A retrospective cohort study of genetic referral and diagnosis of Birt-Hogg-Dubé Syndrome in patients with Trichodiscoma and Fibrofolliculoma skin lesions.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a genetic condition caused by pathogenic variants in the FLCN gene resulting in benign skin lesions, spontaneous pneumothorax, and increased risk for a variety of renal tumors. Skin manifestations of BHD include trichodiscoma (TD) and fibrofolliculoma (FF), which may represent the same pathologic entity. These lesions can identify BHD patients, who upon positive genetic testing can be considered for life-long surveillance for renal neoplasms. OBJECTIVE: To characterize patients diagnosed with TD and FF including rates and outcomes of genetics referral. METHODS: Retrospective chart reviews of patients with confirmed or possible diagnosis of TD or FF at the University of Michigan from September 2002 through October 2020 to assess pathologic findings, personal and family history of BHD manifestations, referral for genetic evaluation, and genetic testing results. RESULTS: 64 patients had a pathologic diagnosis of TD or FF, 16 of whom (25%) were referred to cancer genetics. Fourteen patients completed genetic evaluation, 9 of whom were diagnosed with BHD (64%), with 6 unique pathogenic variants in FLCN. CONCLUSION: Providers should consider referral for genetic evaluation for patients with biopsy-proven TD or FF, as early diagnosis of BHD provides the opportunity for early detection and treatment of other BHD-associated conditions.

Multiple primary dermatofibrosarcoma protuberans tumors in a single patient with chromosomal microarray analysis: A case report and review.

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with a high propensity for local invasion and recurrence. Although it is a rare event, the occurrence of multiple tumors in a single patient raises a diagnostic dilemma, as metastatic disease should be differentiated from multiple primary malignant events. In more than 90% of DFSP, a pathogenic t(17;22) translocation leads to the expression of COL1A1::PDGFB fusion transcripts. Karyotype analysis, fluorescence in situ hybridization, and RT-PCR can be useful ancillary studies in detecting this characteristic rearrangement, and sequencing of the fusion transcript can be used to support a clonal origin in metastatic and multifocal disease. However, previous reports have demonstrated variable sensitivity of these assays, in part due to the high sequence variability of the COL1A1::PDGFB fusion. Here, we report a patient who developed two distinct DFSP tumors over the course of 7 years. Chromosomal microarray analysis identified distinctive genomic alterations in the two tumors, supporting the occurrence of multiple primary malignant events.

A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions.

Immunohistochemistry (IHC) of cutaneous sebaceous lesions (SL) can be used to screen patients for Lynch syndrome (LS). There is little data on rates of genetic referral and outcomes of genetic testing for patients with SL. This single-center retrospective study characterizes 400 + patients with SL, including IHC results, genetics referrals, and outcomes of genetic testing. Retrospective chart reviews were performed for patients with a pathology-confirmed diagnosis of SL at the University of Michigan between January 2009 and December 2019. 447 patients with 473 SL were identified. Excluding 20 patients with known LS, IHC was conducted in 173 (41%) patients. 92/173 (53%) patients had abnormal results. 69 of these 92 (75%) patients were referred to genetics. 32 additional patients were referred with normal IHC (n = 22) or without IHC (n = 10). Of 101 patients referred, 65 (64%) were seen and 47 (47%) completed genetic testing. 7/47 (15%) had pathogenic variants associated with LS, six with concordant abnormal IHC and one without IHC. Cancer genetics referral of patients with SL, particularly for lesions with abnormal IHC, yields a significant rate of LS diagnosis. Providers should consider genetics referral for patients with SL.

Eosinophilic Fasciitis with Concurrent Necrobiotic Granulomatous Dermatitis Related to Checkpoint Inhibition Therapy.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapeutics. However, loss of physiologic tolerance in few cases has triggered rare and novel immune-related adverse events (irAEs). Eosinophilic fasciitis, an infrequently reported diffuse scleroderma-like entity, has been associated with ICI therapy. We report a case of a patient with metastatic melanoma treated with nivolumab who developed eosinophilic fasciitis with concurrent granulomatous dermatitis and lymphadenitis, the latter of which mimicked melanoma recurrence radiographically. Furthermore, this patient had a severe presentation that subsequently proved to be treatment-resistant to both corticosteroid and steroid-sparing therapies. To our knowledge, eosinophilic fasciitis has not been reported concurrently with granulomatous dermatitis in literature. We provide a narrative of this case and a review of therapeutic approaches for severe or refractory irAEs. With the increasing popularity of ICI therapy, we believe it is essential for clinicians to identify novel irAEs and be aware of treatments as late recognition could prove fatal.

