Neutrophilic Microabscesses Research Articles

Histologic Features of Mycobacterial Spindle Cell Pseudotumors: A Multi-institutional Clinicopathologic Analysis of 14 Cases.

Mycobacterial spindle cell pseudotumors (MSPs) are a rare and diagnostically challenging manifestation of non-tuberculous mycobacterial (NTM) infections. Proper recognition of these pseudotumors is important because they are treatable and benign. In this study, we evaluated the morphologic patterns of MSPs to improve their pathologic identification. Clinical and morphologic features of 14 MSPs were analyzed. Histologic factors evaluated included the architectural growth pattern of spindled or epithelioid macrophages, granulomas and their location within the lesion, neutrophilic microabscesses, multinucleated giant cells, necrosis, and effacement of background tissue. The composition of inflammatory infiltrates, organism density by acid-fast staining, and stromal changes were also assessed. In addition, 8 of 14 cases underwent molecular microbiology identification by a clinical amplicon-sequencing assay for non-tuberculous mycobacteria. MSP sites included 2 bowel, 10 lymph nodes, 1 liver, and 1 extremity. Cases with available clinical history (n=10) all occurred in immunocompromised patients. All demonstrated effacement of normal structures with spindled cells arranged in a storiform or fascicular architectural pattern. In addition, all cases showed lymphocytic inflammation, with prominent concurrent neutrophilic inflammation in 50% (7/14) of cases. Other morphologic findings included foamy histiocytes (64%, 9/14), peripherally situated granulomas (21%, 3/14), and neutrophilic microabscesses (21%, 3/14). All tested cases were positive for NTM by PCR methods. Mycobacterium avium was the most commonly isolated pathogen (6/8). Mycobacterial spindle cell pseudotumors show predominantly spindled morphology that may be mistaken as a neoplasm. Surgical pathologists who evaluate lymph nodes, soft tissue, and gastrointestinal tissues should be aware of this spindled tumefactive phenomenon in the setting of immunocompromised patients. Recognition of key morphologic features of neutrophilic inflammation, peripheral granulomas, or foamy histiocytes within a spindled lesion can help guide the pathologist to a correct diagnosis of an inflammatory process secondary to infection rather than a spindle cell neoplasm. Accurate diagnosis to facilitate appropriate antimicrobial and/or surgical therapy requires a comprehensive evaluation combining clinical, histopathologic, and microbiological findings.

Isolated Breast Sarcoidosis

Background: Sarcoidosis is a rare non-caseating granulomatous disease of unknown origin that affects multiple systems in the body occurring more frequently in young women age 17-24 years. Cases with manifestations that doesn’t affect the common organs can be difficult to identify and delay the patient’s diagnosis, meaning that the finding of an isolated breast mass should include sarcoidosis as one of its differentials, to ensure early detection and a better prognosis. Case presentation: We present the case report of a 21-year-old female patient, who had noticed a palpable breast nodule associated with local pain and fever for 2 months. Physical examination detected palpable bilateral axillary lymph nodes, a nodule occupying the lateral quadrants of the left breast and bullous lesions, along with phlogistic signs in the same topography. The imaging exams of the chest, showed a solid-cystic complex in the lateral quadrants of the left breast, in addition to bilateral axillary lymph node enlargement. Laboratory tests was unremarkable. The histopathological tests detected fibroadipose tissue with noncaseating granulomas, neutrophilic microabscesses and Langerhans-type giant cells, causing chronic granulomatous mastitis, which may represent sarcoidosis. The lesions regresed after the use of corticosteroids. Conclusion: Despite its rarity, the clinical and imaging findings such as those of this patient, should warrant the consideration of breast sarcoidosis as a possible diagnosis given the importance of excluding similar conditions, such as neoplasms, early on.

