The Formation and Function of Granulomas.

Granulomas are organized aggregates of macrophages, often with characteristic morphological changes, and other immune cells. These evolutionarily ancient structures form in response to persistent particulate stimuli-infectious or noninfectious-that individual macrophages cannot eradicate. Granulomas evolved as protective responses to destroy or sequester particles but are frequently pathological in the context of foreign bodies, infections, and inflammatory diseases. We summarize recent findings that suggest that the granulomatous response unfolds in a stepwise program characterized by a series of macrophage activations and transformations that in turn recruit additional cells and produce structural changes. We explore why different granulomas vary and the reasons that granulomas are protective and pathogenic. Understanding the mechanisms and role of granuloma formation may uncover new therapies for the multitude of granulomatous diseases that constitute serious medical problems while enhancing the protective function of granulomas in infections.

Differentiation of granulomatous nodules with lobulation and spiculation signs from solid lung adenocarcinomas using a CT deep learning model.

BACKGROUND: The diagnosis of solitary pulmonary nodules has always been a difficult and important point in clinical research, especially granulomatous nodules (GNs) with lobulation and spiculation signs, which are easily misdiagnosed as malignant tumors. Therefore, in this study, we utilised a CT deep learning (DL) model to distinguish GNs with lobulation and spiculation signs from solid lung adenocarcinomas (LADCs), to improve the diagnostic accuracy of preoperative diagnosis. METHODS: 420 patients with pathologically confirmed GNs and LADCs from three medical institutions were retrospectively enrolled. The regions of interest in non-enhanced CT (NECT) and venous contrast-enhanced CT (VECT) were identified and labeled, and self-supervised labels were constructed. Cases from institution 1 were randomly divided into a training set (TS) and an internal validation set (IVS), and cases from institutions 2 and 3 were treated as an external validation set (EVS). Training and validation were performed using self-supervised transfer learning, and the results were compared with the radiologists' diagnoses. RESULTS: The DL model achieved good performance in distinguishing GNs and LADCs, with area under curve (AUC) values of 0.917, 0.876, and 0.896 in the IVS and 0.889, 0.879, and 0.881 in the EVS for NECT, VECT, and non-enhanced with venous contrast-enhanced CT (NEVECT) images, respectively. The AUCs of radiologists 1, 2, 3, and 4 were, respectively, 0.739, 0.783, 0.883, and 0.901 in the (IVS) and 0.760, 0.760, 0.841, and 0.844 in the EVS. CONCLUSIONS: A CT DL model showed great value for preoperative differentiation of GNs with lobulation and spiculation signs from solid LADCs, and its predictive performance was higher than that of radiologists.

Granulomatous meningoencephalitis and blindness associated with Mycobacterium tuberculosis complex infection in a senile female chimpanzee (Pan troglodytes).

A 40-year old female chimpanzee (Pan troglodytes) developed hyporexia, weight loss, followed by progressive and complete blindness. Tomography demonstrated an intracranial mass in the rostroventral brain involving the optic chiasm, with a presumptive diagnosis of neoplasm. However, histopathology revealed a granulomatous meningoencephalitis, and tissue samples tested positive for Mycobacterium tuberculosis.

Immunohistochemistry and real-time Polymerase Chain Reaction: importance in the diagnosis of intestinal tuberculosis in a Peruvian population.

INTRODUCTION: The diagnosis of intestinal tuberculosis is challenging even nowadays. This study aims to report the positivity rates of new diagnostic methods such as immunohistochemistry and Real-Time Polymerase Chain Reaction in patients with intestinal tuberculosis, as well as describe the pathological and endoscopic features of intestinal tuberculosis in our population. METHODS: This was a retrospective observational study conducted in patients diagnosed with intestinal tuberculosis, between 2010 to 2023 from the Hospital Nacional Daniel Alcides Carrion and a Private Pathology Center, both located in Peru. Clinical data was obtained, histologic features were independently re-evaluated by three pathologists; and immunohistochemistry and real-time Polymerase Chain Reaction evaluation were performed. The 33 patients with intestinal tuberculosis who fulfilled the inclusion criteria were recruited. RESULTS: Immunohistochemistry was positive in 90.9% of cases, while real-time Polymerase Chain Reaction was positive in 38.7%. The ileocecal region was the most affected area (33.3%), and the most frequent endoscopic appearance was an ulcer (63.6%). Most of the granulomas were composed solely of epithelioid histiocytes (75.8%). Crypt architectural disarray was the second most frequent histologic finding (78.8%) after granulomas, but most of them were mild. CONCLUSION: Since immunohistochemistry does not require an intact cell wall, it demonstrates higher sensitivity compared to Ziehl-Neelsen staining. Therefore, it could be helpful for the diagnosis of paucibacillary tuberculosis.

