, 50 pure DM) archival annotated samples met inclusion criteria and were immunohistochemically semiquantitatively evaluated. Per established criteria, for PD-L1/L2, cases with ⩾5% tumoral expression, and for CD8, cases with a predominantly peri/intratumoral CD8+ infiltrate were scored positive. Univariate analysis (chi-square and Wilcoxon) identified potential confounders and a nested case-control study was accomplished using multiple logistic regression. For PD-L1, 49% of cases were positive and 71% of cases with thickness >4 mm were positive; PD-L1 expression differed by median depth (3.29 mm, interquartile range=3.58 mm for PD-L1 positives vs 1.75 mm, interquartile range=2.04 mm for PD-L1 negatives, P=0.0002) and was linearly associated with increasing depth of invasion (P=0.0003). PD-L1-positive cases were more likely to display CD8+ lymphocytes (60 vs 28% P=0.0047).The presence of CD8+ lymphocytes correlated significantly with depth of invasion >1 mm (P=0.022). On multivariate analysis, PD-L1 was 6.14 × more likely to be expressed in mixed DM than pure DM (P=0.0131), CD8+ staining was 6.22 × more likely in PD-L1 positive cases than in PD-L1 negative (P=0.0118), and tumor depth was associated with greater odds of PD-L1 expression (OR=1.61, P=0.0181). PD-L2 expression was observed in 48% of cases but did not correlate with any variables. Correlation of tumoral PD-L1 with increased depth and CD8+ lymphocytes implicates the tumoral immune microenvironment with advancing disease in DM. Enhanced tumoral PD-L1 expression in the mixed cytomorphological variant provides an insight into the differential pathogenesis of the subtypes and suggests that these patients are likely better candidates for anti-PD/PD-L1 therapy.

NF1 and Neurofibromin: Emerging Players in the Genetic Landscape of Desmoplastic Melanoma.

Neurofibromatosis type I (NF1), a monogenic disorder with an autosomal dominant mode of inheritance, is caused by alterations in the NF1 gene which codes for the protein neurofibromin. Functionally, NF1 is a tumor suppressor as it is GTPase-activating protein that negatively regulates the MAPK pathway. More recently, much attention has focused on the role of NF1 and neurofibromin in melanoma as mutations in NF1 have been found to constitute 1 of the 4 distinct genomic categories of melanoma, with the other 3 comprising BRAF, NRAS, and "triple-wild-type" subtypes. In this review, we parse the literature on NF1 and neurofibromin with a view to clarifying and gaining a better understanding of their precise role/s in melanomagenesis. We begin with a historic overview, followed by details regarding structure and function and characterization of neural crest development as a model for genetic reversion in neoplasia. Melanogenesis in NF1 sets the stage for the discussion on the roles of NF1 and neurofibromin in neural crest-derived neoplasms including melanoma with particular emphasis on NF1 and neurofibromin as markers of melanocyte dedifferentiation in desmoplastic melanoma.

MSH6, Past and Present and Muir-Torre Syndrome-Connecting the Dots.

Sebaceous neoplasms such as adenoma, sebaceoma, and carcinoma, although sporadic in their occurrence, are clinically significant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous neoplasms and/or keratoacanthomas and visceral malignancies. MTS is usually the result of germline mutations in the DNA mismatch repair genes MSH2 and, albeit less commonly, MLH1. Although less know, MSH6 is yet another key player. Evidence from Lynch syndrome indicates that pathogenic germline mutations in MSH6 are typically microsatellite stable and have a clinical presentation that differs from that associated with germline mutations in MSH2 and/or MLH1. Given this unique mutator phenotype of MSH6, the primary aim of this review was to underscore the clinical manifestations associated with pathogenic mutations in MSH6 in patients with MTS. As the current clinical and laboratory work-up of MTS is geared toward patients harboring a germline mutation in MSH2 and/or MLH1, an additional aim was to provide a scaffolding for the work-up of a patient presenting with an isolated germline mutation in MSH6.

Cutaneous Rosai-Dorfman Disease With Linear Lesions and Monoclonal Gammopathy.

Cutaneous Rosai-Dorfman disease (CRDD), a benign histiocytosis of unknown etiology, typically presents as a solitary or clusters of lesions. Although the histopathology is fairly distinctive, the laboratory abnormalities are not; past reports note elevated erythrocyte sedimentation rate, anemia, and polyclonal hyperglobulinemia. We describe a 61-year-old African American diabetic gentleman who presented with nodules in a linear distribution on the flank. Histopathologic examination of a biopsied nodule revealed a pandermal sheet-like infiltrate of plasma cells and histiocytes, some demonstrating elastophagocytosis and emperipolesis. The lesional histiocytes were S100 and CD68 positive and CD1a negative-findings consistent with a diagnosis of CRDD. Additional laboratory work-up performed 12 weeks after the biopsy was taken revealed an elevated serum κ light chain concentration of 37.26 mg/L (reference range: 3.30-19.40 mg/L), which correlated with an M-protein spike identified as IgG κ proteins per serum protein electrophoresis. Given the difficulty in excising a large area and preexisting diabetes, a course of low-dose methotrexate was selected for therapy with a recommendation of close follow-up for the monoclonal gammopathy. To the best of our knowledge, this is the first report of CRDD associated with a linear distribution of lesions and serum protein electrophoresis-confirmed monoclonal gammopathy.