Paraneoplastic Erythema Annulare Centrifugum Eruption (PEACE) Associated With Metastatic Colorectal Adenocarcinoma.

Erythema annulare centrifugum (EAC) is a figurate erythema presenting with annular, erythematous plaques with a trailing scale. It is considered a hypersensitivity reaction to a variety of antigens and is associated with multiple underlying causes including malignancy. Malignancy-associated EAC is termed paraneoplastic erythema annulare centrifugum eruption (PEACE). Although a specific etiology has yet to be elucidated, this form of EAC is likely to occur due to cytokine and/or antigen stimulation from an underlying malignancy. PEACE is primarily associated with lymphoproliferative disorders and rarely solid tumors. Our report discusses a case of PEACE associated with metastatic colorectal adenocarcinoma. On presentation to our clinic, the patient had developed a migratory annular eruption over a year. His review of symptoms was positive for signs of underlying malignancy, including weight loss and recent lower vertebral fracture. A biopsy of his annular lesion revealed a non-specific pityriasiform dermatitis. A vertebral biopsy uncovered a diagnosis of metastatic colorectal cancer. At that time, clinicopathologic correlation allowed us to reach the diagnosis of PEACE.

Symmetric drug-related intertriginous and flexural exanthema: Clinicopathologic study of 19 cases and review of literature.

BACKGROUND: Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug reaction characterized by gluteal/anogenital erythema and symmetric involvement of other intertriginous location(s) without systemic signs. Clinicopathologic characterization has been limited to case reports and small series. We describe 19 new cases and review the literature to better define the clinical and histopathologic spectrum of SDRIFE. METHODS: Pathology archives were searched for "SDRIFE" and "baboon syndrome." Cases meeting clinical criteria were included. Clinical and histopathologic features were recorded. Previous reports of SDRIFE with histopathologic descriptions were reviewed. RESULTS: Nineteen new cases were included, over half triggered by antibiotics. Six new causative medications were identified. Median onset was 7 days. Typical lesions were erythematous plaques or papules with or without scale. The most common histopathologic finding was superficial perivascular lymphocytic infiltrate followed by dermal eosinophils, spongiosis, and orthokeratosis. Basal vacuolization and apoptotic keratinocytes were less common. Interstitial histiocytes were present in almost half of our cases. Other findings included atypical lymphocytes and "flame figure." CONCLUSIONS: Appreciation of the range of inciting medications and clinicopathologic features in SDRIFE will improve recognition of this condition. Although many histopathologic features overlap with other common dermatitides, biopsy may assist in excluding key clinical mimics.

Cutaneous microsporidiosis in an immunosuppressed patient.

Microsporidia are a group of obligate intracellular parasites that naturally infect domestic and wild animals. Human microsporidiosis is an increasingly recognized multisystem opportunistic infection. The clinical manifestations are diverse with diarrhea being the most common presenting symptom. We present a 52-year-old woman with a history of amyopathic dermatomyositis complicated by interstitial lung disease managed with mycophenolate mofetil and hydroxychloroquine who presented with a 7-month history of recurrent subcutaneous nodules as well as intermittent diarrhea and chronic sinusitis. A punch biopsy showed superficial and deep lymphocytic and granulomatous dermatitis with focal necrosis. Tissue stains for microorganisms revealed oval 1 to 3 µm spores within the necrotic areas in multiple tissue stains. Additional studies at the Centers for Disease Control and Prevention confirmed cutaneous microsporidiosis. This case is one of very few confirmed examples of cutaneous microsporidiosis reported in the literature.

Considerations for Timing of Defect Reconstruction in Cutaneous Melanoma of the Head and Neck.

