Two Cases of Cutaneous Sarcomatoid Squamous Cell Carcinoma Resembling Cutaneous Giant Cell Tumor of Soft Tissue.

ABSTRACT: Cutaneous sarcomatoid squamous cell carcinoma is well-described with histology resembling pleomorphic undifferentiated sarcoma featuring collagenous or myxoid stroma with or without elements of keratinizing squamous carcinoma. This report presents 2 cases of dedifferentiated squamous cell carcinoma (SCC) composed of sheets of malignant mononuclear cells with malignant osteoclast-like multinucleated giant cells, extravasated blood, and hemosiderin resembling cutaneous giant cell tumor (cGCT). In the first case, an exophytic facial mass of a 96-year-old woman removed by shave showing extensive cGCT-like tumor but with microscopic elements of SCC in situ and positivity for cytokeratin 5/6 in the malignant spindle cells and SCC. The second case involved a 32-year-old man with a pedunculated penile mass removed by shave biopsy, displaying malignant cytology resembling cGCT, focal staining for cytokeratin AE1/AE3 and p63, and CD68 highlighting the osteoclast-like giant cells. Molecular analysis revealed CDKN2A, TP53, and TERT. Upon reexcision, case 2 showed focally invasive keratinizing SCC associated with differentiated penile intraepithelial neoplasia and lichen sclerosus. Skin specimens with an exophytic mass histologically resembling cGCT but with malignant cytology should be meticulously evaluated for elements of SCC. Molecular analysis, detecting mutations like H3F3 or HMGA2-NCOR2 fusion, can aid in distinguishing cutaneous sarcomatoid squamous cell carcinoma from GCT bone or GCT soft tissue.

Lymphangitic Melanomatosis: Case Report of Intralymphatic Spread of Melanoma in a 66-year-old Man.

ABSTRACT: Melanoma with lymphatic invasion has been associated with increased risk of metastasis, but the mechanisms and clinical implications are poorly understood. Although current reports have documented angiotropic spread of melanoma and suggest lymphatic spread of melanoma to increase the likelihood of metastasis, to our knowledge, lymphangitic metastatic melanoma resembling cutaneous carcinomatosis or presenting with facial hyperpigmentation has not been described. In this case report, we describe extensive cutaneous intralymphatic spread of melanoma, or lymphangitic melanomatosis, producing macular skin pigmentation in a 66-year-old man.

The Successful Use of Upadacitinib as Monotherapy for Hidradenitis Suppurativa and Ulcerative Colitis in the Setting of Refractory Disease.

Hidradenitis suppurativa (HS) and ulcerative colitis (UC) are associated chronic inflammatory conditions with complex disease courses and potential for overlapping therapeutic management. We describe a case of severe pediatric HS and UC that were poorly controlled despite several standard-of-care therapies, including infliximab and ustekinumab. Transitioning the patient to upadacitinib monotherapy resulted in clinical improvement of both her UC and HS within 3 months, and she was then able to be weaned off her other systemic therapies. While upadacitinib is not currently FDA-approved for HS or pediatric UC, this case report shows promise for upadacitinib monotherapy for both of these complex inflammatory disorders.

The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma.

BACKGROUND: Melanoma-intrinsic activated ß-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). METHODS: We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. RESULTS: In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated ß-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. CONCLUSIONS: APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

A unique case of concurrent cutaneous lichen amyloidosis and myxedema.

Lichen amyloidosis is believed to be caused by damage to keratinocytes, often by chronic scratching. It has also been associated with autoimmune conditions, including thyroid disease. Dermatologic manifestations of poorly controlled thyroid disease are well described within the medical literature, within both hypothyroid and hyperthyroid states. Myxedema is a rare complication of Graves disease. We report a unique case of concurrent myxedema and lichen amyloidosis in a 63-year-old patient with uncontrolled hypothyroidism in the setting of post-ablative Graves disease.

Uterine Cellular Blue Nevus Arising in Mullerian and Pelvic Dendritic Melanocytosis: Case Report of a Rare Phenomenon to Be Distinguished From Uterine Melanoma.