Retrospective clinical and microbiologic analysis of metagenomic next-generation sequencing in the microbiological diagnosis of cutaneous infectious granulomas.

BACKGROUND: Cutaneous infectious granulomas (CIG) are localized and chronic skin infection caused by a variety of pathogens such as protozoans, bacteria, worms, viruses and fungi. The diagnosis of CIG is difficult because microbiological examination shows low sensitivity and the histomorphological findings of CIG caused by different pathogens are commonly difficult to be distinguished. OBJECTIVE: The objective of this study is to explore the application of mNGS in tissue sample testing for CIG cases, and to compare mNGS with traditional microbiological methods by evaluating sensitivity and specificity. METHODS: We conducted a retrospective study at the Department of Dermatology of Sun Yat-sen Memorial Hospital, Sun Yat-sen University from January 1st, 2020, to May 31st, 2024. Specimens from CIG patients with a clinical presentation of cutaneous infection that was supported by histological examination were retrospectively enrolled. Specimens were delivered to be tested for microbiological examinations and mNGS. RESULTS: Our data show that mNGS detected Non-tuberculosis mycobacteria, Mycobacterium tuberculosis, fungi and bacteria in CIG. Compared to culture, mNGS showed a higher positive rate (80.77% vs. 57.7%) with high sensitivity rate (100%) and negative predictive value (100%). In addition, mNGS can detect more pathogens in one sample and can be used to detect variable samples including the samples of paraffin-embedded tissue with shorter detective time. Of the 21 patients who showed clinical improvement within a 30-day follow-up, eighteen had their treatments adjusted, including fifteen who continued treatment based on the results of mNGS. CONCLUSIONS: mNGS could provide a potentially rapid and effective alternative detection method for diagnosis of cutaneous infectious granulomas and mNGS results may affect the clinical prognosis resulting from enabling the patients to initiate timely treatment.

Granulomas in Pediatric Liver Biopsies: Single Center Experience.

BACKGROUND: Granulomas in pediatric liver biopsies (GPLB) are rare with the largest pediatric cohort reported over 25 years ago. METHODS: Single-center retrospective study of GPLB. RESULTS: Seventeen liver biopsies from 16 patients with granulomas were identified (9 boys, 56%) with a median age of 13 years (range: 1-18) for which the most common indication was the presence of a nodule/mass (47%). Significant comorbidities were seen in 13 patients (81%) and included: liver transplant (25%), history of a neoplasm (25%), autoimmune hepatitis (6%), Crohn disease (6%), bipolar disorder (6%), severe combined immunodeficiency (6%), and sickle cell disease (6%). Eleven patients were taking multiple medications at the time of biopsy. Granulomas were more commonly pan-acinar (11 cases) followed by subcapsular (4 cases), portal (1 case), and periportal (1 case). Necrosis was seen in 10 cases (59%). GMS stain was positive in 2 cases for Histoplasma-like yeast; microbiological cultures were negative in all cases (no: 4). A 18S and 16S rRNA gene sequencing performed in 15 cases revealed only 1 with a pathogenic microorganism, Mycobacterium angelicum. CONCLUSION: In our experience, GPLB are heterogenous with only 3 cases having an identifiable infectious etiology and many of the remaining cases being associated to multiple medications, suggesting drug-induced liver injury as possible etiology.

Tuberculous ciliary body granuloma initially diagnosed as bullous retinal detachment: a case report.

