Pyoderma Gangrenosum Associated With Iatrogenic Interleukin 17A Blockade: A Report of Two Cases and a Review of the Literature.

Pyoderma gangrenosum (PG) is a rare necrotizing neutrophilic dermatosis driven by monokines and cytokines elaborated by monocytes and autoreactive T cells, respectively. Th1-mediated autoimmune disorders and myeloproliferative disease are among the potential disease associations. More recently, certain medications were implicated, including TNF-alpha inhibitors, rituximab, and IL-17A inhibitors, such as secukinumab, where the development of PG is held to represent a cutaneous immune adverse effect. We present two patients who developed an autoinflammatory syndrome resembling PG in the setting of drug therapy with agents exhibiting an IL-17A inhibitory effect. The drugs were erunumab in one and secukinumab in the other. One patient received the anti-calcitonin gene-related peptide targeted therapy, erenumab, for migraine prophylaxis. While this drug has not been previously implicated in the development of PG, it can cause IL-17A blockade. The other patient was on secukinumab, a monoclonal antibody that selectively targets IL-17A. We documented a microenvironment enriched in IL-17A, emphasizing that the blockade impacts the functionality of the receptor as opposed to a quantitative reduction in IL-17A production by T cells. Qualitative functional IL-17A blockade could result in a paradoxical increase in IL-23, a pro-inflammatory cytokine that may contribute to the influx of neutrophils pathogenetically implicated in PG.

THE UTILITY OF THE NORMAL THIN SECTION SKIN BIOPSY IN THE ASSESSMENT OF SYSTEMIC/EXTRACUTANEOUS DISEASE.

BACKGROUND: Diseases reflective of multiorgan vascular injury of diverse etiology, peripheral nerve disease, dysautonomia syndromes and intravascular lymphoma malignancies may potentially exhibit abnormalities on a normal skin biopsy that may be instrumental in establishing a diagnosis. MATERIALS AND METHODS: A retrospective review of our data base was conducted to uncover cases where a normal skin biopsy was performed to rule in or out certain systemic diseases such as complement driven thrombotic microvascular disease including atypical hemolytic uremic syndrome, post transplant thrombotic microangiopathy, and severe/critical COVID-19, systemic capillary leak syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) intravascular B cell lymphoma, dysautonomia syndromes and mast cell activation syndrome. Immunohistochemical stains were conducted inclu C5b-9, CD56, MXA, B and T cell markers. RESULTS: There were expected patterns critical in establishing diagnosis based on evaluating certain parameters including assessing for increased C5b-9 microvascular deposition from the deltoid area(atypical hemolytic uremic syndrome, post-transplant thrombotic microangiopathy, catastrophic antiphospholipid antibody syndrome and severe/critical COVID-19), enhanced type I interferon signaling (systemic capillary leak syndrome), ultrastructural arteriopathic changes (CADASIL),lower extremity reduced cutaneous autonomic innervation (small fiber neuropathy and POTS), abdominal, thigh and buttock skin for the presence of intravascular lymphocytes on biopsy(intravascular B cell lymphoma), distinct structural changes in elastic fibers supportive of pseudoxanthoma elasticum and a higher than normal density of mast cells in the absence of other inflammatory cell types (mast cell activation syndrome). CONCLUSION: The skin is a critical window for understanding disease, a concept well exemplified by the myriad of diseases that can be suggested by the microscopic and or ultrastructural examination of clinically normal skin, hence establishing the normal skin biopsy as an important tool for understanding extracutaneous disease.

Tumor necrosis factor ALPHA Inhibitor Associated Köhlmeier-Degos Disease as a Novel Iatrogenic Paradigm That Underscores Excessive Type I Interferon in Its Pathogenesis.

