Spitz melanocytic neoplasms with MLPH::ALK fusions: Report of two cases with previously unreported features and literature review.

ALK-fused Spitz melanocytic neoplasms are a distinct subgroup of melanocytic lesions exhibiting unique histopathologic characteristics. These lesions often manifest as exophytic or polypoid tumors, characterized by fusiform-to-epithelioid melanocytes arranged in a nested, fascicular, or plexiform growth pattern. Several fusion partners of the ALK gene have been identified in spitzoid melanocytic neoplasms, with TPM3 and DCTN1 being the most prevalent. Less common fusion partners include NPM1, TPR, CLIP1, GTF3C2, EEF2, MYO5A, KANK1, and EHBP1. The MLPH gene, which encodes melanophilin (MLPH), playing a crucial role in regulating skin pigmentation by acting as a linker between RAB27A and myosin Va during melanosome transport, has also recently been recognized as a rare fusion partner of ALK in Spitz melanocytic neoplasms. Currently, there exists a sparse documentation within English literature, illustrating a limited number of cases featuring MLPH::ALK fusion in Spitz melanocytic neoplasms. In this report, we present two additional cases, including a previously unreported instance of Spitz melanoma, contributing to the expanding knowledge on ALK-fused Spitz melanocytic neoplasms. In addition, we provide a comprehensive review of the clinical, histopathologic, and molecular features observed in documented cases with this novel fusion.

Nectin-4 expression in a subset of cutaneous adnexal carcinomas: A potential target for therapy with enfortumab vedotin.

BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. METHODS: Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. RESULTS: Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). CONCLUSIONS: Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

Apoptosis Pathway-Associated Proteins Are Frequently Expressed in Melanoma: A Study of 32 Cases With Focus on Acral Lentiginous Melanoma.

ABSTRACT: Acral lentiginous melanoma (ALM) is an aggressive type of cutaneous melanoma (CM) that arises on palms, soles, and nail units. ALM is rare in White population, but it is relatively more frequent in dark-skinned populations. There is an unmet need to develop new personalized and more effective treatments strategies for ALM. Increased expression of antiapoptotic proteins (ie, BCL2, MCL1) has been shown to contribute to tumorigenesis and therapeutic resistance in multiple tumor types and has been observed in a subset of ALM and mucosal melanoma cell lines in vivo and in vitro. However, little is known about their expression and clinical significance in patients with ALM. Thus, we assessed protein expression of BCL2, MCL1, BIM, and BRAF V600E by immunohistochemistry in 32 melanoma samples from White and Hispanic populations, including ALM and non-ALM (NALM). BCL2, MCL1, and BIM were expressed in both ALM and NALM tumors, and no significant differences in expression of any of these proteins were detected between the groups, in our relatively small cohort. There were no significant associations between protein expression and BRAF V600E status, overall survival, or ethnicity. In summary, ALM and NALM demonstrate frequent expressions of apoptosis-related proteins BCL2, MCL1, and BIM. Our findings suggest that patients with melanoma, including ALM, may be potential candidates for apoptosis-directed therapies.

Condyloma and coincidental epidermodysplasia verruciformis acanthoma positive for human papillomavirus-14 and -21.

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes individuals to persistent infection with ß-human papillomavirus (HPV) genotypes. The term EDV acanthoma may be applied to lesions with incidental findings of EDV-defining histopathological features without clinical signs of EDV. We report a case of HPV-14- and -21-positive EDV acanthoma arising in association with condyloma in a female patient with a history of low-grade squamous intraepithelial lesion of the cervix positive for high-risk HPV (non-16/18), chronic kidney disease, and systemic lupus erythematosus. The patient had no family or personal history of EDV, but the patient was on immunosuppressive therapy with mycophenolate mofetil and prednisone. A biopsy specimen from one of the perianal lesions revealed histopathologic changes consistent with EDV in the setting of condyloma. Molecular testing showed HPV-14 and -21, which supported the coexistence of condyloma with EDV acanthoma.