Tumor infiltrating neutrophil microabscess in OSCC: A poorly understood histopathologic prognosticator

ObjectiveRole of neutrophils in shaping the tumor microenvironment is well known in oral squamous cell carcinoma (OSCC). However, neutrophil microabscess (NM) formation within the tumor islands is distinctive phenomenon and has never been investigated in the literature. This pilot observational study identifies the incidence of NM in OSCC and its clinicopathologic correlation as a platform for the future studies. MethodologyA retrospective study was carried out on archival specimens of 121 cases of surgically excised OSCC specimens for identification of NM formations within the tumor islands using compound microscope. Mean NM density was calculated based on the quantification done at five randomly selected hotspots. ResultsOut of total 121 cases of OSCC, thirteen (10.74%) cases showed a frank evidence of NM within tumor islands. The hotspot analysis showed that the NM density ranges from 2 to 7 with mean of 3.76 ± 1.39 per high power field. NM density was higher in moderately differentiated OSCC (3.76 ± 1.93) than well differentiated (3.76 ± 1.93) however the differences were not statistically significant (p = 0.165). Similarly, higher NM density was reported in advanced T stage, lymph node involvement, advanced TNM stage and lymphovascular invasion, however, the results were statistically insignificant. ConclusionThere is evidence of NM formation in the tumor islands of OSCC, however their exact role as a prognosticator needs further exploration with large sample size and follow-up data.

P21 Facial papules in an immunocompromised patient

Abstract A 29-year-old man presented with a 6-week history of clustered facial papules. Of note, he had a diagnosis of HIV 5 months previously and was on maintenance antiretroviral treatment. His initial CD4 count was 5, which increased to 38, and his viral load was now no longer detectable. He had also been treated for cytomegalovirus reactivation, pneumocystis pneumonia and suspected mycobacterium infection for the previous 3 months. He had ongoing symptoms of malaise, fevers, weight loss and nausea, along with abnormal liver function tests and a raised C-reactive protein. A bone marrow trephine showed noncaseating discrete small granulomas; Grocott and periodic acid–Schiff (PAS) stains were negative. Prior to his dermatology review, the papules were initially perioral and he had been treated with empiric valaciclovir for suspected herpes simplex virus (HSV) but with no resolution. Testing for HSV DNA and syphilis was negative. On examination, there were clusters of small nontender, well-circumscribed papules (some umbilicated), distributed on the forehead, cheeks, and cutaneous and mucosal lips. A diagnostic punch biopsy was taken of one of the characteristic papules. Histological examination demonstrated a dense dermal infiltrate of histiocytes with focal non-necrotizing granuloma formation. Interspersed neutrophilic microabscesses and occasional eosinophils were present. PAS stain for fungi confirmed the presence of numerous thick-walled spherules, many with a single distinct nucleus, with some showing binucleation, consistent with fungal organisms located within the histiocytes in the dermis. Differential diagnosis included histoplasmosis, cryptococcosis, blastomycosis and coccidiomycosis. He was commenced on intravenous liposomal amphotericin B for disseminated endemic mycosis while awaiting definitive diagnosis. Formal identification by panfungal polymerase chain reaction of skin tissue was positive for Histoplasma capsulatum and itraconazole was added. The diagnosis was consistent with disseminated histoplasmosis with cutaneous involvement. The lesions resolved completely over 4 weeks, with some residual hyperpigmentation remaining. Histoplasma capsulatum is a dimorphic fungus found in soil and the droppings of bats and birds. Infection is through spore inhalation, with most patients being asymptomatic. It is more prevalent in temperate and tropical climates. Disseminated histoplasmosis occurs mostly in immunocompromised individuals and can be fatal if left untreated. Although endemic to specific world regions, disseminated histoplasmosis should be considered in immunocompromised patients presenting with atypical cutaneous findings, even in regions of low prevalence.

A rupioid rash.

A 72-year-old man presented for a thick hyperkeratotic skin rash on the shins that had erupted 7 months earlier after minimal local trauma (Fig. 1A, B). Topical treatments with glucocorticoids and antibiotics were ineffective, although a slight improvement was noted during summer. Additionally, low-grade fevers and an asymmetric oligoarthritis of the upper and lower limbs and dactylitis of the thumb and fourth toe on the left appeared over the last weeks. Mild non-specific onychodystrophy of the toes was found, whereas no inflammatory back pain or enthesitis was present. Plain radiographs did not reveal disease-specific deformities, erosions or osteo-proliferative lesions. Laboratory tests showed raised inflammatory markers (CRP: 17.7 mg/dl, ESR: 107 mm/h), leukopoenia (2.580/μL) and anaemia (haemoglobin: 10.3 g/dl). Differential diagnosis of the rash included crusted scabies, secondary syphilis, neutrophilic dermatoses, histoplasmosis and a hyperkeratotic psoriasis variant [1]. Skin biopsy revealed psoriasiform acanthosis, thick parakeratosis, dense neutrophilic infiltration and microabscess formation (Fig. 1C). Based on the type of musculoskeletal involvement and the skin histopathology, the patient was diagnosed with psoriatic arthritis with rupioid psoriasis. Treatment with medium-to-low dose systemic glucocorticoids and infliximab led to arthritis remission, skin (Fig. 1D) and laboratory improvement. Rupioid psoriasis (derived from the Greek word ρύπος = dirt) is a rare hyperkeratotic variant of psoriasis characterized by well-demarcated plaques with thick, dirty-appearing adherent crusts. It is associated with local treatment failure [2], psoriatic arthritis and male sex and it may present challenges in the diagnosis of patients with arthritis and systemic inflammation. Written informed consent has been obtained from the patient.