ABSTRACT: Malignant atrophic papulosis/Köhlmeier-Degos disease was first described in 1941 by Köhlmeier in an anecdotal case report that described a young man who presented with extensive multiple intestinal perforations and a papular skin rash. Köhlmeier-Degos disease represents a unique vasculopathy targeting both the microvasculature and the arterial system. One of its most characteristic features is reflected by the discrete multifocal depressed porcelain lesions involving the skin and gastrointestinal tract. The pathological findings are striking and can be broadly categorized into those that are vascular in nature versus extravascular matrix production in the context of extensive extravascular hyaluronic acid and collagen deposition. A dynamic evolutionary morphology is observed not only clinically but also histologically. The microvascular alterations are particularly evident in the skin and are characterized by endothelial cell necrosis with subsequent endothelial cell detachment accompanied by intraluminal fibrin deposition, defining a thrombogenic microangiopathy that in later stage lesions is typically pauci-inflammatory. The arterial lesions are very distinctive and include significant neointimal proliferation with vascular luminal occlusion by amorphous plugs of collagen intimately admixed with platelets. Pathogenetically enhanced type I interferon signaling and endothelial cell injury mediated by the membranolytic attack complex (ie, C5b-9) are key in the evolution of the thrombotic microvascular and obliterative fibrosing arteriopathic changes. We describe a case of Köhlmeier-Degos disease that developed in the setting of tumor necrosis factor (TNF)-alpha inhibitor therapy with the drug golimumab. The clinical features, light microscopic findings, and a pathophysiologic paradigm based on the critical role of TNF-alpha in controlling the type I interferon response are discussed.

Exploring cutaneous lymphoproliferative disorders in the wake of COVID-19 vaccination.

Background: Individual reports have described lymphoproliferative disorders (LPDs) and cutaneous lymphomas emerging after administration of the COVID-19 vaccine; however, the relationship between reactions and vaccine types has not yet been examined. Objective: Determine if there are cases of cutaneous LPDs associated with certain COVID-19 vaccines and their outcomes. Methods: We analysed PubMed, the Vaccine Adverse Events Reporting System (VAERS), and our database for instances of biopsy-proven LPDs following COVID-19 vaccines. Results: Fifty cases of biopsy-proven LPDs arising after COVID-19 vaccination were found: 37 from medical literature, 11 from VAERS and two from our institution. Geographical distribution revealed the most cases in the United States, Italy, and Greece, with single cases in Spain, Colombia, Canada, Japan, and Romania. The average age of patients was 53; with a slight male predominance (male-to-female ratio of 1.5:1). The Pfizer-BioNTech vaccine was associated with LPDs in 36/50 (72%) cases, aligning with its 70% share of the global vaccine market. Histopathology revealed CD30+ in 80% of cases. The most prevalent form of LPD was lymphomatoid papulosis (LyP, 30%). All reported cases produced favourable outcomes (either complete or near-complete remission). Therapeutic approaches ranged from observation to treatment with steroids, methotrexate, or excision. Conclusion: LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character.

Febrile Ulceronecrotic Mucha-Habermann Disease Associated With Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature.

ABSTRACT: Mucha-Habermann disease (MHD) is an inflammatory skin disease characterized by polymorphous eruptions of erythematous, necrotic macules that have been reported for similarities to cutaneous T-cell lymphoma. Febrile ulceronecrotic MHD (FUMHD) represents a severe variant of MHD, marked by ulcers, hemorrhagic bullae, and systemic symptoms. Herein, we report a case of a severely atypical lymphomatoid expression of FUMHD associated with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 21-year-old woman was admitted to the hospital with a rapidly progressive necrotic papular rash. Physical examination revealed right orbital swelling, bilateral hemorrhagic auricular bullae, and multiple ulcerative purpuric papulonodules on the trunk, face, and extremities. Biopsy indicated a dermal and subcutaneous infiltrate of atypical CD8 + lymphocytes with loss of CD5 and reduction in CD7 expression, along with features of lymphomatoid vasculitis. A diagnosis of a severely atypical lymphomatoid expression of FUMHD was made. The patient also met 7 of 9 HLH-2004 criteria, leading to a diagnosis of HLH. Positron emission tomography/computed tomography, flow cytometry, and rheumatologic workup were unremarkable. Treatment with an eight-week course of etoposide and dexamethasone for HLH led to rapid clinical improvement. Over time, her skin lesions regressed and eventually scabbed over to leave hyperpigmented scars, confirming the diagnosis of MHD. She has remained stable, off therapy for 4 years. Although potentially fatal, FUMHD often exhibits favorable outcomes and may resolve without recurrence, as in our patient. FUMHD should be considered in the differential diagnosis for patients presenting with cutaneous CD8 + necrotizing angiocentric lymphoproliferative disease complicated by HLH.

Expanding the Differential Diagnosis of the Painful Nail: A Case of an Onychopapilloma with Neuroma.