BRAF V600E immunohistochemistry as a useful tool in the diagnosis of melanomas with ambiguous morphologies and immunophenotypes.

We report three melanoma cases in which BRAF V600E immunohistochemistry (IHC) was valuable for diagnosis. Patient 1: In a patient with a history of primary melanoma on the chest and metastatic melanoma to right breast after undergoing multiple local and systemic therapies, a lung metastasis exhibited chondroid differentiation, aberrant myofibroblastic marker expression, and rare pancytokeratin positivity, without melanocytic marker expression. Patient 2: After targeted and immunotherapy for primary melanoma on the scalp as well as regional and distant metastatic melanoma, an omental metastasis showed CDX2-positive glandular structures that were negative for melanocytic markers. It was initially misdiagnosed as primary gastrointestinal adenocarcinoma. Patient 3: A patient with history of melanoma showing epithelioid morphology on the right thigh presented with multiple soft tissue nodules on skin, lymph nodes and internal organs after being lost to follow-up for 4 years. A biopsy specimen from the right thigh showed spindled cells with scattered pancytokeratin cocktail positivity and ambiguous staining for melanocytic markers. For melanomas with ambiguous morphologies and/or immunophenotypes in each of the three patients, BRAF V600E expression by IHC was maintained in both primary and metastatic melanoma specimens examined. These cases highlight the utility of BRAF V600E IHC in the diagnosis of melanoma.

Immunohistochemical expression of TRPS1 in mammary Paget disease, extramammary Paget disease, and their close histopathologic mimics.

BACKGROUND: Trichorhinophalangeal syndrome type 1 (TPRS1) expression has been found to be highly sensitive and specific for breast carcinomas. The frequency of TRPS1 expression in cutaneous neoplasms such as mammary Paget disease (MPD) and extramammary PD (EMPD) is currently unknown. We assessed the utility of TRPS1 immunohistochemistry (IHC) in the evaluation of MPD, EMPD, and their histopathologic mimics, squamous cell carcinoma in situ (SCCIS) and melanoma in situ (MIS). METHODS: Twenty-four MPDs, 19 EMPDs, 13 SCCISs, and 9 MISs were subjected to immunohistochemical analysis using anti-TRPS1 antibody. The intensity (none, 0; weak, 1+ ; moderate, 2+ ; strong, 3+ ) and proportion (<1%, absent; 1%-25%, focal; 26%-75%, patchy; >75%, diffuse) of TRPS1 expression were recorded. Relevant clinical data were documented. RESULTS: TPRS1 expression was present in 100% (24/24) of MPDs, with 88% (21/24) of MPDs exhibiting strong, diffuse immunoreactivity. Sixty-eight percent (13/19) of EMPDs showed TRPS1 expression. Intriguingly, EMPDs lacking TRPS1 expression were consistently of perianal origin. TRPS1 expression was seen in 92% (12/13) of SCCISs but was absent in all MISs. CONCLUSIONS: TRPS1 may be useful to distinguish MPDs/EMPDs from MISs, but its utility is limited in distinguishing them from other pagetoid intraepidermal neoplasms such as SCCISs.

Telomerase reverse transcriptase immunohistochemical expression is sensitive but not specific for TERT gene amplification in acral melanoma.