BACKGROUND: Ocular tuberculosis is a relatively rare extrapulmonary manifestation of tuberculosis. This vision-threatening disease is extremely challenging to diagnose, particularly because it can mimic other diseases. We report a case of tuberculous ciliary body granuloma initially diagnosed as bullous retinal detachment. CASE REPORT: A 52-year-old female presented with bullous retinal detachment in her left eye, and ultrasound biomicroscopy (UBM) verified the presence of a lesion with ciliary body granulomatous inflammation. The T-SPOT was positive, and the purified protein derivative (PPD) test was strongly positive (diameter of 20 mm). Following the administration of oral anti-tuberculosis regimen combined with prednisone, the retina gradually became reattached, the ciliary body granuloma became significantly reduced in size, and the visual acuity of the patient noticeably improved. CONCLUSIONS: Tuberculous ciliary body granulomas can cause bullous exudative retinal detachment and can be diagnosed with UBM. Early and full-course anti-tuberculosis treatment (ATT) combined with corticosteroid therapy can improve the patient prognosis.

Idiopathic aseptic facial granuloma: A retrospective study of 43 cases.

BACKGROUND: Idiopathic aseptic facial granuloma (IAFG) is an underrecognized pediatric skin disease, currently considered within the spectrum of rosacea. It usually manifests as a solitary, reddish, asymptomatic nodule on the cheek that resolves spontaneously. METHODS: Retrospective and descriptive observational study of 43 pediatric patients with a clinical diagnosis of IAFG, followed between 2004 and 2022, at two general hospitals in Argentina. RESULTS: IAFG predominated in girls (65%) and the average age of onset was about 6 years. A single asymptomatic nodule was seen in 79% of patients. The most common localization was the cheek (58%) followed by lower eyelids (41%). Family history of rosacea was present in 16% of patients. A concomitant diagnosis of rosacea and periorificial dermatitis was made in 14% and 9% of our population, respectively. Past or present history of chalazia was detected in 42% of the children. IAFG diagnosis was mainly clinical (88% of cases). Oral antibiotics were the most common indicated treatment (84%). Complete healing was achieved by the majority, but 18% of those with eyelid compromise healed with scars. CONCLUSIONS: IAFG is a benign pediatric condition that physicians should recognize in order to manage correctly. We herein refer to a particular morphologic aspect of IAFG lesions affecting the lower eyelids, where nodules adopt a linear distribution and have a higher probability of involute leaving a scar. Also, we consider that the concomitant findings of rosacea, periorificial dermatitis and chalazia in our patients, reinforce the consideration of IAFG within the spectrum of rosacea.

Clinical and pathological findings in five dogs with nodular histiocytic iritis in the United Kingdom: A case series.

PURPOSE: The aim of this study was to describe the clinical presentation, histopathology, management, and outcome of nodular histiocytic iritis, an intraocular variant of nodular granulomatous episcleritis (NGE). METHODS: A retrospective review of the medical records of five dogs with intraocular NGE-type inflammation as diagnosed by histopathology. RESULTS: Four Border Collies and one crossbreed dog, aged 1.5-3.4 years (mean age 2.38 years). The clinical presentation was an extensive, raised, pale iris lesion of variable location. All cases were unilateral. The physical examination was normal. Complete blood count/serum biochemistry (n = 1) and thoracic radiography (n = 1) were normal. Ocular ultrasound (n = 2) was normal apart from increased iris thickness. Enucleation (n = 4) or excisional biopsy (iridectomy, n = 1) was performed because of suspected neoplasia. Following enucleation, the remaining, contralateral eye did not develop additional lesions (9 days-3.7 years follow-up). There was no recurrence following sector iridectomy with 5 months topical 1% prednisolone acetate (3.9 years follow-up). The histopathologic findings in all five cases indicated a focal histiocytic and lymphoplasmacytic anterior uveitis (iritis), similar to that seen in cases of NGE. CONCLUSION: Nodular histiocytic iritis presents as unilateral iris thickening in isolation and young Collies appear to be predisposed. The histopathological findings are similar to NGE. Although the clinical presentation resembles intraocular neoplasia, an inflammatory process should be considered, which may be amenable to medical management. Definitive diagnosis may be obtained by iris sampling.