Introduction: Onychopapilloma most commonly presents as longitudinal erythronychia, but diagnosis may be challenging in some cases due to varied clinical presentations. Most patients with onychopapillomas do not report associated pain but instead more commonly report functional interference. Case Report: We present a case of a 74-year-old female with a 5-year history of splitting and lifting of the right thumbnail, accompanied by nail sensitivity and intermittent painful throbbing. Clinical examination was significant for a less than 1 mm red line with distal onycholysis. Love's test and a cold test performed with ice pack were negative. X-ray of the right thumb was negative for erosion or exostosis. Nail biopsy was performed, and dermatopathology was consistent with onychopapilloma with a concomitant traumatic neuroma. Conclusion: We report a case of onychopapilloma with a concomitant traumatic neuroma. Subungual neuromas are extremely rare and have not previously been associated with onychopapilloma. Our case supports the expansion of the differential diagnosis for a painful nail and demonstrates the importance of diagnostic confirmation with biopsy and histopathology.

Horrifying Basal Cell Carcinoma Presenting as Progressive Pyoderma Gangrenosum: Case Report.

Introduction: Skin ulcers can be challenging to diagnose and manage, particularly with comorbid autoimmune and gastrointestinal diseases. Occam's razor encourages the simplest explanation to guide care, but reconsideration must occur when intervention proves futile. Case Presentation: We report the case of a 70-year-old male, with a 17-year history of expanding pretibial skin ulcer, presumed by prior care providers to be pyoderma gangrenosum related to Crohn's disease. A surgical biopsy performed upon presentation to our institution revealed basal cell carcinoma of the skin, invasive to the proximal tibia with associated deep infection, prompting transfemoral amputation. Conclusion: This report is written as a reminder to reconsider a diagnosis and consider seeking additional expertise when a patient's condition progressively worsens despite intervention. Earlier diagnosis likely would have facilitated therapeutic limb salvage care.

Subcutaneous panniculitic-like T-cell lymphoma localized to a site of peginterferon alfa-2a administration.

T cell dyscrasias that demonstrate a proclivity for the subcutaneous fat include atypical lymphocytic lobular panniculitis, lupus profundus, and primary subcutaneous T cell lymphoma, including subcutaneous panniculitis-like T cell lymphoma (SPTCL). We encountered two patients who developed fever and indurated abdominal erythema at their peginterferon alfa-2a injection sites. Biopsies showed an atypical CD8 positive, granzyme positive, CD5 negative, MXA negative lymphocytic lobular panniculitis, diagnostic of SPTCL. Peginterferon alfa-2a was held in both patients. One patient received chemotherapy with an excellent response, while the other continued to have progressive disease. Peginterferon alfa-2a is known to significantly elevate serum MXA, which may induce high levels of MXA expression at the injection site, creating a microenvironment for the development of lupus profundus, which may eventuate into SPTCL. In summation, a potential risk of peginterferon alfa-2a injections is the development of SPTCL potentially arising in a background of an exogenous interferon triggered lymphocytic panniculitis.

Cutaneous lymphoproliferative disorders after COVID-19 vaccination: clinical presentation, histopathology, and outcomes.

Individual reports described lymphoproliferative disorders (LPDs) after COVID-19 vaccination; however, the relationship between cases is unexamined. We aim to determine if there are cases of cutaneous LPDs associated with COVID-19 vaccination and their outcomes. We present a review of world literature, vaccine registries, and two unreported cases of LPDs after COVID-19 vaccination. Review of the medical literature, VAERS, and our two cases reveal predominance of Pfizer-BioNTech vaccine, younger patients, and males. All cases resulted in favorable outcomes. Approximately 84% of cases demonstrated CD30+ positivity in their skin biopsies, suggesting that an antigenic trigger may lead to a type IV adaptive immune response, with clonal expansion of CD30+ T-cells and subsequent oncogenic mutational hits eventuating in transient LPDs. LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character.

TEMPI syndrome: A clinical, light-microscopic and phenotypic evaluation with review of the literature.

