Granulomatous Lung Diseases: A Practical Approach and Review of Common Entities.

Granulomas are frequently encountered by pathologists in all types of lung specimens and arise from diverse etiologies. They should always be reported as necrotizing or non-necrotizing, with microorganism stains performed to evaluate for infection. With attention to distribution, quality (poorly vs well-formed), associated features, and correlation with clinical, radiologic, and laboratory data, the differential diagnosis for granulomatous lung disease can usually be narrowed to a clinically helpful "short list." This review describes a practical approach to pulmonary granulomas and reviews the clinicopathological aspects of common entities, including infectious (mycobacteria, fungi) and noninfectious (hypersensitivity pneumonitis, sarcoid, and vasculitis) causes.

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.

A confounding clinically aggressive case of necrotizing granulomatous and suppurative dermatitis.

Superficial granulomatous pyoderma gangrenosum is a rare, superficial, vegetating form of pyoderma gangrenosum that tends to occur as a single lesion, most commonly on the trunk. Herein, we report a clinically confounding case of disseminated superficial granulomatous pyoderma gangrenosum in a patient with a 5-year history of painful and chronic ulcerations of the bilateral upper extremities and face in a sun exposed distribution. This was a diagnostically challenging case due to the treatment-refractory nature of our patient's skin lesions and the atypical clinical and histologic presentations encountered. We review our clinical decision process and acknowledge other entities that were considered during the clinical course of this case. Additionally, we discuss the lack of responsiveness to various treatment options with eventual successful clearance of this patient's active skin disease with initiation of adalimumab.

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.

Investigating cryopreserved PBMC functionality in an antigen-induced model of sarcoidosis granuloma formation.

Sarcoidosis, a systemic inflammatory disease, poses challenges in understanding its etiology and variable clinical courses. Despite ongoing uncertainty about causative agents and genetic predisposition, granuloma formation remains its hallmark feature. To address this, we developed a validated in vitro human granuloma model using patient-derived peripheral blood mononuclear cells (PBMCs), offering a dynamic platform for studying early granuloma formation and sarcoidosis pathogenesis. However, a current limitation of this model is its dependence on freshly isolated PBMCs obtained from whole blood. While cryopreservation is a common method for long-term sample preservation, the biological effects of freezing and thawing PBMCs on granuloma formation remain unclear. This study aimed to assess the viability and functionality of cryopreserved sarcoidosis PBMCs within the granuloma model, revealing similar granulomatous responses to fresh cells and highlighting the potential of cryopreserved PBMCs as a valuable tool for studying sarcoidosis and related diseases.

Cutaneous Crohn disease presenting as "knife-edged" ulcers: a case report.

BACKGROUND: CCD presents as non-caseating granulomas within the skin at a site distant from the GI tract. CCD is a debilitating extraintestinal sequela of CD that can sometimes precede its GI manifestations. In the absence of GI symptoms, the histopathologic and clinical features of CCD can present as a variety of inflammatory skin conditions that can range from ruptured follicle-associated granulomas to cutaneous ulcerations. While a variety of therapeutic options for patients with CCD and concurrent luminal CD have been described in the literature, there is no standard treatment algorithm for the management of refractory CCD with limited or covert GI involvement. CASE REPORT: The authors discuss the case of a 33-year-old female who presented to the wound care clinic with multiple "knife-edged" cutaneous ulcerations involving the intertriginous spaces, found to be consistent with CCD. Her original cutaneous symptoms and diagnosis manifested with minimal GI involvement and responded to IVIG treatment. CONCLUSIONS: This case supports the inclusion of CCD in the differential diagnosis in patients with knife-edged granulomatous skin lesions in intertriginous locations. This clinical condition may present in the setting of no or limited GI symptoms. The management of CCD and a proposed treatment algorithm are also presented.

[Xanthogranulomatous adrenalitis : A rare and difficult differential diagnosis of adrenal gland tumors]. / Xanthogranulomatöse Adrenalitis : Seltene und schwierige Differentialdiagnose von Nebennierentumoren.

A radiologically diagnosed tumor in a 29-year-old woman with a fever of around 39 °C was operated on under the suspicion of cholecystitis or a liver abscess. A solid tumor was found in the adrenal gland and resected. The frozen section findings did not reveal a clear diagnosis of entity and assignment. Histologically, the tumor was found to consist of densely clustered large histiocyte-like cells with expression of vimentin, CD68, and CD163 as well as negativity for keratin, langerin, and SMA. We diagnosed xanthogranulomatous adrenalitis and discussed the differential diagnoses (Langerhans cell histiocytosis, Rosai-Dorfman disease, malakoplakia, Erdheim-Chester disease).

Evaluation of Ki-67, goblet cell and MUC2 mucin RNA expression in dogs with lymphoplasmacytic and granulomatous colitis.

