Granulomatous dermatitis in the context of chronic myelomonocytic leukemia: More than just reactive infiltrates. An illustrative case report with literature review.

Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous dermatitis included in the latter group. More recently, the true nature of the myeloid cells present in the cutaneous infiltrates of this theoretically reactive dermatitis is being clarified with the use of new molecular techniques such as next-generation sequencing. The same mutations in bone marrow (BM) myeloid neoplastic cells and in the cells of cutaneous infiltrates have been found. We present the case of a 77-year-old man who presented with spread and treatment-resistant skin granulomatous lesions previous to the diagnosis of CMML. The same clonal mutations in SRSF2, IDH1, and RUNX1 were found in both skin and BM with resolution of the lesions after the initiation of azacytidine. In conclusion, we report an exceptional case in which specific granulomatous cutaneous lesions have preceded and allowed the earlier diagnosis of an underlying CMML and a review of all previous similar cases in the literature, including molecular alterations.

Reactive Granulomatous Dermatitis: A Descriptive Study of 10 Patients.

BACKGROUND: Reactive granulomatous dermatitis (RGD) is a rare and misunderstood skin disorder. It includes interstitial granulomatous dermatitis and palisaded neutrophilic and granulomatous dermatitis: 2 entities of the same spectrum. Multiple associations are described with RGD in the literature, including autoimmune diseases, malignancy, and drugs. OBJECTIVE: To report and describe the suspected associations with RGD at the time of diagnosis and in the following year. METHODS: We retrieved and described cases of RGD confirmed by skin biopsy and clinicopathologic correlation. All patients were evaluated in the Centre Hospitalier Universitaire de Québec-Université Laval between January 2000 and December 2020. Collected data include the systemic diseases (autoimmune disease, malignancy) and suspected drugs, in addition to the clinical presentation and prescribed treatments. RESULTS: Out of the 10 patients with RGD, 7 patients were known to have an autoimmune disease at the time of diagnosis. They either had inflammatory arthritis (3/10) or inflammatory bowel disease (4/10). There was a clinical suspicion of a possible association with a tumor necrosis factor (TNF) inhibitor in 2 of these 7 patients. Among the 3 patients with idiopathic RGD at the time of diagnosis, 1 patient developed a high-grade B-cell lymphoma 6 months later. There was no new association identified in the following year for patients with a known autoimmune condition. CONCLUSION: This descriptive study supports RGD and its previously described systemic associations, particularly autoimmune diseases, malignancy, and certain drugs (specifically TNF inhibitors). The majority of patients already had one of these associations identified at the time of histopathological diagnosis.

A case of reactive granulomatous dermatitis associated with neonatal lupus erythematosus.

Neonatal lupus erythematosus (NLE) is an uncommon disorder affecting approximately one out of 20 000 live births in the United States. Common manifestations of NLE include cutaneous eruptions and cardiac involvement. The typical rash of NLE most closely resembles the rash of subacute cutaneous lupus erythematosus both clinically and histopathologically. We present a case of reactive granulomatous dermatitis (RGD) associated with NLE in a 3-month-old male in whom the initial histopathology and immunohistochemistry were concerning for hematologic malignancy. RGD is a unifying term used to describe cutaneous granulomatous eruptions that occur in response to a variety of stimuli, including autoimmune connective tissue diseases. Our case demonstrates the range of histopathological findings that may be present in the setting of NLE.

Underlying Systemic Diseases in Interstitial Granulomatous Dermatitis and Palisaded Neutrophilic Granulomatous Dermatitis: A Systematic Review.