A case of pituitary gland abscess associated with granulomatous hypophysitis

BackgroundGranulomatous hypophysitis is a rare disease that presents with chronic inflammation of the pituitary gland. In this study, we reported a case of granulomatous hypophysitis associated with a pituitary abscess.Case presentationA 39-year-old woman presented with a 2-year history of infertility. For the past six months, she has suffered from amenorrhea, decreased libido, headaches, and vertigo. She was referred to our hospital with a suspected diagnosis of nonfunctioning pituitary adenoma based on her presentation and brain MRI findings. She underwent trans-sphenoidal surgery (TSS). Direct observation during surgery revealed drainage of malodor pus and pituitary gland abscess. The histopathological evaluation also showed granulomatous hypophysitis and neutrophilic microabscess formation.The patient was initially treated with high doses of ceftriaxone (2 g twice daily) and metronidazole (500 mg (mg) four times per day). Also, the patient received cortisol replacement therapy after the operation. After obtaining the antibiogram and culture results, the treatment regimen was continued for 4 weeks postoperatively, followed by amoxicillin-clavulanate (500/125 mg three times daily) for a total duration of 12 weeks.ConclusionThe patient recovered uneventfully and the postoperative MRI was normal without any remnant lesions.

Injury patterns and potential diagnostic pitfalls associated with radiation and radio-chemotherapy in the stomach and gastroesophageal junction

Chemoradiation-associated injury may cause marked epithelial and stromal changes in gastric specimens. We characterized these histologic features in a retrospective series of cases. Nineteen cases of radiochemotherapy-associated gastropathy were identified, including 16 from our institution and 3 from consultation material. Patient charts and hematoxylin and eosin-stained slides were reviewed. Most patients were men (79%) with a median age of 66 years. All patients had a documented history of radiation and 15 patients also received chemotherapy. The median time from treatment to biopsy or resection was 2.3 months. Gross and endoscopic findings included erythematous, hemorrhagic, or ulcerated mucosa. Mucosal eosinophilia was seen in 16 cases (84%) while 10 cases (53%) featured acute inflammation including neutrophilic microabscesses. Epithelial changes included increased apoptosis (6 cases, 32%) and marked epithelial atypia (10 cases, 53%), potentially mimicking malignancy in some cases. However, the atypical cells featured voluminous eosinophilic cytoplasm with low nuclear-to-cytoplasmic ratio, a clue to their benign nature. Neuroendocrine cell nests were seen in 4 cases (21%) and loosely aggregated in 1 case, potentially mimicking a well-differentiated neuroendocrine tumor or enterochromaffin-like (ECL) cell hyperplasia in autoimmune gastritis. Eleven cases (58%) featured vascular changes that included vessel dilation, hobnailed endothelial cells, and fibrin thrombi. Stromal changes were seen in 11 cases (58%) and included lamina propria hyalinization, submucosal fibrosis, and myofibroblast atypia. Injury associated with radiochemotherapy is histologically varied and may affect epithelial, stromal, and vascular compartments. Familiarity with these features is important as a subset of these findings may provoke concern for neoplasia.