BACKGROUND AND OBJECTIVES: TEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonaryshunting) syndrome is a rare multisystemic disease classified as a monoclonal gammopathy of cutaneous significance. The pathogenesis and etiology of TEMPIare not well known because of the rarity of this disorder. Although telangiectasias are the hallmark of this syndrome, skin biopsies are rarely performed. We aim to further characterize TEMPI syndrome through the evaluationof a skin biopsy. METHODS: We reviewed the histopathology and immunophenotypic profile of a skin biopsy from a 53-year-oldwoman diagnosed with TEMPI syndrome. Other components of her syndromic complex included an IgA myeloma, elevated vascular endothelial growth factor (VEGF), and erythrocytosis. RESULTS: A biopsy showed prominent vascular ectasia with some degree of microvascular basement membranezone thickening. Our patient had a reduction in neoplastic plasma cell burdenand clearing of her telangiectasias following myeloma directed treatment. CONCLUSIONS: TEMPI can beviewed as a reactive vascular paraneoplastic syndrome in the setting of a plasma cell dyscrasia. Elaboration of VEGF from neoplastic plasma cells is likely pathogenetically implicated and appears to be a common link that explains other vascular lesions associated with monoclonal gammopathy syndromes.

Bullous Lichen Planus of the Nails: A Case Report and Review of the Literature.

Lichen planus is a chronic inflammatory disorder that may affect the skin, nails, and/or oral mucosa. Bullous lichen planus is a rare variant of lichen planus, which is even less common in the nails. We present a case of nail bullous lichen planus, in a 48-year-old male presenting with a 10-month history of onychodystrophy of all ten fingernails. A longitudinal excision of the left thumbnail was performed, with histopathology consistent with lichen planus with focal transition to bullous lichen planus. He was treated with intralesional triamcinolone injections to the fingernails monthly, with improvements noted after three treatments. Our patient's nail bullous lichen planus manifested with longitudinal ridging, white-yellow discoloration, onycholysis, subungual hyperkeratosis, and v-shaped nicking. Histopathological findings included classical lichen planus changes, as well as formation of subepidermal bullae, colloid bodies, and extensive inflammatory infiltrate. Increased awareness and high index of suspicion for this condition are necessary, given the often late diagnosis reported in previously published cases.

Primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder: A clinical and histologic retrospective cohort study.

Clonally restricted, non-epidermotropic, low-grade, CD8-positive T-cell infiltrates of the skin was recognized as a unique form of indolent CD8-positive lymphoproliferative disease in 2007 when it was first called primary cutaneous indolent CD8-positive lymphoid proliferation. More recently, the designation of primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder has been used. It is unique as a cutaneous lymphoproliferative disorder because of relative uniformity in its clinical presentation and histomorphology. It has been recognized as having an interesting predilection for the ear and acral sites, characteristically presenting as a solitary lesion. The basic morphology is one characterized by a non-epidermotropic, tumefactive infiltrate of well-differentiated, noncerebriform, atypical, small- to intermediate-sized lymphocytes that exhibit a specific phenotype characterized by CD8 and TIA positivity in concert with a distinct perinuclear Golgi staining pattern for CD68. The typical presentation is in the context of a solitary lesion, which can be treated surgically or with local irradiation. We describe in detail two very unusual cases that expand the clinical spectrum of this condition given the non-acral localization, the multiplicity of lesions to involve the trunk and extremities, and, in one case, the stable but recalcitrant course over 30 years. In addition, the second patient developed paraneoplastic dermatomyositis. We also retrospectively review our database for other cases that represent the entity of primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder and review the literature focusing on non-acral cases. Nomenclature evolution from its first recognition in 2007 to the present is discussed.

Panniculitic primary cutaneous gamma delta T-cell lymphoma with concomitant features of autoimmune disease emphasizing a pathophysiologic continuum of lupus profundus with the panniculitic T cell lymphomas.