BACKGROUND: Interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic granulomatous dermatitis (PNGD) are uncommon presentations of reactive granulomatous dermatitis. Histologic lesions characterized by IGD/PNGD patterns have been associated with systemic diseases, causing an unmet need for revealing clinical correlates. OBJECTIVE: The aim of this study was to unravel the systemic diseases beyond dermatitis of IGD/PNGD. METHODS: This study analyzed data from case studies, case series, and retrospective cohorts by searching PubMed, Embase, Web of Science, and the Cochrane Library, with no start date or language restrictions on Sep 4, 2021. RESULTS: One hundred ninety-six publications were included (458 cases in total, 216 with details). Systemic diseases associated with IGD/PNGD were classified into 5 groups. Autoimmune disorders (n = 103, 47.6%) including rheumatoid arthritis (n = 51, 23.6%), systemic lupus erythematosus (n = 20, 9.3%), and others were the most common across all underlying diseases, followed by drug eruption (n = 52, 24.1%) such as tumor necrotic factor inhibitor reaction (n = 18, 8.3%) and malignancies (n = 27, 12.5%) such as hematologic malignancy (n = 20, 9.3%). The rest were infectious diseases (n = 12, 5.6%) and accidental conditions (n = 3, 1.4%). CONCLUSION: IGD/PNGD might be associated with autoimmune disorders, drug eruption, malignancies, infectious diseases, and accidental conditions. Patients with IGD/PNGD need further follow-up.

Paraconiothyrium cyclothyrioides, a novel cutaneous fungal pathogen in a dog and a cat.

A dog and a cat presented with pyogranulomatous mycotic pododermatitis. Panfungal PCR and next-generation sequencing identified Paraconiothyrium cyclothyrioides with 100% identity. Paraconiothyrium cyclothyrioides can rarely cause cutaneous infection and systemic disease in immunocompromised humans. This is the first report of infections in domestic animal species.

Un chien et un chat sont présentés avec une pododermatite pyogranulomateuse d'origine fongique. La PCR panfongique et le séquençage de nouvelle génération ont identifié Paraconiothyrium cyclothyrioides avec un pourcentage d'identité de 100 %. Rarement, Paraconiothyrium cyclothyrioides peut provoquer une infection cutanée et une maladie systémique chez des humains immunodéprimés. Il s'agit du premier signalement d'infection dans des espèces animales domestiques.

Un perro y un gato presentaron pododermatitis micótica piogranulomatosa. La PCR panfúngica y la secuenciación de última generación identificaron Paraconiothyrium cyclothyrioides con un 100 % de identidad. Paraconiothyrium cyclothyrioides rara vez puede causar infección cutánea y enfermedad sistémica en humanos inmunocomprometidos. Este es el primer reporte de infecciones en especies de animales domésticos.

Um cão e um gato foram apresentados com pododermatite micótica piogranulomatosa. PCR panfúngico e sequenciamento de última geração identificaram Paraconiothyrium cyclothyrioides com 100% de identidade. Paraconiothyrium cyclothyrioides pode raramente causar infecções cutâneas e doença sistêmica em humanos imunocomprometidos. Este á o primeiro relato de infecções em animais domésticos.

Two cases of granulomatous mycosis fungoides mimicking interstitial granulomatous dermatosis.

Two patients presented with erythematous papules within larger patches and thin plaques. Following biopsies, each case was initially thought to represent interstitial granulomatous dermatitis (IGD); however, clinicopathological correlation led to a diagnosis of granulomatous mycosis fungoides (GMF). Drawing upon the similarities between these cases, this report explores the clinical and histological manifestations of GMF, features distinguishing GMF from other granulomatous diseases like IGD and the prognostic significance of distinguishing GMF from classic mycosis fungoides. This report also shows that despite the potential for histological overlap between GMF and IGD, the existing literature does not reveal an epidemiological or pathophysiological link between these two conditions.

Palisading granulomatous dermatitis and panniculitis (palisading granuloma) of dogs.