BACKGROUND: TERT gene amplification (TGA) is a mechanism of telomerase reverse transcriptase (TERT) upregulation frequently utilized by acral melanomas (AMs). Currently, the utility of TERT immunohistochemistry (IHC) to predict TGA status in AMs is poorly documented. METHODS: AMs (26 primary and 3 metastatic) and non-acral cutaneous melanomas (6 primary) were subjected to immunohistochemical analysis using anti-TERT antibody to demonstrate protein expression and fluorescence in situ hybridization (FISH) to assess genomic copy number alteration. The relationship between TERT immunoreactivity and TGA confirmed by FISH was assessed using logistic regression. RESULTS: TERT expression was seen in 50% (13/26) of primary and 100% (3/3) of metastatic AMs and 50% (3/6) of primary non-acral cutaneous melanomas. TGA was found in 15% (4/26) and 67% (2/3) of primary and metastatic AMs and 17% (1/6) of non-acral cutaneous melanomas. The intensity of TERT immunoreactivity correlated with TGA (p = 0.04) and a higher TERT copy number-to-control ratio in AMs, with a correlation coefficient of 0.41 (p = 0.03). The sensitivity and specificity of TERT immunoreactivity for predicting TGA in AMs were 100% and 57%, with corresponding positive and negative predictive values of 38% and 100%, respectively. CONCLUSIONS: The clinical utility of TERT IHC to predict TGA status in AMs appears to be limited given its low specificity and positive predictive value.

Ductal differentiation: A rare phenomenon in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that may occasionally present divergent histopathologic features. We present two cases of MCC demonstrating ductal differentiation, one on the lower lip of an 81-year-old man and another on the right forearm of a 67-year-old man. The histopathologic features included TTF1-negative, infiltrative, high-grade basaloid tumor with paranuclear punctate positivity for cytokeratin (CK) 20 and synaptophysin. Rare luminal structures lined by atypical epithelioid cells positive for CEA and CK19 were noted, confirming the presence of ductal differentiation. Although the ductal differentiation is unusual, other histopathologic features and the immunohistochemical profile supported the diagnosis of MCC. Like most divergent features, ductal differentiation is rare in MCC and typically constitutes a very small proportion of the tumor, and is therefore under-recognized. Although the clinical significance of this feature is unclear, recognition and documentation of ductal differentiation and distinguishing it from other mimics such as acantholysis within squamous nests and entrapped eccrine ducts is essential to determine its clinical significance. We also discuss the differential diagnoses of cutaneous basaloid neoplasms with ductal differentiation.

The diverse landscape of dermatologic toxicities of non-immune checkpoint inhibitor monoclonal antibody-based cancer therapy.

BACKGROUND: Since their first approval 25 years ago, monoclonal antibodies (mAbs) have become important targeted cancer therapeutics. However, dermatologic toxicities associated with non-immune checkpoint inhibitor (non-ICI) mAbs may complicate the course of cancer treatment. Data on the incidence and types of these reactions are limited. METHODS: A comprehensive review was conducted on dermatologic toxicities associated with different classes of non-ICI mAbs approved for treatment of solid tumors and hematologic malignancies. The review included prospective Phase 1, 2, and 3 clinical trials; retrospective literature reviews; systematic reviews/meta-analyses; and case series/reports. RESULTS: Dermatologic toxicities were associated with several types of non-ICI mAbs. Inflammatory reactions were the most common dermatologic toxicities, manifesting as maculopapular, urticarial, papulopustular/acneiform, and lichenoid/interface cutaneous adverse events (cAEs) with non-ICI mAbs. Immunobullous reactions were rare and a subset of non-ICI mAbs were associated with the development of vitiligo cAEs. CONCLUSION: Dermatologic toxicities of non-ICI mAbs are diverse and mostly limited to inflammatory reactions. Awareness of the spectrum of the histopathologic patterns of cAE from non-ICI mAbs therapy is critical in the era of oncodermatology and oncodermatopathology.

Lymphomatoid papulosis with DUSP22-IRF4 rearrangement: A case report and literature review.