Certain T-cell lymphomas exhibit unique homing properties of the neoplastic lymphocytes for the subcutaneous fat. There are two primary forms of subcutaneous panniculitic lymphomas of T-cell origin. One falls under the designation of primary cutaneous gamma-delta T-cell lymphomas (PGD-TCL) whereby there is dominant involvement of the fat defininng a panniculitic form of PGD-TCL. The neoplastic cells are of the gamma-delta subset and are either double negative for CD4 and CD8 and/or can express CD8. They often have an aggressive clinical course. The other form of panniculitic T-cell lymphoma falls under the designation of subcutaneous panniculitis-like T-cell lymphoma (SPTCL). It represents a subcutaneous lymphoma derived from CD8+ T cells of the alpha-beta subset and typically has an indolent course. These two forms of panniculitic T-cell lymphoma exhibit overlapping histologic features with lupus profundus (LP), a putative form of panniculitic T-cell dyscrasia. We present three cases of PGD-TCL of the fat in the setting of lupus erythematosus (LE) (two cases) and dermatomyositis (DM) (one case), respectively. There were concurrent features of LE and DM in their lymphoma biopsies in two cases while a prior biopsy in one was interpreted as LP. In this latter case, the LP diagnosis presaged the diagnosis of panniculitic PGD-TCL by three years. One patient diagnosed with panniculitic PGD-TCL had hemophagocytic syndrome after developing a lupus-like complex including certain supportive serologies such as antibodies to double-stranded DNA following initiation of statin therapy. The second patient presented with PGD-TCL and concomitant features of anti-nuclear matrix 2 (NXP2) DM. The third patient presented in 2003 with LP and overlying skin features of acute LE, initially responding to Plaquenil, and then four years later was diagnosed with PGD-TCL heralded by Plaquenil treatment resistance. Two of the patients died of their lymphoma. All biopsies showed a characteristic histopathology of PGD-TCL. In two cases, the PGD-TCL was associated with overlying LE-cutaneous findings; another case had skin changes of lymphocyte-rich DM. In two cases, the MXA stain was strikingly positive, the surrogate type I interferon marker that is typically upregulated in biopsies of LE and DM. There are eight prior reported cases describing SPTCL with concomitant cutaneous changes of LE. In six cases there was an established history of LE, including LP responding initially to Plaquenil, similar to one of our cases. In the context of SPTCL or panniculitic PGD-TCL, panniculitic T-cell lymphomas can be associated with concomitant clinical and histologic features of LE or DM, including an upregulated type I interferon signature. Identifying histologic features associated with either of these prototypic autoimmune conditions should not be considered exclusionary to diagnosing any panniculitic T-cell lymphoma. A clinical, histomorphologic, and pathophysiologic continuum exists with LP, SPTCL and panniculitic PGD-TCL.

Nail Unit Arteriovenous Hemangioma Presenting as Longitudinal Erythronychia.

Introduction: Localized longitudinal erythronychia is defined as a single nail with a longitudinal red band extending the length of a nail plate. It has a broad differential of benign and malignant etiologies, and is rarely due to benign vascular proliferations. Case Presentation: We present a unique case of nail unit arteriovenous hemangioma presenting as longitudinal erythronychia of the left thumbnail in a 76-year-old male. The band was 6 mm and encompassed over 40% of the surface area of the nail plate. Dermoscopy showed red bands that were regular in terms of color, but not thickness or spacing. Due to concern for an amelanotic melanoma, a longitudinal excision was performed. Histopathology was consistent with a diagnosis of nail unit arteriovenous hemangioma. Conclusion: Arteriovenous hemangiomas were rarely present in the nail unit. They can be present as a blue or red nodule/macule, or as longitudinal erythronychia. Diagnosis often requires an excisional biopsy, with histopathology notable for a proliferation of multiple thick- and thin-walled vascular structures lined by a flattened endothelium. Our case emphasizes the need to consider vascular proliferations, such as arteriovenous hemangioma, in the differential diagnosis of longitudinal erythronychia.

Nail Unit Squamous Cell Carcinoma with Onycholemmal Features: Case Report and Review of the Literature.

Introduction: Onycholemmal carcinoma (OC) is a rare subtype of squamous cell carcinoma (SCC) that originates from the epithelium of the nail bed. It is characterized by distinct histopathologic features including small clusters of atypical squamous epithelium devoid of a granular layer, with abrupt onycholemmal keratinization. Case Presentation: We present a case of a 75-year-old male with right thumbnail onycholysis, yellow-green nail plate discoloration, as well as bleeding and purulence of the lateral nail fold. Histopathologic evaluation revealed high-grade squamous dysplasia, small clusters of severely atypical epithelial cells, and a pattern of abrupt keratinization consistent with the diagnosis of SCC carcinoma with onycholemmal features. GMS and PAS staining indicated concomitant onychomycosis. Pathologic analysis also disclosed residual SCC and concomitant amyloidosis, possibly light chain related and hence reflective of his underlying multi-organ lymphoplasmacytic lymphoma. The patient subsequently underwent Mohs micrographic surgery. Conclusion: Clinical presentation of nail unit SCC with onycholemmal features is highly variable, making differentiating between similarly presenting benign and malignant nail disorders particularly challenging. This case report demonstrates clinical and histopathological features of nail unit SCC with onycholemmal features to improve diagnosis and management.