Diagnostic Approach to Keratoacanthoma : Differentiating with Squamous Cell Carcinoma

Keratoacanthoma (KA) is a cutaneous neoplasms from the pilosebaseous unit, characterized as a rapidly growing tumor and usually show spontaneous regression. A major difficulty in dealing with these neoplasms is to differentiating them from squamous cell carcinoma, clinically and histologically. However, the change for regression has led keratoacanthoma as benign tumors with different pathophysiological mechanism from cutaneous squamous cell carcinoma (cSCC). The similarities between keratoacanthoma and cSCC, especially the well-differentiated variant cSCC, has led to the general recommendation for surgical excision of keratoacanthoma to make sure that a potentially malignant cSCC is not left untreated. Differentiating KA with cSCC would change management strategies to the less invasive treatment modalities, prevent surgical morbidity, and reduce healthcare costs. Methods : We searched for relevant journal articles in PubMed with a systematic search using PICO, with the keyword “Keratoacanthoma“ or “Squamous cell carcinoma“ and “Diagnostic“ or “History, physical examination, histology“. We got 825 publications and we filtered by the last five years and we generated 12 publications from 2017-2022 after we checked from the title and abstract for relevancy. Conclusion : The review revealed that keratoacanthoma can be distinguished from squamous cell carcinoma from the biological differences of spontaneous regression, very rapid growth and the absence of malignant features. It can also be distinguished by the histological and immunohistochemistry examination such as the presence of epithelial lips, neutrophilic microabscesses within the atypical epithelium, firm boundaries between tumor and stroma, ulceration, many mitotic cells and pleomorphic or anaplastic. The study also show that CD1a and Hsp60 can help distinguish between KA and SCC.

Dermatitis Herpetiformis (Duhring Disease)

A19-years-old male patient presented to the dermatology clinic complaining of severe itching with excoriations of the skin for 7 months ago. On examination, there were multiple crusted erosions, some vesicles, and scars of previous attacks on both elbows (Panel A), knees, thigh, upper back, forehead, scalp, and sides of the face. Punch biopsy was taken that revealed neutrophilic microabscess at the tip of the dermal papillae with subepidermal separation with mainly neutrophils infiltrates (Panel B-X10 and C-X40). Immunofluorescence studies and enzymes assays for dermatitis herpetiformis (DH) and celiac disease are not available in our locality. Accordingly, DH was diagnosed and treated with Dapsone 100 mg/day after no remarkable changes on hematological investigations. DH is a vesicobullous disease manifested as severely pruritic and grouped excoriations of the skin. The lesions are symmetrically distributed on the extensor surfaces of the elbows, knees, scalp, back, and buttocks. There is usually an associated gluten-sensitive enteropathy. Histopathologically, subepidermal separation with neutrophilic microabscess at the tips of dermal papillae are seen. Immunofluorescence shows granular IgA deposits at the dermo-epidermal junction that differentiate it from a linear IgA bullous disease which resembles it clinically. Dapsone is the drug of choice with a gluten-free diet. At three-months follow-up, the patient was put on Dapsone 75 mg/day and advise him to attend regular follow-ups every three months in order to reduce the dose of Dapsone to a minimum dose to control his condition.

Gastrointestinal: Autoimmune enteropathy associated with thymoma.

A 50-year-old gentleman presented with 4 months of chronic watery, non-bloody diarrhea up to 10 times a day, and weight loss. He had a history of a thymoma first diagnosed 7 years earlier, which was resected with positive histological margins. There was no macroscopic residual disease or vascular invasion. He did not receive any adjuvant treatment and developed recurrent Masaoka-Koga stage IVa thymoma with pleural, pericardial, and lung invasion requiring further treatment with resection, chemotherapy (3 cycles of cisplatin, doxorubicin, and cyclophosphamide), and radiotherapy (54 Gy in 30 fractions). There was no mediastinal lymph node involvement or evidence of distant hematogenous metastasis. Histopathology demonstrated multiple nodules of mixed WHO type B1 and B2, but predominantly type B1 thymoma. His diarrhea commenced after his thymoma recurrence. He did not have any features suggesting other autoimmune diseases associated with thymoma including myasthenia gravis. Physical examination and initial laboratory investigations were unremarkable. Stool cultures were negative for bacterial, viral, and parasitic infections. A computed tomography (CT) scan of the abdomen revealed wall thickening and fat stranding affecting the small intestine and colon (Fig. 1a). Correspondingly, mild patchy erythematous colitis in the rectum and sigmoid colon was seen on colonoscopy (Fig. 1b). Histologically, colonic biopsies showed active colitis with prominent regenerative changes. Goblet cells were noticeably absent, and there was prominent apoptosis, features typical of autoimmune enteropathy (Fig. 1c). Patient serum was incubated with frozen sections of normal small intestinal mucosa, showing strong staining by immunofluorescence for human IgA and IgG with a goblet cell distribution (Fig. 2). A diagnosis of thymoma-associated autoimmune enteropathy was made, and the patient was commenced on a weaning dose of prednisone starting at 25 mg daily leading to resolution of his symptoms. Thymomas are associated with concomitant autoimmune diseases in up to 30% of patients, possibly due to defective immune regulation. Differentials for thymoma-associated autoimmune conditions causing diarrhea include autoimmune enteropathy and Good's syndrome (thymoma-associated hypogammaglobulinemia). Thymoma-associated autoimmune enteropathy is rare with only five reported cases in the literature. Proposed diagnostic criteria include chronic diarrhea lasting over 6 weeks, malabsorption, and abnormal histology of the small bowel (villous blunting, deep crypt lymphocytosis, minimal intraepithelial lymphocytosis, and increased crypt apoptotic bodies). A spectrum of changes can be seen in the colon including increased mononuclear inflammatory infiltrate, active inflammation including neutrophilic cryptitis and microabscesses, intraepithelial lymphocytosis, and increased crypt epithelial apoptosis. Changes of chronicity including crypt architectural distortion and Paneth cell metaplasia have also been described. The presence of anti-enterocyte or anti-goblet antibodies is supportive, but the sensitivity and specificity of these markers are unknown. Steroids are the first-line management for autoimmune enteropathy; however, further immunosuppression (azathioprine, cyclosporin, tacrolimus, or infliximab) may be required in up to 90% of cases. For patients with thymoma-associated autoimmune enteropathy, resection of the thymoma may also improve symptoms.