Lymphomatoid papulosis (LyP) with DUSP22-IRF4 rearrangement is a rare, recently described variant of LyP histopathologically characterized by a biphasic growth pattern, with epidermotropic small-to-medium-sized atypical T-cells and dermal large and transformed T-cells diffusely expressing CD30. LyP with DUSP22-IRF4 rearrangement can mimic other cutaneous lymphoproliferative disorders, particularly primary cutaneous anaplastic large cell lymphoma (PCALCL) or transformed mycosis fungoides (MF). Unlike PCALCL or transformed MF, LyP with DUSP22-IRF4 rearrangement shows an indolent clinical behavior, with frequent spontaneous regression of untreated lesions. Thus, it is important to recognize this rare variant of LyP to avoid misclassification, which may potentially lead to unnecessarily aggressive patient management. To our knowledge, only 13 cases of LyP with DUSP22-IRF4 rearrangement have been reported to date in the English literature. Herein, we describe an additional case of LyP with DUSP22-IRF4 rearrangement in a 63-year-old man and provide a comprehensive literature review with regards to the clinical, histopathologic, and molecular features of this novel entity.

Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune-related adverse event reveal upregulation of toll-like receptor 4/complement-induced innate immune response and increased density of TH 1 T-cells.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. METHODS: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH 1) cells (Tbet), TH 2 cells (Gata3), TH 17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. RESULTS: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH 2, TH 17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH 1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. CONCLUSIONS: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH 1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.

PRAME and LEF1 in Combined Deep Penetrating Nevus and Combined Blue Nevus: Utility and Pitfalls.

ABSTRACT: Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer-binding factor 1 (LEF1) has been proposed to be used in conjunction with ß-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME was negative in most DPN (n = 10/10, n = 9/10, one case with discrepancy between readers) and all BN (n = 16/16), while the 2 melanomas included were positive (n = 2/2). All DPN were positive for LEF1 (n = 9/9) while only a subset of BN were positive (n = 6/16, P = 0.0028; n = 5/16, P = 0.001, per both readers). LEF1 seemed to be easier to interpret than ß-catenin because of its nuclear pattern of expression. The expression of LEF1 in the regular nevus component of combined BN presents a potential pitfall in practice because it may lead to misinterpretation of LEF1 as positive in the BN component of the lesion. However, a subset (approximately one-third) of combined BN seemed to show true LEF1 expression. Taking into account pitfalls in interpretation, the combinatorial panel of PRAME and LEF1, in addition to conventional histopathological features, may be useful to distinguish CDPN from combined BN and other benign and malignant mimics.

Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency, genetic mechanisms, and clinical significance.

Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.

Ibrutinib skin toxicities: Report of two cases.

Ibrutinib is a Bruton tyrosine kinase inhibitor used to treat many hematologic conditions, most commonly B-cell lymphomas and leukemias. Reportedly, skin rash is an adverse event in up to 27% of treated patients. Histopathologic description of these lesions is limited. We present two cases of ibrutinib-associated skin toxicities showing diverse histopathologic features. Case 1: A 72-year-old man was started on ibrutinib for chronic lymphocytic leukemia. Two months later, he developed multiple erythematous crusted papules on the chest, abdomen, and extremities. Biopsies revealed varied histopathology including poorly formed granulomatous dermatitis, epidermal necrosis, ulceration, and panniculitis. Ibrutinib was discontinued and his skin lesions resolved within 1 month. Case 2: A 48-year-old man received ibrutinib after failing standard therapy for primary central nervous system EBV positive diffuse large B-cell lymphoma. Two months after initiation of ibrutinib, he developed multiple firm, red, non-tender nodules on the forehead, buttock, and thigh. Biopsies revealed "pseudolymphoma"-like reaction with dense pandermal lymphohistiocytic inflammation and granulomas. His skin toxicity resolved without cessation of therapy. Awareness of the spectrum of histopathologic features that may be encountered in skin lesions of patients treated with ibrutinib, as illustrated by these two cases, will be critical for optimal patient management.

Eosinophilic homogeneous intracytoplasmic inclusion bodies: Unique viral cytopathic changes associated with epidermodysplasia verruciformis and human papillomavirus type 49.