The objective of this study is to identify the incidence and characteristics of cases with positive margins on wide local excision for cutaneous melanoma of the head and neck (CMHN) and therefore provide a potential basis for selectively delaying reconstruction pending final histological clearance of melanoma. A systematic review of English language articles was performed on studies retrieved from PubMed and Web of Science. Original investigations published between July 1999 and June 2018 reporting on margin status of CMHN wide local excision specimens were included in the review. The incidence of positive margins after definitive resection for cutaneous melanoma in the literature ranges from 6 to 20.9%. The incidence is higher in cases of advanced patient age, diagnosis by shave biopsy, lentigo maligna melanoma subtype, desmoplastic subtype, tumor thickness, and ulceration. Delayed reconstruction remains the most oncologically sound decision, allowing for interpretation of margin status on paraffin-embedded tissue sections. However, resection and the resultant defect closure in a single stage is more expedient and potentially a more efficient use of resources. The risk-benefit ratio of immediate versus delayed reconstruction must be considered for each case. The incidence of positive margins is higher in cases of advanced patient age, diagnosis by shave biopsy, lentigo maligna melanoma subtype, desmoplastic subtype, increasing tumor thickness, and the presence of ulceration; delayed reconstruction should be strongly considered in these cases.

Inflammatory Dermatopathology for General Surgical Pathologists.

Owing to the wide variety and complexity of inflammatory skin diseases, inflammatory dermatopathology can be a challenging topic for dermatopathologists and general surgical pathologists alike. Following a basic tissue reaction pattern approach, this article reviews the most common and important entities of each pattern, with emphasis on differential diagnosis, diagnostic pitfalls, and appropriate workup when indicated. A few dermatologic emergencies are also discussed.

Facial Erosive Pustular Dermatosis After Cosmetic Resurfacing.

Importance: Erosive pustular dermatosis (EPD) is a rare condition that typically affects actinically damaged skin of the scalp. Characterized by sterile pustules, erosions, and crusts, EPD is difficult to treat and heals slowly. The exact cause of EPD is unknown, although trauma is an inciting factor. Objective: To describe 3 women who presented with prolonged facial erosions after cosmetic resurfacing procedures, specifically fully ablative carbon dioxide laser or medium-depth chemical peel. Design, Setting, and Participants: This case series describes the clinical features, histopathological findings, laboratory results, and treatment of 3 patients with an ultimate diagnosis most consistent with facial EPD. Patients were evaluated between September 10, 2010, and May 6, 2016, in a dermatology clinic in an academic medical center. The patients were 3 women seeking diagnostic evaluation and therapeutic options for nonhealing facial erosions occurring after ablative procedures (carbon dioxide laser resurfacing or Jessner solution/trichloroacetic acid chemical peel). Main Outcomes and Measures: Histologic examination and wound culture from initial presentation as well as clinical follow-up documenting improvement with therapeutic interventions. Results: All 3 patients were women in their 50s or 60s for whom EPD was deemed to be the best diagnosis, after infection, immunobullous disorders, and other pustular dermatoses were considered. Histologic features were nonspecific. Treatment included a combination of topical and systemic therapies, such as corticosteroids, dapsone, isotretinoin, and/or antibiotics. Watchful waiting (tincture of time) appeared to be central to the healing process. Conclusions and Relevance: After cosmetic resurfacing, patients may develop EPD isolated to the face. As a diagnosis of exclusion that should be considered in patients who have nonhealing wounds following ablative procedures, EPD is challenging to treat and may require the use of anti-inflammatory agents. Recognizing this condition is important, especially as cosmetic procedures become more widespread.

The expression of RUNDC3B is associated with promoter methylation in lymphoid malignancies.

DNA methylation is an epigenetic modification that plays an important role in the regulation of gene expression. The function of RUNDC3B has yet to be determined, although its dysregulated expression has been associated with malignant potential of both breast and lung carcinoma. To elucidate the potential of using DNA methylation in RUNDC3B as a biomarker in lymphoid malignancies, the methylation status of six regions spanning the CpG island in the promoter region of RUNDC3B was determined in cancer cell lines. Lymphoid malignancies were found to have more prominent methylation and did not express RUNDC3B compared with myeloid malignancies and solid tumours, supporting the potential use of DNA methylation in this region as a biomarker for lymphoid malignancies. RUNDC3B contains a RUN domain in its N-terminal region that mediates interaction with Rap2, an important component of the mitogen-activated protein kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. The protein sequence of RUNDC3B also contains characteristic binding sites for MAPK intermediates. Therefore, it is possible that RUNDC3B serves as a mediator between Rap2 and the MAPK signalling cascade. Three genes with MAPK-inducible expression were downregulated in a methylated leukaemia cell line (HSPA5, Jun and Fos). Jun and Fos combine to form the activating protein 1 transcription factor, and loss of this factor is associated with the dysregulation of genes involved in differentiation and proliferation. We hypothesize that the loss of RUNDC3B secondary to aberrant hypermethylation of the early growth response 3 transcription factor binding site results in dysregulated MAPK signalling and carcinogenesis in lymphoid malignancies. © 2015 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.