Hist-O-02 - High PD1 expression H score is associated with Sézary diagnosis: study of 91 patients with erythroderma

Erythroderma is a diagnostic challenge for dermatologists and pathologists. We aimed to identify clinical, histological and immunohistochemical markers that can be used to improve erythroderma diagnosis. This single-centre retrospective study included patients with erythroderma. To be included, erythroderma cases needed an accurate final diagnosis, at minimum one year of follow-up, available pictures and available skin biopsies to be reviewed. The demographic, clinical, biological (lactate deshydrogenase, eosinophilia, immunophenotype) and molecular features (T-cell clone in blood and skin) were recorded. All skin biopsies were reviewed for the following features: psoriasiform hyperplasia, parakeratosis, neutrophil microabscess, spongiosis, eosinophil infiltrate, lichenoid lesion, necrotic keratinocytes, epidermotropism, atypical lymphocytes, as well as routine immunostainings (CD3, CD4, CD8). Additional T follicular helper markers (PD1, ICOS and CXCL13), CD7 loss and Ki-67 proliferation index were also studied. For PD1 expression, percentage of positive lymphocytes as well as staining intensity (+ to +++) were recorded, all together combined in the semi-quantitative H score= [0 × (% cells 0) + 1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]. Among 91 patients included with erythroderma, 21 were diagnosed as eczema, 17 as psoriasis, 20 as drug-induced erythroderma (DE), 13 as erythrodermic mycosis fungoides (E-MF) and 20 as Sézary syndrome (SS). Nail alterations, ear involvement and severe scaling were associated with psoriasis (p=0.044). Fever and hypereosinophilia were associated with DE diagnosis (p=0.044 and p=0.0003). Atypical lymphocytes in the skin were more frequent in E-MF and SS (p=0.044), as well as an abnormal blood immunophenotype and identical skin and blood T-cell clone. In SS, PD1 expression by T cells was significantly higher than in other aetiologies, as percentage of positive lymphocytes and intensity. PD1 H-score >50 was associated with SS (p<0.001, Se=75%; Sp=92%), with good reproducibility between observers, kappa coefficient of 0.66 (95% CI 0.33–1.00). CXCL13 expression was also associated with SS (p=0.044); CD7 loss was more frequent in E-MF and SS (p=0.022), and Ki-67 index was higher in SS and DE (p=0.041). In this large series erythroderma, we report the PD1 expression, and specifically the PD1 H-score combining percentage and intensity scoring, as a tool for differential diagnosis between SS and other aetiologies including E-MF. Interdisciplinary expertise combining clinical, pathological, and molecular data remain essential for erythroderma diagnosis. Erythroderma is a diagnostic challenge for dermatologists and pathologists. We aimed to identify clinical, histological and immunohistochemical markers that can be used to improve erythroderma diagnosis. This single-centre retrospective study included patients with erythroderma. To be included, erythroderma cases needed an accurate final diagnosis, at minimum one year of follow-up, available pictures and available skin biopsies to be reviewed. The demographic, clinical, biological (lactate deshydrogenase, eosinophilia, immunophenotype) and molecular features (T-cell clone in blood and skin) were recorded. All skin biopsies were reviewed for the following features: psoriasiform hyperplasia, parakeratosis, neutrophil microabscess, spongiosis, eosinophil infiltrate, lichenoid lesion, necrotic keratinocytes, epidermotropism, atypical lymphocytes, as well as routine immunostainings (CD3, CD4, CD8). Additional T follicular helper markers (PD1, ICOS and CXCL13), CD7 loss and Ki-67 proliferation index were also studied. For PD1 expression, percentage of positive lymphocytes as well as staining intensity (+ to +++) were recorded, all together combined in the semi-quantitative H score= [0 × (% cells 0) + 1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]. Among 91 patients included with erythroderma, 21 were diagnosed as eczema, 17 as psoriasis, 20 as drug-induced erythroderma (DE), 13 as erythrodermic mycosis fungoides (E-MF) and 20 as Sézary syndrome (SS). Nail alterations, ear involvement and severe scaling were associated with psoriasis (p=0.044). Fever and hypereosinophilia were associated with DE diagnosis (p=0.044 and p=0.0003). Atypical lymphocytes in the skin were more frequent in E-MF and SS (p=0.044), as well as an abnormal blood immunophenotype and identical skin and blood T-cell clone. In SS, PD1 expression by T cells was significantly higher than in other aetiologies, as percentage of positive lymphocytes and intensity. PD1 H-score >50 was associated with SS (p<0.001, Se=75%; Sp=92%), with good reproducibility between observers, kappa coefficient of 0.66 (95% CI 0.33–1.00). CXCL13 expression was also associated with SS (p=0.044); CD7 loss was more frequent in E-MF and SS (p=0.022), and Ki-67 index was higher in SS and DE (p=0.041). In this large series erythroderma, we report the PD1 expression, and specifically the PD1 H-score combining percentage and intensity scoring, as a tool for differential diagnosis between SS and other aetiologies including E-MF. Interdisciplinary expertise combining clinical, pathological, and molecular data remain essential for erythroderma diagnosis.