A 37-yr-old woman presented to the gynecology clinic with abnormal uterine bleeding in the setting of known, large uterine fibroids. Preoperative endometrial biopsy identified atypical melanocytic cells concerning for uterine melanoma. Care was transferred to the gynecologic oncology service for hysterectomy. Intraoperative findings included macular, blue-black pigmentation of the peritoneum of the bladder and cervix, which was resected and sent for frozen section, confirming melanocytic neoplasia. The hysterectomy revealed multiple tan leiomyomas up to 12 cm, and a distinct 3 cm black, incompletely circumscribed mass in the endomyometrium composed of bland spindled cells with delicate melanin granules. The tumor cells were positive for Sox-10, BAP1, and Mart-1 (Melan-A) and negative for PRAME, PD-L1, and BRAFV600E by immunostains. Microscopic elements of similar melanocytes and melanophages were found in the cervix and bladder peritoneum. Molecular analysis of the uterine tumor identified a GNA11 mutation but no TERT or BAP1 mutation. The uterine melanocytic tumor has characteristic findings of a cellular blue nevus arising in association with dendritic melanocytosis of Mullerian and pelvic tissues, a rarely seen benign phenomenon that should be distinguished from malignant melanoma of the upper genital tract.

Carbol fuchsin stain enhances detection of poly-(d, l-lactide-co-glycolide) microspheres in exenatide extended-release cutaneous injection-site foreign body reaction.

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.

PD-L1 Expression in Extramammary Paget Disease: A Case Series.

ABSTRACT: The PD-1/PD-L1 pathway plays a critical role in the physiologic inhibition and modulation of the immune response in normal tissue. Many tumors evade immune detection and response by upregulating PD-L1 expression. Humanized monoclonal PD-1 and PD-L1 antibodies have proven as both tolerable and effective treatment in many neoplasms. Extramammary Paget disease (EMPD) is a deformative and debilitating cutaneous malignancy in which definitive treatment options are limited with high recurrence rates after surgical excision. To the best of our knowledge, there is little published information regarding EMPD and PD-L1 expression. We evaluated 18 EMPD surgical pathology cases for tumor cell and tumor-associated inflammatory (TAI) cell PD-L1 expression. We identified PD-L1 tumor cell expression in 3 (17%) of the cases: 2 of 4 invasive cases (50%) and 1 of 14 (7%) noninvasive cases. One invasive case had lymph nodal metastasis with PD-L1 tumor cell expression. The host inflammatory response intensity and PD-L1 expression were variable in cases negative for tumor cell PD-L1 expression; however, a marked inflammatory response and TAI PD-L1 expression were present in all cases positive for tumor cell PD-L1 expression. In conclusion, 1 in 14 (7%) in situ EMPD cases showed tumor cell PD-L1 expression and 2 of 4 invasive cases (50%) showed tumor cell PD-L1 expression. TAI cells were more often positive (83%) than tumor cells (17%) for PD-L1 expression.

Preferentially Expressed Antigen in Melanoma Immunostaining in a Series of Melanocytic Neoplasms.

ABSTRACT: In their 2018 article, Lezcano et al [AJSP 2018(11):1456] show that diffuse tumor cell nuclear reactivity for Preferentially expressed Antigen in Melanoma (PRAME) is a feature of melanoma and that benign and atypical melanocytic tumors are PRAME negative or show only focal positivity for PRAME. We report our observations of PRAME staining in 253 melanocytic tumors. Tumors were classified by hematoxylin and eosin sections. The nuclear PRAME staining of neoplastic melanocytes in each case was categorized as absent, focally present, or diffusely present. The results were compared with those of Lezcano et al 105 of 134 (78%) melanocytic nevi were completely PRAME negative. Of the 29 PRAME-positive benign lesions, 28 exhibited focal but not diffuse positivity, including atypical (n = 11) and dysplastic nevi (n = 11). One of 11 Spitz nevi showed diffuse positivity (9%). Thirty-nine of 51 (76%) invasive melanomas, 41 of 50 (82%) melanoma in situ, and 15 of 18 (83%) metastatic melanomas were diffusely PRAME positive. Excluding desmoplastic melanomas, 39 of 49 (80%) primary melanomas were diffusely PRAME positive. Our findings of PRAME staining in melanocytic neoplasia are in general agreement with those of Lezcano et al. Diffuse PRAME reactivity in neoplastic melanocytes is a feature of malignancy and was only otherwise seen in 1 Spitz nevus. Caution is advised in interpretation of PRAME reactivity in melanocytic tumors of uncertain classification because melanoma arising in association with nevus and some atypical melanocytic tumors may show focal or incomplete PRAME staining. Routine histopathological findings, clinical information, PRAME staining, and judicious application of molecular studies are steps leading to accurate classification of melanocytic neoplasia.