Isolated Cutaneous Granuloma Caused by Candida Parapsilosis: Case Report and Literature Review.

Candidal granuloma is an uncommon type of deep chronic cutaneous candidiasis. Candida albican is the most common causative pathogen for candidal granuloma. We report herein the original case of a 69-year-old Chinese woman presented with a 3-year of painful cutaneous lesion on the back of left hand. Physical examination revealed a 4 × 5 cm large infiltrative reddish plaque with unclear boundaries. The yellow-white crusts were observed on the uneven surface of plaque. Histopathological examination of biopsy tissue revealed that yeast cells and the horizontal section of hyphae in the dermis by hematoxylin eosin staining and periodic acid-Schiff staining. Finally, the pathogen was identified as Candida parapsilosis by mycological examination and molecular identification. The patient was treated with itraconazole oral 200 mg twice daily combined with topical terbinafine hydrochloride cream for 2 months. The lesions were fully resolved and no recurrence was observed. Since the cutaneous infection caused by C. parasilosis were rarely reported, we also reviewed all 11 cases of cutaneous infection caused by C. parapsilosis in the PubMed. Our study highlighted that chronic unilateral infiltrated plaques or ulcers should be aware of the occurrence of fungal granuloma including candidal granuloma especially in immunocompromised patients.

If not angioedema, what is it? Diagnostic approach to facial edema.

Facial edema is a relatively frequent clinical presentation encountered in patients seen in allergology and dermatology clinics. The differential diagnosis is broad, and sometimes the definitive diagnosis can be a challenge for the clinician. Facial angioedema itself encompasses different etiopathologies (histaminergic, bradykinergic, etc.) that must be distinguished from other causes of facial edema, such as allergic contact dermatitis, granulomatous conditions, inflammatory causes, infections, neoplasms or paraneoplastic syndromes, autoimmune diseases, among other entities hereby referred as miscellanea. A proper diagnostic approach is essential to order the appropriate tests, as well as to prescribe a targeted treatment. This review focuses on entities that present with facial edema and summarize their characteristic clinical features.

The rope sign, a typical and yet infrequent clue.

Cutaneous granulomatous reactions are diverse, both from the clinical and the pathological perspective. Most underlying pathophysiological aspects remain elusive. Interstitial granulomatous dermatitis and palisaded neutrophilic and granulomatous dermatitis have been claimed to be reactions to systemic disorders, such as infectious, inflammatory, or neoplastic conditions. Recently, the overarching term "reactive granulomatous dermatitis" has been coined to unify both entities. We herein report two cases of reactive granulomatous dermatitis presenting with the widely known, albeit infrequent "rope sign" and provide clinicopathological correlation. The two patients included a 53-year-old woman with enlarging erythematous plaques and underlying palpable cords on both sides of trunk near axillae (rope sign), and a 51-year-old woman with personal history of rheumatoid arthritis and a palpable cord on the left aspect of the trunk. Pathological findings were compatible with reactive granulomatous dermatitis in both cases. In conclusion, the rope sign represents a strikingly infrequent but decisive diagnostic clue of reactive granulomatous dermatitis.

Antemortem Diagnosis and Successful Long-term Management of Disseminated Intracoelomic Xanthogranulomatous Disease in an Eclectus Parrot (Eclectus roratus).