Palisading granulomatous dermatitis and panniculitis is recognized in various cutaneous inflammatory lesions secondary to presumed collagen damage. Cutaneous nodules with a palisading arrangement of histiocytes surrounding foci of collagen degeneration have been clinically termed palisading granuloma in dogs. Study aims were to characterize the cellular infiltrate of canine palisading granuloma and document salient clinical features. Inclusion criteria were met for 36 dogs and encompassed nodular dermal and subcutaneous histiocyte-predominant cellular infiltrates targeting and enveloping collagen fibers/necrotic foci with palisading configurations. Infectious causes were ruled out via standard histochemical stains and/or clinical data. Medical records were reviewed for signalment, clinical features, treatment, outcome, and comorbidities. Immunohistochemistry (IBA1, CD204, E-cadherin) and Masson's trichrome stain were used to assess histiocytic populations and dermal collagen, respectively. The histiocytes had moderate or strong immunolabeling for IBA1 and CD204 in 36/36 dogs (100%) and mild positive immunolabeling for E-cadherin in 3/36 dogs (8%). Alteration of collagen was graded as moderate or strong in 32/36 dogs (89%) and mild in 3/36 dogs (8%). Large breeds predominated with 30/36 dogs (83%) being ≥23 kg. Focal nodules were identified in 31/36 dogs (86%). The head/face were involved in 19/36 dogs (53%) and the extremities in 18/36 dogs (50%). Lesions from the 5/36 dogs (14%) with multiple nodules contained prominent eosinophilic infiltrates. Following excision, there was no evidence of recurrence. In conclusion, palisading granulomas are a distinct, non-neoplastic, histiocyte-predominant inflammatory condition in dogs associated with altered dermal collagen and favorable prognosis.

Granulomatous dermatitis following measles, mumps, and rubella vaccination.

Granulomatous dermatitis following the administration of various vaccines has previously been reported. However, cases of cutaneous granulomatosis following the measles, mumps, and rubella (MMR) vaccine have not yet been reported. We report the case of a 3-year-old boy with a granuloma annulare-like reaction following MMR vaccination.

In vivo cutaneous antinuclear antibody positivity in palisaded neutrophilic and granulomatous dermatitis.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is commonly associated with underlying systemic inflammatory and neoplastic diseases, infections, and drug reactions. In vivo cutaneous antinuclear antibodies (ANA) have been described in skin biopsies from patients with known autoimmune disorders, but not previously reported in the setting of PNGD. We present two patients with systemic lupus erythematosus (SLE) and histopathologically confirmed PNGD. Direct immunofluorescence (DIF) studies revealed in vivo cutaneous ANA positivity in both patients. DIF findings in the skin mirrored serum autoantibody results. ANA positivity in skin specimens is reported as highly predictive of systemic connective tissue diseases (SCTD), although specific testing is not currently recommended as part of the laboratory work-up or diagnostic criteria for these disorders. In this case report, positive ANA results in skin biopsies of PNGD reflect the serological findings and clinical evidence of SLE in both patients. In vivo cutaneous ANA positivity is an interesting and supportive finding in PNGD in the setting of SCTD.

Lichenoid granulomatous dermatitis as a tuberculid in association with spondylitis due to Mycobacterium tuberculosis.

Lichenoid granulomatous dermatitis (LGD) is a histopathologic pattern with a band-like lymphocytic infiltrate, typical of lichenoid dermatitis, combined with dermal histiocytes and granulomatous inflammation. Prior reports have described cases of LGD caused by non-tuberculous mycobacteria, with evidence of intralesional acid-fast bacilli or mycobacterial DNA. Herein, we report a patient with pulmonary and extrapulmonary Mycobacterium tuberculosis infection who developed LGD. No evidence of M. tuberculosis was detected within the cutaneous lesions, suggesting a potential delayed-type hypersensitivity reaction to tuberculosis.

Interstitial granulomatous dermatitis and granulomatous arteritis in the setting of PD-1 inhibitor therapy for metastatic melanoma.

Checkpoint inhibition has become an important target in the management of malignant melanoma. As anti-CTLA4 inhibitors and anti-PD1 antibodies are increasingly utilized, reports of immune-related adverse events (IRAEs) are becoming more frequent. Common noted cutaneous IRAEs are morbilliform, lichenoid, bullous, granulomatous, psoriasiform, and eczematous eruptions. We report a case of interstitial granulomatous dermatitis and granulomatous arteritis in the setting of nivolumab (anti-PD1) monotherapy for metastatic melanoma. There are many different causes for granulomatous vasculitis, such as herpes virus infection, lymphoproliferative disorders, systemic vasculitis, and inflammatory bowel disease. This report adds to the growing literature on granulomatous IRAEs due to checkpoint inhibition.