Immune Checkpoint Markers in Superficial Angiosarcomas: PD-L1, PD-1, CD8, LAG-3, and Tumor-Infiltrating Lymphocytes.

ABSTRACT: Cutaneous angiosarcomas may express programmed death ligand-1 (PD-L1) and PD-L1 expression, and the presence of tumor-infiltrating lymphocytes (TILs) correlates with outcome. These observations provide a basis for PD-1/PD-L1 inhibitor therapy. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that interacts with the PD-L1 axis and is considered to be a marker of immune exhaustion. The presence of LAG-3-positive lymphocytes in cutaneous angiosarcoma has not been established. We reviewed 10 cases of treatment naive angiosarcoma of skin and superficial soft tissue and assessed for PD-L1 (ZR3) expression, presence of TILs, and expression of CD8, PD1, and LAG-3 by tumor-associated inflammatory cells by immunohistochemistry. All 10 angiosarcomas were positive for PD-L1: 7 with high expression and 3 with low expression. TILs were present in all tumors: brisk in 7 and nonbrisk in 3. CD8 lymphocytes were present in all tumors with a range of 212-1274 cells per square millimeter (mean 557 CD8 cells/mm2). LAG-3-positive lymphocytes were present in 9 of 10 angiosarcomas with a range of 0-728 cells/mm2 (mean 146 LAG-3 cells cells/mm2). The ratio of LAG-3 lymphocytes to CD8 lymphocytes was 0%-59% (mean 27%). The PD1 cell counts were intermediate between CD8 and LAG3 counts. Cutaneous angiosarcomas frequently express PD-L1, have prominent numbers of CD8 positive, and have smaller numbers of LAG-3-positive and PD-1-positive TILs. Our findings provide further evidence of PD-L1 expression in cutaneous angiosarcoma and the promise for immune checkpoint inhibitor therapy.

PD-L1 and LAG-3 expression in advanced cutaneous squamous cell carcinomas.

BACKGROUND: Expression of programmed death ligand 1 (PD-L1) by cutaneous squamous cell carcinomas has been shown to correlate with advanced disease and risk of metastasis. Lymphocyte activation gene 3 (LAG-3, or CD223) is an inhibitory receptor that interacts with the PD-L1 axis, which has been shown to be a marker of immune exhaustion and a potential immunotherapy target. However, the role of LAG-3 in cutaneous squamous cell carcinoma has not been established. METHODS: We reviewed 18 cases of locally advanced and/or metastatic cutaneous squamous cell carcinomas and assessed for PD-L1 expression, presence or absence of tumor-infiltrating lymphocytes (TILs), and expression of LAG-3 by TILs. RESULTS: PD-L1 expression was present in 11 of 13 locally advanced primary tumors and 5 of 5 metastases. TILs were present in all 18 tumors, of which 14 cases were positive for LAG-3 expression. In positive cases, LAG-3 was expressed on average by 32% of TILs. CONCLUSIONS: Advanced cutaneous squamous cell carcinomas frequently express PD-L1 and are associated with an inflammatory response. LAG-3 expression by TILs was identified in a majority of cases. Our findings suggest that LAG-3 positive tumor-associated inflammatory cells may play a role in the development of advanced disease and offer another potential target for drug therapy.

Novel CARD9 mutation in a patient with chronic invasive dermatophyte infection (tinea profunda).

Caspase Recruitment Domain Family Member 9 (CARD9) is an adaptor molecule that drives antifungal activity of macrophages and neutrophils in the skin. Autosomal recessive loss-of-function mutations in CARD9 confer increased susceptibility to invasive disease with select fungi in non-immunosuppressed patients. We report on a patient with X-linked ichthyosis complicated by chronic cutaneous invasive dermatophyte infection. We identified a previously reported c.271T>C (p.Y91H) mutation and a novel intronic c.1269+18G>A mutation in CARD9 underlying recurrent deep dermatophytosis in this patient despite various antifungals for over three decades. Our case highlights susceptibility to invasive dermatophytosis related to autosomal recessive CARD9 deficiency and illustrates the range of CARD9 mutations to be pursued in immunocompetent patients with unexplained deep dermatophyte infections. Further studies are needed to define the best therapeutic regimen.

A case of bullous Sézary syndrome.