A 12-year-old male eclectus parrot (Eclectus roratus) was referred for evaluation of coelomic distention. Computed tomography and blood work revealed coelomic effusion with free coelomic mineral-attenuating material and elevations in the bile acids and aspartate aminotransferase activity, respectively. Coelomic effusion was consistent with macrophagic inflammation with abundant intracellular lipids. Initial treatment with meloxicam resulted in minimal patient improvement. Disseminated xanthogranulomatous inflammation was suspected based on imaging and diagnostic laboratory results, which were consistent with those previously reported. Biopsy samples of liver tissue and intracoelomic masses confirmed this diagnosis. Treatment was initiated with prednisolone 1 mg/kg/d for 6 months, followed by 0.5 mg/kg/d for 3 months. Clinical improvement was assessed based on owner evaluation, plasma bile acid concentrations, and repeated computed tomographic scans. After 2 months of treatment, the owner reported improved behavior and appetite; this persisted throughout treatment and when the bird was reexamined 17 months following the cessation of steroid therapy. Bile acid concentrations were normal 10 months after the prednisolone therapy was discontinued. Diagnostic imaging showed minimal coelomic effusion 10 months after the last prednisolone dose was administered, with improved ventilation of the air sacs and static to improved dystrophic mineral foci. This report describes the antemortem diagnosis and treatment of disseminated coelomic xanthogranulomatous disease in a psittacine species, with an observed measurable therapeutic response.

Histiocytosis and adult-onset orbital xanthogranuloma in 2023: a review of the literature and mini case series.

PURPOSE: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities. METHODS: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined. RESULTS: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary. CONCLUSION: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis.

[Conjunctival fungal infection mimicking a recurrent conjunctival mass: a case report].

A 40-year-old man presented with recurrent ocular surface masses in his left eye persisting for over a year. Despite undergoing resection of the conjunctival mass and receiving anti-inflammatory treatment at another hospital, the mass reappeared within a week post-surgery. Over the past 6 months, the mass gradually increased in size, accompanied by a decline in vision. Following conjunctival mass excision combined with amniotic membrane transplantation at Beijing Tongren Hospital, Capital Medical University, histopathological examination revealed a fungal infection of the conjunctiva, resulting in a diagnosis of fungal conjunctivitis and conjunctival granuloma in the left eye. The patient received systemic antifungal medications and local therapy, resulting in a stable condition with no recurrence of the mass.

Neurosarcoidosis: Diagnostic Challenges and Mimics A Review.

PURPOSE OF REVIEW: Neurosarcoidosis is a rare manifestation of sarcoidosis that is challenging to diagnose. Biopsy confirmation of granulomas is not sufficient, as other granulomatous diseases can present similarly. This review is intended to guide the clinician in identifying key conditions to exclude prior to concluding a diagnosis of neurosarcoidosis. RECENT FINDINGS: Although new biomarkers are being studied, there are no reliable tests for neurosarcoidosis. Advances in serum testing and imaging have improved the diagnosis for key mimics of neurosarcoidosis in certain clinical scenarios, but biopsy remains an important method of differentiation. Key mimics of neurosarcoidosis in all cases include infections (tuberculosis, fungal), autoimmune disease (vasculitis, IgG4-related disease), and lymphoma. As neurosarcoidosis can affect any part of the nervous system, patients should have a unique differential diagnosis tailored to their clinical presentation. Although biopsy can assist with excluding mimics, diagnosis is ultimately clinical.

Cutaneous sarcoidosis mimicking pigmented purpuric dermatosis.

Sarcoidosis is a systemic inflammatory disorder characterized by the formation of non-caseating granulomas. Cutaneous involvement of sarcoidosis is common and has a wide variety of clinical presentations. Herein, we present a case of cutaneous sarcoidosis mimicking pigmented purpuric dermatosis (PPD) in a 26-year-old female treated with topical tofacitinib cream and a literature review of all other reported cases of cutaneous sarcoidosis with PPD-like features.

Rosacea in children: a review.

Rosacea is a facial inflammatory disorder that shows an increasing incidence with age. While rosacea is common > 60 years of age, pediatric rosacea is uncommon. Diagnostic criteria are based on clinical symptoms. Laboratory investigations and histopathology are only needed to exclude other differential diagnoses. There are several subtypes such as erythemato-telangiectatic, papulo-pustular, periorificial, and granulomatous variants. In contrast to adult rosacea, phymatous subtypes do not belong to pediatric rosacea. A special subtype seen in infants and children is an idiopathic facial aseptic granuloma. Genetic and environmental factors contribute to its pathogenesis. Treatment options are in analogy to adult rosacea classified into topical and systemic drugs. In the case of oral tetracyclines, discoloration of teeth and impairment of enamel are possible adverse events. CONCLUSION: Pediatric rosacea belongs to the rosacea spectrum but has peculiarities compared to the adult subtype. WHAT IS KNOWN: • Rosacea is a chronic inflammatory disorder different from acne. • Rosacea gets more common with advanced age. WHAT IS NEW: • Pediatric rosacea is an uncommon subtype with peculiar clinical presentation. • Demodicosis is very rare in immunocompetent children.