Interstitial granulomatous dermatitis following tocilizumab, a paradoxical reaction?

Interstitial granulomatous dermatitis (IGD) is a rare dermatosis generally seen in the setting of rheumatic diseases, but also hematological disorders, internal malignances, infections, or drug induced. Herein, we report an exceptional case of an IGD with a clear chronological association with tocilizumab onset and cessation in a patient with adult-onset Still's disease. We review the granulomatous cutaneous reactions so far reported with this novel therapy: sarcoidosis, granuloma annulare, and IGD. Tocilizumab is a humanized anti-interleukin 6 receptor monoclonal antibody useful for the treatment of various systemic inflammatory disorders. Lately, it has found useful also for granulomatous diseases such as giant cell arteritis and even a promising response in IGD. Therefore, we believe our case adds the possibility of an IGD presenting as a paradoxical reaction.

Lichenoid granulomatous dermatitis revisited: A retrospective case series.

BACKGROUND: Lichenoid granulomatous dermatitis (LGD) is an uncommon reaction pattern for which clinical correlates can be difficult to establish. LGD combines vacuolar degeneration with variable types of granulomas. OBJECTIVE: To determine clinical correlates of LGD. METHODS: The laboratory information systems at the University of Florida, the Medical College of Wisconsin, and Inform Diagnostics Research Institute were queried to identify 56 cases of LGD. Cases were reviewed for information regarding eosinophils, plasma cells, deep perivascular infiltrates, granuloma subtype, parakeratosis, epidermal atrophy, psoriasiform epidermal changes, pseudoepitheliomatous hyperplasia, periadnexal inflammation, vasculitis, and red blood cell extravasation. RESULTS: The most common clinical correlates were drug eruption (39.3%, n = 22) and lichenoid keratosis (19.6%, n = 11). Tattoo reaction, postherpetic dermatitis, and scabies or postscabietic dermatitis each accounted for 7.1% (n = 4) of cases. Pigmented purpuric dermatosis and lichen striatus each accounted for 5.4% (n = 3) of cases. Dermal eosinophils (P = .005) and psoriasiform epidermal changes (P = .055) were associated with drug hypersensitivity. Perineural (P = .049) and perifollicular (P = .003) inflammation were associated with tattoo reaction and postherpetic dermatitis. Red blood cell extravasation was helpful in cases of pigmented purpuric dermatosis (P = .049). LIMITATIONS: This study is limited by its retrospective nature and statistical power. CONCLUSION: Dermal eosinophilia, psoriasiform epidermal changes, periadnexal inflammation, and red blood cell extravasation might aid in the clinical diagnosis of patients with LGD.

Immune checkpoint inhibitors and the development of granulomatous reactions.

Immune checkpoint inhibitors (ICPIs) have emerged as a frontline treatment for a growing list of malignancies. Disruption of the negative regulatory immune checkpoints by ICPIs has been associated with many immune-related adverse events. Granulomatous reactions, such as sarcoidosis-like reactions, granulomatous panniculitis, granuloma annulare, and granulomatous dermatitis, are uncommon but increasingly recognized immune-related adverse events seen in patients treated with ICPIs. The frequency and significance of these eruptions, including whether they portend responsiveness to treatment, remain unclear. Additionally, understanding the role of immune checkpoint blockade in these reactions may provide mechanistic insight into the relevant signaling pathways involved in sarcoidosis and other granulomatous disorders.

Palisaded neutrophilic and granulomatous dermatitis associated with systemic lupus erythematosus: possible involvement of CD163+ M2 macrophages in two cases, and a review of published works.