Sézary syndrome is a rare leukemic subtype of cutaneous T cell lymphoma that is characterized by erythroderma, lymphadenopathy, and malignant T cells in the peripheral blood. Poor prognostic factors of Sézary syndrome include advanced disease stage, older age at onset, and large cell transformation. Presentation with bullous lesions, though rare, has been reported in a few patients. We present an elderly woman with bullous Sézary syndrome who presented with a two-month history of progressive rash. Upon admission, the patient had pruritic, erythematous, edematous plaques with overlying flaccid bullae and erosions involving the scalp, neck, torso, and extremities. Despite treatment, the patient died two months after presentation. Although rare, bullous lesions associated with Sézary syndrome may indicate poor prognosis.

Idiopathic, Refractory Sweet's Syndrome Associated with Common Variable Immunodeficiency: a Case Report and Literature Review.

PURPOSE OF REVIEW: Sweet's syndrome (SS) is classically considered a hypersensitivity reaction often associated with autoimmune disorders and malignancy. SS has also been increasingly reported to occur with immunodeficiencies. We present a case of treatment-refractory, systemic SS as the initial manifestation in a young child with common variable immunodeficiency (CVID). We also review current literature about SS and concurrent immunodeficiencies and autoimmunity in CVID patients. RECENT FINDINGS: Few case reports exist regarding the co-occurrence of Sweet's syndrome and primary immunodeficiencies. SS is characterized by a pro-inflammatory state with a neutrophil predominance resulting in a spectrum of clinical manifestations. CVID is a multifactorial antibody deficiency that can be associated with autoimmunity, which some studies have proposed to be secondary to altered CD21 expression. SS occurring in patients with CVID has been infrequently reported, and one case study demonstrated improvement of Sweet's associated skin lesions with immunoglobulin replacement. In our case, the patient had multi-system SS refractory to multiple immunomodulatory therapies. To our knowledge, this is the first report of the effective and safe use of intravenous tocilizumab and oral lenalidomide to treat SS in a child with CVID. Immunoglobulin replacement reduced the frequency of infections and may have contributed to the opportunity to wean the immunosuppressive therapies for Sweet's syndrome. Sweet's syndrome as an initial manifestation of co-occurring immunodeficiencies is rare, and providers need a high index of suspicion. In addition, treatment of SS associated with an immunodeficiency can be a challenge. Treatment with immunoglobulin replacement reduces the frequency of infections, and in some patients with concurrent SS may improve skin lesions and reduce the need for immunomodulator therapy. Further study is necessary to better understand the pathogenesis of CVID in patients with SS and to identify possible biomarkers that predict who with SS are at risk for developing hypogammaglobulinemia.

Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis.

Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.

Childhood pemphigus foliaceus presenting as a polycyclic eruption: Case report and review of the literature.

Pemphigus foliaceus (PF) is an autoimmune bullous disorder that has occasionally been reported to present as a polycyclic or arcuate eruption in children. We present a case of childhood PF presenting as an annular and polycyclic eruption, which initially led to a diagnostic conundrum and a delay in diagnosis but which ultimately responded well to therapy with systemic steroids and rituximab infusions. We briefly review the literature on polycyclic presentations of PF in childhood as well as the use of rituximab for pediatric pemphigus.

Solitary plaque on the leg of a child: A report of two cases and a brief review of acral pseudolymphomatous angiokeratoma of children and unilesional mycosis fungoides.

Acral pseudolymphomatous angiokeratoma of children (APACHE) and unilesional mycosis fungoides (MF) are two rare dermatoses in the pediatric population which may have overlapping clinical and histopathologic features, making differentiation between these two diagnoses difficult. We present two similar cases of a solitary plaque on the thigh of a child, one representing APACHE and the other representing unilesional MF with granulomatous features, and we provide a brief overview of the clinical and histopathologic features of APACHE and unilesional MF.

A 61-year-old man with erythematous forearm papules three months after liver transplantation.

A 61-year-old Caucasian man presented with papules on his left forearm and hand three months after liver transplantation: images from physical exam, pathology, and microbiology are presented. Skin biopsy confirmed the presence of fungal elements within the hair shaft, which is consistent with Majocchi granuloma, also known as nodular granulomatous perifolliculitis. A combination of fungal culture, microscopic morphology, and gene sequencing was used to identify the causative organism. The patient recovered with appropriate systemic antifungal therapy.