Immunohistochemical evaluation of p16 expression in cutaneous histiocytic, fibrohistiocytic and undifferentiated lesions.

BACKGROUND: Expression of p16 is frequently evaluated in melanocytic lesions. Expression of p16 in cutaneous histiocytic, fibrohistiocytic and undifferentiated lesions has not been well characterized. METHODS: We evaluated p16 expression in a cohort of histiocytic (reticulohistiocytoma, Langerhans cell histiocytosis, xanthogranuloma, Rosai Dorfman disease and xanthoma), fibrohistiocytic (dermatofibroma, epithelioid fibrous histiocytoma and dermatofibrosarcoma protuberans) and undifferentiated (atypical fibroxanthoma and pleomorphic undifferentiated sarcoma) lesions. A group of melanocytic lesions (Spitz nevus, ordinary nevus, spitzoid melanoma and non-spitzoid melanoma) were also evaluated as reference. Each case was scored by the proportion of p16-positive cells and by staining intensity. RESULTS: Immunoreactivity for p16 was found in almost all histiocytic (28/30, 93%) and fibrohistiocytic (22/24, 92%) lesions. About half of the undifferentiated lesions also exhibited p16 staining (9/17, 53%). Most of the melanocytic cases examined in this study expressed p16. A wide range of staining intensity and proportion of p16-positive cells was observed in most groups. CONCLUSION: Expression of p16 is common, albeit variable in proportion and intensity, amongst a wide variety of cutaneous histiocytic, fibrohistiocytic and undifferentiated lesions. Further studies are required to determine if p16 expression is useful in distinguishing benign from malignant neoplasms of these types.

Dermatofibrosarcoma Protuberans in a Patient With Cowden Syndrome: Revisiting the PTEN and PDGF Pathways.

PTEN hamartoma tumor syndrome, of which Cowden syndrome (CS) is the most recognized variant, is characterized by multiple benign and malignant tumors of ectodermal, mesodermal, and endodermal origins, secondary to germline mutation in the phosphatase and tensin homolog (PTEN) gene. Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive malignant fibroblastic/myofibroblastic tumor of the skin, characterized by the t(17:22)(q22:q13) translocation resulting in fusion of the COL1A1 and PDGFB genes. An association between CS and DFSP has not been reported in the literature to date. The authors have encountered a male patient with CS and a history of DFSP that developed adjacent to a sclerotic fibroma on the parietal scalp, both excised at age 7. He presented at age 21 with an enlarging pink nodule at the same site on the parietal scalp. Excision revealed a dermal and subcutaneous storiform spindle cell proliferation with fat entrapment and positive staining for CD34, consistent with DFSP. Fluorescence in situ hybridization confirmed PDGFB gene rearrangement. PTEN expression in the patient's recurrent DFSP was nearly absent when compared with that of sporadic DFSP. To our knowledge, this is the first report of DFSP in a patient with CS. Although the association is likely to be coincidental, the authors revisited the PTEN and the PDGF pathways to speculate any possible interplay of the 2 conditions on a molecular level.

Enhanced interpretation of newborn screening results without analyte cutoff values.

PURPOSE: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. METHODS: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. RESULTS: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. CONCLUSION: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.

Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.

Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or "variant of unknown significance (VUS)," presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.

Acylcarnitine analysis by tandem mass spectrometry.

Carnitine plays an essential role in fatty acid metabolism, as well as modulation of intracellular concentrations of free coenzyme A by esterification of acyl residues. Acylcarnitine analysis of various biological fluids is a sensitive method to detect >20 inborn errors of metabolism that result in abnormal accumulation of acylcarnitine species due to several organic acidemias and most fatty acid beta-oxidation disorders. In addition, acylcarnitine analysis may aid in monitoring treatment of known patients affected with these inborn errors of metabolism. This unit describes protocols that can be used to measure acylcarnitine species of various carbon chain lengths in several biological specimen types including plasma, dried blood and bile spots, and urine, by derivatization to butylesters and flow-injection electrospray ionization tandem mass spectrometry (ESI-MS/MS).