Granulomatous Inflammation in ANCA-Associated Vasculitis.

ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.

Changes in connexin 43 in inflammatory skin disorders: Eczema, psoriasis, and Steven-Johnson syndrome/toxic epidermal necrolysis.

BackgroundConnexin 43 (Cx43) plays a central role in the inflammatory response and wound healing. Targeting Cx43 expression reduces inflammation in a variety of injuries. The expression pattern of Cx43 has not been described for many inflammatory skin diseases.ObjectivesTo describe the expression patterns of Cx43 in eczema, psoriasis, Steven‐Johnson syndrome/toxic epidermal necrolysis.MethodsArchival skin biopsies from patients with eczema, psoriasis, and Steven‐Johnson syndrome/toxic epidermal necrosis were identified and examined, with sister sections stained for Cx43 and imaged by confocal microscopy. All samples were compared to age and site‐matched normal skin controls.ResultsEpidermal Cx43 is reduced in acute eczema, absent in regions of spongiosis, and is highly elevated in subacute and chronic eczema. In plaque psoriasis, Cx43 is overexpressed in areas with psoriasiform hyperplasia with a fish‐scale‐like appearance but is lost in regions surrounding neutrophil microabscesses. Cx43 staining is strong in the neutrophils within these microabscesses. In SJS/TEN, Cx43 expression is elevated in areas bordering normal tissue but is rapidly lost in areas of keratinocyte necrosis.ConclusionsDynamic changes in Cx43 levels are seen in inflammatory skin diseases and may represent future potential therapeutic targets.