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes affected individuals to persistent infection with certain types of human papillomavirus (HPV), particularly those that belong to the genus beta-HPV, including HPV-5 and HPV-8, which carry high oncogenic potential. There are three main HPV-related viral cytopathic changes in cutaneous verrucae in terms of intracytoplasmic inclusion bodies (ICBs), namely, granular, filamentous, and homogeneous type ICBs. To date, only HPV-4, HPV-60, and HPV-65 have been found in association with homogeneous ICBs. We report a unique case of HPV-49-associated EDV in a 41-year-old woman with common variable immunodeficiency, mycosis fungoides, and multiple cutaneous malignancies, including squamous cell carcinoma and Merkel cell carcinoma who presented with multiple pink papules and hyperpigmented macules on the left upper extremity. One of the skin lesions histopathologically revealed keratinocytic nuclear enlargement with abundant blue-gray cytoplasm, accompanied by hypergranulosis, characteristic of EDV, along with peculiar bright eosinophilic and homogeneous ICBs. To the best of our knowledge, this is the first reported case of EDV with detection of HPV-49 by genotyping, which features eosinophilic homogeneous ICBs, like those seen in the setting of HPV-4, HPV-60, or HPV-65 infection.

Amyloid deposition with a granulomatous reaction in a resection specimen: A clue for a pre-existing Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive, highly metastatic, cutaneous neuroendocrine malignancy with poor prognosis. Here, we describe a MCC excision specimen with a rare case of tumor-associated amyloid deposition in the absence of residual tumor cells. A 72-year-old man presented with a lesion of 5-6 months' duration on his left elbow, clinically thought to be a ganglion cyst. The biopsy specimen revealed a Stage IIA MCC with classic histomorphologic and immunophenotypic findings, with tumor extending to the tissue edges. The patient underwent wide local excision with negative margins and a negative sentinel lymph node biopsy. Although the patient did not receive any presurgical chemotherapy, immunotherapy, or targeted therapy, the re-excision specimen showed only amphophilic, feathery deposits that were salmon-pink with Congo red stain and further confirmed as amyloid by electron microscopy; there were no residual carcinoma cells. Amyloid deposition in MCC has been described in rare case reports. Our case was extraordinary in that there was only amyloid deposition and an associated granulomatous reaction, without identifiable MCC cells. This case demonstrates that amyloid deposition may be evidence of a prior MCC at the site of a prior procedure and may warrant careful evaluation for residual MCC.

Diagnostic utility of PRAME expression by immunohistochemistry in subungual and non-subungual acral melanocytic lesions.

BACKGROUND: The immunohistochemical (IHC) marker PReferentially expressed Antigen in MElanoma (PRAME) has shown promise in the diagnosis of melanocytic lesions. A few studies have investigated PRAME IHC expression in acral melanomas, but PRAME expression in subungual melanomas is largely unknown. We evaluated the utility of PRAME IHC expression in distinguishing subungual melanomas (SUM) and non-subungual acral melanomas (AM) from acral nevi (AN). METHODS: Twenty-two SUM, 20 AM, and 14 AN were identified. IHC studies were performed using an anti-PRAME antibody. The percentage of lesional cells with PRAME expression was recorded and categorized as follows: 0%, 0; 1%-25%, 1+; 26%-50%, 2+; 51%-75%, 3+; and >75%, 4+. Patient demographics and other relevant clinicopathologic parameters were recorded. RESULTS: Diffuse (4+) PRAME IHC expression was identified in 55% (12/22) SUM and 70% (14/20) AM, respectively. Any PRAME expression (1+ to 4+) was identified in 73% (16/22) SUMs and 95% (19/20) AM, respectively. One of 14 (7%) AN exhibited PRAME expression; interestingly, the pattern of expression was diffuse. CONCLUSIONS: In our study, PRAME IHC expression was useful in identifying AM, including SUM. However, there are exceptions of PRAME-negative melanomas and PRAME-positive nevi.

Diverse landscape of dermatologic toxicities from small-molecule inhibitor cancer therapy.