SARCOID GRANULOMA OF THE CHOROID AND CILIARY BODY IN 50 CASES.

PURPOSE: To describe the clinical and imaging features of sarcoid granuloma of the choroid and ciliary body. METHODS: Retrospective case series of patients with choroid and/or ciliary body sarcoid granuloma managed at the Ocular Oncology Service at Wills Eye Hospital. RESULTS: The mean patient age at diagnosis was 51.0 years (54.1, 11.0-83.8 years). The mean logMAR visual acuity at presentation was 0.3 (0.2, 0.0-3.0) [Snellen equivalent 20/40 (20/30, HM-20/20)]. Clinical features included mean basal dimension of 5.2 mm (4.0, 0.3-20.0 mm) and thickness of 1.7 mm (1.8, 0.0-3.6 mm), yellow color (41, 82%), multifocality (18, 36%), and irregular vermiform margins (46, 92%). Related clinical features included inflammation of the anterior chamber (1, 2%), vitreous (5, 10%), and retina (5, 10%). Imaging features by optical coherence tomography of the choroid lesions (n = 49) demonstrated clear subretinal fluid (6, 12%), "dirty" subretinal fluid (14, 28%), cystoid macular edema (1, 2%), overlying retinal edema (6, 12%), and localized vitreous cellularity (1, 2%). Management included sub-Tenon's triamcinolone (11, 22%), intravitreal triamcinolone (3, 6%), systemic corticosteroids (19, 38%), or observation (26, 52%). Systemic sarcoidosis was present before ocular diagnosis (13, 26%), detected during ophthalmic care (4, 8%), detected after ocular diagnosis (3, 6%), or not found (30, 60%) over a mean follow-up of 13.7 months (6.9, 0.0-138.2). CONCLUSION: Sarcoid granuloma of the choroid and/or ciliary body can manifest without anterior segment or vitreous/retina inflammation in many cases and reveal underlying systemic sarcoidosis in 40% of cases. A distinguishing feature of choroidal sarcoid granuloma was its vermiform margin.

Orbitofrontal cholesterol granuloma masquerading as frontal sinus mucoceles: report of two cases.

BACKGROUND: Two cases of orbitofrontal cholesterol granuloma masquerading as frontal sinus mucoceles were reported to understand image findings, clinical and histopathologic features of orbitofrontal cholesterol granuloma to improve its diagnosis and treatment. CASE PRESENTATION: Two East Asian patients aged 41 and 27 without personal or familial medical or trauma history presented with the common complaint of proptosis and inferomedial displacement of the eyeballs. The computed tomography (CT) of both cases showed an irregularly shaped, well-defined lesion in the left frontal bone associated with bony erosion. The lesions resulted in the bone absorption of frontal bone and orbital roof, which extended into the superior orbital space. Anterior orbitotomy through subbrow incision by drainage and curettage resulted in a curative outcome. The histopathological examination revealed inflammatory granulation tissues, fibrous capsule wall, cholesterol clefts with altered blood pigments, and calcifications, consistent with the diagnosis of cholesterol granuloma. No recurrence was observed for one year after surgery in one case and three years in the other. CONCLUSIONS: When the following features are observed: orbital CT exhibits cystic lesion with irregular bone destruction in the superolateral orbit, magnetic resonance imaging (MRI) depicts lesions are hyperintense signals on T1 weighted images (T1WI), and T2 weighted images (T2WI), and the contrast-enhanced imaging reveals that the most of tumor is showed a non-significant enhancement, orbitofrontal cholesterol granuloma should be considered.