Childhood bullous systemic lupus erythematosus

Background Bullous systemic lupus erythematosus (BSLE) has rarely been described in pediatric lupus population, and the real prevalence of childhood-onset BSLE has not been reported. BSLE is a rare manifestation of systemic lupus erythematosus and is very rare in children. BSLE affects women more often than men, reflecting the female preponderance in systemic lupus erythematosus. It most often manifests in the second through fourth decades of life, but it has also been reported in children and older adults. Patients and methods Herein, we describe a case of a 10-year-old female patient who presented with a 1-year history of recurrent itchy urticated skin eruption, which was followed 2 months later (after the first year) by a generalized blistering eruption with photosensitivity. Results Histopathologic examination revealed a subepidermal blister and papillary-tip neutrophil microabscesses. Immunofluorescence studies showed linear immunoglobulin G (IgG) and IgC deposition along the BMZ with weaker staining of IgA and IgM. Laboratory tests revealed positive ANA, dsDNA, anti-SM antibodies, elevated erythrocyte sedimentation rate, and proteinuria. Conclusion Although the course of BSLE is often remitting, but not in our case, treatment with dapsone is successful in most cases of BSLE.

Identification of a TH 2-high psoriasis cluster based on skin biomarker analysis in a Chinese psoriasis population.

Psoriasis is an immune-mediated, chronic inflammatory disease with diverse phenotypes. However, its biological diversity has not been well-characterized in Chinese psoriasis population. To characterize psoriasis biological heterogenicity using gene expression profiles of lesional skin biopsy specimens in a Chinese psoriasis population. Lesional tissues and blood samples from Chinese psoriasis patients (n=40), atopic dermatitis (AD) patients (n=25) and age-matched healthy controls (n=19) were investigated by using real-time PCR array, histological evaluation and flow cytometry. Unsupervised hierarchical clustering was performed using gene expression profiles of patients with psoriasis. Two distinct psoriasis clusters were identified. Both clusters indicated high TH 17 activation. One cluster (n=6 of 40 consecutive psoriasis patients) indicated a strong TH 2 component in skin lesions, with early onset and low peripheral blood eosinophil level. Significantly higher IL-4, IL-13, IL-25, IL-31 and TSLP gene induction typified this cluster of psoriasis patients, even compared with AD patients. Both psoriasis clusters were characterized by neutrophilic microabscess formation. Histologically, the TH 2 high psoriasis cluster indicated a low percentage of perivascular eosinophils. Two distinct psoriasis clusters were identified. One presented early onset and a low eosinophil level, indicating TH 17 polarization and a strong TH 2 component. These results laid the foundation for further demonstrating the pathogenesis of psoriasis in Chinese population.

Interleukin-17A and Keratinocytes in Psoriasis.

The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6+ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6+ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.

Clinicopathologic features of Buschke-Löwenstein tumor: a multi-institutional analysis of 38 cases.

Buschke-Löwenstein tumor (BLT) is a rare sexually transmitted disease, mostly described in clinical literature as case reports or small series. Here, we investigated the clinicopathologic features of BLT in a total of 38 cases retrieved from multiple academic institutions. The average age was 47.6 ± 12.8 (mean ± SD) years old at diagnosis. The male to female ratio was 4.4:1. Common presenting symptoms were pain/discomfort, bleeding, mass lesion, and discharge. It was frequently linked to smoking and positive human immunodeficiency virus status. The tumor size and thickness were 8.5 ± 6.6 cm and 1.5 ± 1.3 cm, respectively. Histologically, 19 (50%) cases had an invasive squamous cell carcinoma component and were associated with high-risk human papillomavirus infection. There was no lymphovascular or perineural invasion, or nodal metastasis at initial diagnosis. BLTs with invasion had higher frequency of dyskeratosis, neutrophilic microabscesses, and abnormal mitoses, but lower frequency of pushing border compared with BLTs without invasion. All patients underwent wide excision, and some also received chemoradiation therapy. After a median follow-up of 23 months (range 1-207), the recurrence rate was 23.7% and disease-specific mortality was 2.6%. In summary, we presented the largest case series of BLT to date to characterize its unique clinicopathologic features. Our study indicated that certain histologic features such as dyskeratosis, neutrophilic microabscess, and abnormal mitosis in the non-invasive portion may be important clues on lesional biopsy to predict the presence of underlying invasive carcinoma.