BACKGROUND: Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a commonly occurring condition related to systemic autoimmune disease. It is characterized histopathologically by a distinct pattern of granulomatous inflammation in the presence or absence of leukocytoclastic vasculitis. The properties of granulomatous cells in PNGD are still uncertain. OBJECTIVE: We sought further investigation on the phenotype of the infiltrated cells in PNGD from two patients with systemic lupus erythematosus (SLE) and reviewed the previous published reports in order to provide a comprehensive summary on the clinical features of PNGD in SLE. METHODS: The immunohistochemical features of granulomatous cells in PNGD associated with SLE were analyzed. Immunohistochemical studies were performed on sections from our two cases using antibodies against CD68, CD163, CD15, Factor XIIIa, myeloperoxidase and neutrophil elastase. The clinical characteristics of the SLE patients who developed PNGD were also evaluated. We included all cases retrieved through a PubMed search with the key words PNGD and SLE. RESULTS: Cutaneous lesions consisted of erythematous plaques distributed on the face and upper limbs in both cases. The infiltrated cells were mainly positive for CD68 and CD163, a phenotype suggestive of M2 macrophages. Some mature neutrophils and lymphocytes were also present. A review of the literature of PNGD associated with SLE revealed a predominance in females, high prevalence of lupus nephritis and a good response to systemic steroids, with frequent skin lesions relapses during tapering of the treatment. LIMITATIONS: This study examined only two cases; the pathogenesis of the disease remains to be clarified. CONCLUSION: PNGD lesions were abundantly infiltrated by M2 macrophages, suggesting that they may have a role in this condition. SLE accompanied by PNGD might be associated with lupus nephritis and frequent relapses of skin lesions.

Palisading neutrophilic and granulomatous dermatitis as a presentation of Hodgkin lymphoma: A case and review.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a histopathological diagnosis, characterized by a pattern of granulomatosis, which may be associated with leukocytoclastic vasculitis. PNGD most commonly occurs in association with systemic inflammatory disorders, typically autoimmune conditions, such as rheumatoid arthritis and systemic lupus erythromatosus. There are very rare reports of PNGD in patients with lymphoma. We report the case of a 53-year-old female with an erythematous, papular eruption occurring in association with Hodgkin lymphoma. Histopathological evaluation of the rash confirmed PNGD. To the best of our knowledge, this is the first case of PNGD occurring in association with Hodgkin lymphoma. Although extremely rare, underlying malignancy should be considered in patients with PNGD, particularly in individuals with constitutional symptoms and the absence of an obvious inflammatory etiology.

Dermatologic toxicity from immune checkpoint blockade therapy with an interstitial granulomatous pattern.

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed significant therapeutic benefit in patients with clinically advanced solid malignancies, including melanoma. However, immune-related adverse events (irAE) are common, and novel dermatologic toxicities continue to emerge as more patients are treated with immunotherapy. Here we describe a patient treated with combination immunotherapy of ipilimumab and pembrolizumab, who developed asymptomatic erythematous patches on both legs. Histopathologic examination revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled. This case expands the dermatologic toxicity profile of immune checkpoint blockade, as recognition of such toxicities is critical to optimal patient management.

Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody therapy for advanced cancer.

Nivolumab is a fully human IgG4 monoclonal antibody directed against programmed cell death protein 1 (PD-1). PD-1 inhibition allows T-cell activation and recruitment to destroy cancer cells. Checkpoint inhibitors have shown significant survival advantage and relatively low side-effects in comparison with conventional chemotherapy in several types of advanced cancer. Granulomatous cutaneous reactions have been reported showing sarcoidal and panniculitic morphology. Here we present a case of drug-induced lichenoid and granulomatous dermatitis after checkpoint inhibitor therapy observed in a 63-year-old male treated with nivolumab for advanced glioblastoma. This morphology has not been previously reported. We documented a high number of CD8+ T-cells within the lesions. Additionally, we review the side-effects observed with the use of checkpoint inhibitors, with special focus on cutaneous manifestations.

Granulomatous dermatitis secondary to vemurafenib in a child with Langerhans cell histiocytosis.

We present a 3-year-old boy with Langerhans cell histiocytosis who developed granulomatous dermatitis while taking vemurafenib. Vemurafenib currently has Food and Drug Administration approval for the treatment of BRAF V600E+ metastatic melanoma in adults, but recent discoveries of BRAF V600E in more than half of tested Langerhans cell histiocytosis lesions have prompted clinical trials of vemurafenib therapy for children with refractory, multisystem Langerhans cell histiocytosis. This report contributes to the knowledge of its potential side effects when used in children.