BACKGROUND: Advances in molecular biology and genetics have contributed to breakthrough treatments directed at specific pathways associated with the development of cancer. Small-molecule inhibitors (Nibs) aimed at a variety of cellular pathways have been efficacious; however, they are associated with significant dermatologic toxicities. METHODS: We conducted a comprehensive review of dermatologic toxicities associated with Nibs categorized into the following five groups: (a) mitogen-activated protein kinase; (b) growth factor/multi-tyrosine kinase; (c) cell division/DNA repair; (d) signaling associated with myeloproliferative neoplasms; and (e) other signaling pathways. Prospective phase I, II, or III clinical trials, retrospective literature reviews, systematic reviews/meta-analyses, and case reviews/reports were included for analysis. RESULTS: Dermatologic toxicities reviewed were associated with every class of Nibs and ranged from mild to severe or life-threatening adverse skin reactions. Inflammatory reactions manifesting as maculopapular, papulopustular/acneiform, and eczematous lesions were frequent types of dermatologic toxicities seen with Nibs. Squamous cell carcinoma with keratoacanthoma-like features was associated with a subset of Nibs. Substantial overlap in dermatologic toxicities was found between Nibs. CONCLUSIONS: Dermatologic toxicities from Nibs are diverse and may overlap between classes of Nibs. Recognition of the various types of toxicities from Nibs is critical for patient care in the era of "oncodermatology/dermatopathology."

Severe de novo pustular psoriasiform immune-related adverse event associated with nivolumab treatment for metastatic esophageal adenocarcinoma.

Breakthrough targeted therapies have produced significant improvements in survival for cancer patients, but have a propensity to cause cutaneous immune-related adverse events (irAEs). Psoriasiform irAEs, representing about 4% of dermatologic toxicities associated with immune checkpoint inhibitor (ICI) therapy, are usually mild, occur in older patients and present as an exacerbation of existing psoriasis after several doses of ICI therapy. We report a case of a 58-year-old woman with metastatic esophageal adenocarcinoma and no prior history of psoriasis who developed a pustular psoriasiform irAE, beginning 3 days after initiation of nivolumab and progressing to confluent erythroderma with pustules over 2 weeks despite topical steroid use. She had concurrent acrodermatitis enteropathica, clinically diagnosed and confirmed with a low serum zinc level, that improved with supplementation. Her psoriasiform irAE was refractory to systemic steroids and acitretin, prompting discontinuation of nivolumab and treatment with ustekinumab and concomitant slow taper of acitretin and prednisone. Pustular psoriasiform irAE is a rare but severe dermatologic toxicity resulting from ICI therapy. Given the diverse morphologic types of cutaneous irAEs that can occur during ICI therapy, a clinical and histopathologic examination of dermatologic toxicities is critical to identify patients who may benefit from biologic therapy.

Cutaneous Lymphoid Hyperplasia With T-Cell Clonality and Monotypic Plasma Cells Secondary to a Tick Bite: A Hidden Critter and the Power of Deeper Levels.

ABSTRACT: Cutaneous lymphoid hyperplasia (CLH) is a benign reactive process with T-cell or B-cell lymphocytic infiltration in the skin, which can simulate cutaneous lymphomas both clinically and histologically. Various antigenic stimuli have been implicated in the development of CLH, including tick bites. Finding histologic evidence of such triggering factors, however, is often difficult. Moreover, the presence of clonality in CLH can potentially be interpreted as a neoplastic process, posing a further diagnostic challenge to dermatopathologists, if one is not aware of such peculiar phenomena. Herein, we describe a case of CLH secondary to a tick bite, featuring both T-cell clonality and monotypic plasma cells with lambda light chain restriction; the diagnostic clue being tick parts, which became evident on assessment of deeper levels. To the best of our knowledge, this is the first reported case of a tick-associated clonal CLH with simultaneous detection of monoclonal T cells and monotypic lambda light chain restriction, mimicking primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and Borrelia-associated primary cutaneous marginal zone B-cell lymphoma, respectively.