The Influence of Ketogenic Diets on Psoriasiform-Like Skin Inflammation

The Influence of Ketogenic Diets on Psoriasiform-Like Skin Inflammation

3039 Esophageal Ulcers: A Presenting Symptom of Acute HIV Infection

INTRODUCTION: Dysphagia and odynophagia are commonly encountered in patients who are immunocompromised from chronic Human Immunodeficiency Virus (HIV) infection. Acute HIV infection can also cause odynophagia due to abrupt onset of oropharyngeal mucosal disease. We describe the eventual diagnosis of acute HIV infection in a patient presenting with dysphagia and odynophagia following endoscopic finding of esophageal ulceration. CASE DESCRIPTION/METHODS: A 43-year-old man presented with one week of epigastric pain, dysphagia, and odynophagia in the setting of recent fever (TMax 102.8F) and chills. He had intermittently taken a PPI following an emergency room visit the previous week. Oropharyngeal exam was negative for ulcers or thrush and abdominal exam was benign. Initial labs were normal aside from mild leukopenia (WBC 3,100/uL) with a low absolute neutrophil count. He underwent EGD showing several deep distal esophageal ulcers. Pathology showed acute esophagitis with mild to severe neutrophilic infiltrate and neutrophilic microabscesses. Staining of the ulcer biopsy specimens was negative for cytomegalovirus (CMV), herpes simplex virus (HSV) and fungal elements. The unknown etiology of his esophageal ulcers prompted testing for HIV. HIV immunoassay was positive however antibody differentiation was indeterminate. A subsequent HIV viral load was positive indicating acute HIV-1 infection. He was placed on anti-retroviral therapy soon after. A repeat EGD was performed three months later, demonstrating complete resolution of the previously seen ulcers. DISCUSSION: Presenting signs and symptoms of acute symptomatic HIV infection are nonspecific and the diagnosis is often missed or delayed. Esophageal ulceration may be underrecognized as an acute manifestation of illness. In one study of 16 men presenting with odynophagia who were eventually found to have acute HIV infection (HIV serology negative at presentation), all 16 were found to have esophageal ulceration during index endoscopy. Identification of viral particles resembling HIV-1 within ulcer biopsies with electron microscopy and isolation of HIV-1 from an ulcer biopsy specimen raise the possibility of direct viral infection of esophageal cells. With this in mind, endoscopists and gastroenterology providers should have a high index of suspicion for acute HIV infection in patients with odynophagia secondary to esophageal ulcer of unknown etiology.

2734 Immunotherapy-Mediated Hemorrhagic Gastritis After Ipilimumab and Nivolumab Therapy

INTRODUCTION: Combined checkpoint inhibitor immunotherapy with ipilimumab (anti-cytotoxic T-lymphocyte antigen 4 antibody) and nivolumab (anti-programmed cell death receptor 1 antibody) has greatly advanced the treatment of multiple malignancies but is associated with increased immune-related toxicities. Gastrointestinal toxicity is one of the most frequent adverse effects, and while lower GI tract toxicity, such as anti-CTLA-4-mediated colitis, is well known, severe toxicity of the upper GI tract is rare and not well described. We report a case of severe hemorrhagic gastritis in a patient after initiation of ipilimumab and nivolumab therapy for metastatic renal cell carcinoma. CASE DESCRIPTION/METHODS: A 70-year-old man with history of metastatic renal cell carcinoma and recent immune-related myocarditis initially presented with myasthenic weakness after receiving single doses of ipilimumab and nivolumab 5 weeks prior. His presentation was most consistent with seronegative, immune-mediated myasthenia gravis-like syndrome. He was treated with intravenous steroids and plasmapheresis. After 9 days of steroid therapy, he developed large volume melena requiring 4 units of blood despite twice-daily proton pump inhibitor therapy. Endoscopic evaluation revealed diffuse, severe inflammation with hemorrhage characterized by adherent blood and erythematous, friable gastric mucosa in the body, antrum, and prepyloric regions. Hemostatic spray was applied as a temporizing measure to control bleeding. Biopsy specimens demonstrated neutrophilic microabscesses with intraglandular apoptotic bodies, increased lymphocytes and scattered neutrophils in lamina propria, and reactive mucosal features. These findings were compatible with checkpoint inhibitor-induced acute gastritis. Immunohistochemical stains for H. pylori and cytomegalovirus were negative. Despite immunosuppressive therapy with high dose steroids, mycophenalate mofetil, and trial of infliximab, he continued to decline with ongoing anemia and progressive weakness. He was transitioned to comfort measures and died soon afterward. DISCUSSION: To our knowledge, this is the first reported case of severe hemorrhagic, non-infectious gastritis as a rare complication of immunotherapy with ipilimumab and nivolumab. Physicians should be aware that checkpoint inhibitor-induced toxicity of the upper GI tract can occur early after initiation of therapy and have a severe, refractory course. Management includes exclusion of infectious process and immunosuppressive therapy.