Intestinal mucus barrier disruption may occur with chronic inflammatory enteropathies. The lack of studies evaluating mucus health in dogs with chronic colitis arises from inherent challenges with assessment of the intestinal mucus layer. It is therefore unknown if reduced goblet cell (GBC) numbers and/or mucin 2 (MUC2) expression, which are responsible for mucus production and secretion, correlate with inflammation severity in dogs with granulomatous colitis (GC) or lymphocytic-plasmacytic colitis (LPC). It is undetermined if Ki-67 immunoreactivity, which has been evaluated in dogs with small intestinal inflammation, similarly correlates to histologic severity in GC and LPC. Study objectives included comparing Ki-67 immunoreactivity, GBC population and MUC2 expression in dogs with GC, LPC and non-inflamed colon; and exploring the use of ribonucleic acid (RNAscope®) in-situ hybridization (ISH) to evaluate MUC2 expression in canine colon. Formalin-fixed endoscopic colonic biopsies were obtained from 48 dogs over an eight-year period. A blinded pathologist reviewed all biopsies. Dogs were classified into the GC (n=19), LPC (n=19) or no colitis (NC) (n=10) group based on final histopathological diagnosis. Ki-67 immunohistochemistry, Alcian-Blue/PAS staining to highlight GBCs, and RNAscope® ISH using customized canine MUC2-targeted probes were performed. At least five microscopic fields per dog were selected to measure Ki-67 labelling index (KI67%), GBC staining percentage (GBC%) and MUC2 expression (MUC2%) using image analysis software. Spearman's correlation coefficients were used to determine associations between World Small Animal Veterinary Association histologic score (WHS) and measured variables. Linear regression models were used to compare relationships between WHS with KI67%, GBC%, and MUC2%; and between GBC% and MUC2%. Median WHS was highest in dogs with GC. Median KI67% normalised to WHS was highest in the NC group (6.69%; range, 1.70-23.60%). Median GBC% did not correlate with colonic inflammation overall. Median MUC2% normalised to WHS in the NC group (10.02%; range, 3.05-39.09%) was two- and three-fold higher than in the GC and LPC groups respectively. With increased colonic inflammation, despite minimal changes in GBC% overall, MUC2 expression markedly declined in the LPC group (-27.4%; 95%-CI, -49.8, 5.9%) and mildly declined in the GC and NC groups. Granulomatous colitis and LPC likely involve different pathways regulating MUC2 expression. Decreased MUC2 gene expression is observed in dogs with chronic colitis compared to dogs without colonic signs. Changes in MUC2 expression appear influenced by GBC activity rather than quantity in GC and LPC.

Recurrent Idiopathic Granulomatous Mastitis: A Case Report.

Idiopathic granulomatous mastitis is a rare benign breast disease of unknown aetiology mostly presenting as a breast abscess but not responding to usual conservative management with incision and drainage and frequently mimics breast cancer. We present a case 31-year-old female presented with complaints of right breast pain and redness who was initially diagnosed and treated as a case of breast abscess with repeated incision and drainage and antibiotics but did not improve. Later histopathology revealed granuloma with giant cell reaction and the patient was given a trial of steroids which showed no improvement. Wide local excision with a long course of broad-spectrum antibiotics was performed which led into remission. This case report highlights the importance of considering idiopathic granulomatous mastitis as differentials in non-responding breast abscesses. Histopathology for diagnosis and trial of wide local excision with a long course of broad-spectrum antibiotics as treatment may be done for management. Keywords: antibiotics; case reports; granuloma; mastitis.

Hepatic granulomas following liver transplantation: A retrospective survey, and analysis of possible microbiological etiology.

BACKGROUND: Liver granulomas have always been a diagnostic challenge for pathologists. They have been described in up to 15% of liver biopsies and can also be seen in liver allograft biopsy specimens, but there is a paucity of information regarding the prevalence and associated etiologic factors of granulomas in liver transplanted patients. The aim of this study is to shed light on the etiology of liver granulomas. METHODS: Liver biopsies from liver transplanted patients, in the period from 01.01.2011 - 01.05.2017, were examined. We registered the histo-morphological characteristics and clinicopathological data of all biopsies and performed next-generation sequencing (NGS) to detect possible pathogens (bacteria, fungi, and parasites) in the biopsies containing granulomas. RESULTS: We reviewed a total of 400 liver biopsies from 217 liver transplant patients. Of these, 131 liver biopsies (32.8%) from 98 patients (45.2%) revealed granulomas. Most were epithelioid granulomas located parenchymal and were detected in 115 (87.7%) biopsies. We also identified 10 cases (7.6%) with both lobular and portal granulomas and six biopsies (4.5%) with portal granulomas alone. In 54 biopsies (41.2%), granulomas were found in biopsies with acute cellular rejection (ACR). Fifty (51%) patients with granulomas underwent liver transplantation for autoimmune-related end-stage liver disease (AILD). The granulomas were found most frequently in the first six months after transplantation, where patients also more often were biopsied. NGS analysis did not reveal any potential infectious agent, and no significant differences were observed in the microbiological diversity (microbiome) between clinical- and granuloma characteristics concerning bacteria, fungi, and parasites. CONCLUSION: Our study confirmed that granulomas are frequently seen in liver allograft biopsy specimens, and most often localized in the parenchyma, occurring in the first post-transplant period in patients with AILD, and often seen simultaneously with episodes of ACR. Neither a specific microbiological etiological agent nor a consistent microbiome was detected in any case.

Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas.

Physiological abnormalities in pulmonary granulomas-pathological hallmarks of tuberculosis (TB)-compromise the transport of oxygen, nutrients, and drugs. In prior studies, we demonstrated mathematically and experimentally that hypoxia and necrosis emerge in the granuloma microenvironment (GME) as a direct result of limited oxygen availability. Building on our initial model of avascular oxygen diffusion, here we explore additional aspects of oxygen transport, including the roles of granuloma vasculature, transcapillary transport, plasma dilution, and interstitial convection, followed by cellular metabolism. Approximate analytical solutions are provided for oxygen and glucose concentration, interstitial fluid velocity, interstitial fluid pressure, and the thickness of the convective zone. These predictions are in agreement with prior experimental results from rabbit TB granulomas and from rat carcinoma models, which share similar transport limitations. Additional drug delivery predictions for anti-TB-agents (rifampicin and clofazimine) strikingly match recent spatially-resolved experimental results from a mouse model of TB. Finally, an approach to improve molecular transport in granulomas by modulating interstitial hydraulic conductivity is tested in silico.

The Pattern of Granuloma Formation in the Liver of Rats as a Reflection of the Mechanism of Internalization of Submicron Silicon Particles.

A morphological analysis of the liver of Wistar rats was performed 2 months after a single intravenous injection of porous silicon particles of different sizes (60-80, 250-300, and 500-600 nm; 2 mg/ml, 1 ml). Histological, immunohistochemical, and electron microscopic methods showed the development of CD68+ granulomas in all experimental groups. Injection of 60-80-nm porous silicon particles led to the formation of single large granulomas (>2000 µm2), while 500-600-nm nanoparticles caused the formation of numerous smaller granulomas. The mechanism of involution of granulomas by apoptosis of Kupffer cells and the absence of subsequent connective tissue remodeling of the organ tissue is shown.

Traumatic Ulcerative Granuloma with Stromal Eosinophilia on the Tongue.

BACKGROUND: Traumatic Ulcerative Granuloma with Stromal Eosinophilia, commonly known as Eosinophilic Ulcer, is a reactive solitary and self-limiting benign lesion. It manifests as a punched-out ulcer with a distinct surrounding indurated border, often raising concerns about malignancy. METHODS: A 44-year-old male presented with a painless, indurated tongue ulcer evolving over three months. Despite being asymptomatic, the patient underwent an incisional biopsy due to suspicions of oral squamous cell carcinoma. RESULTS: Histological analysis revealed a disrupted epithelial lining, dense necrotic connective tissue, and a fibrino-purulent pseudomembrane. Proximal to the ulcer, a collar-like projection of reactive epithelial tissue hyperplasia was noted, accompanied by mononuclear cells and a predominantly histiocytic infiltrate in the submucosal layer surrounding skeletal muscle fibers. The final diagnosis was Traumatic Ulcerative Granuloma with Stromal Eosinophilia. Remarkably, the lesion spontaneously healed within 2 weeks post-biopsy, with no recurrence over 6 months. CONCLUSION: This case emphasizes considering this benign condition in the differential diagnosis of oral ulcers, highlighting the importance of accurate histopathological evaluation to rule out cancer.

Immunopathology of Pulmonary Mycobacterium tuberculosis Infection in a Humanized Mouse Model.

Despite the availability of antibiotic therapy, tuberculosis (TB) is prevailing as a leading killer among human infectious diseases, which highlights the need for better intervention strategies to control TB. Several animal model systems, including mice, guinea pigs, rabbits, and non-human primates have been developed and explored to understand TB pathogenesis. Although each of these models contributes to our current understanding of host-Mycobacterium tuberculosis (Mtb) interactions, none of these models fully recapitulate the pathological spectrum of clinical TB seen in human patients. Recently, humanized mouse models are being developed to improvise the limitations associated with the standard mouse model of TB, including lack of necrotic caseation of granulomas, a pathological hallmark of TB in humans. However, the spatial immunopathology of pulmonary TB in humanized mice is not fully understood. In this study, using a novel humanized mouse model, we evaluated the spatial immunopathology of pulmonary Mtb infection with a low-dose inoculum. Humanized NOD/LtSscidIL2Rγ null mice containing human fetal liver, thymus, and hematopoietic CD34+ cells and treated with human cytokines were aerosol challenged to implant <50 pathogenic Mtb (low dose) in the lungs. At 2 and 4 weeks post infection, the tissue bacterial load, disease pathology, and spatial immunohistology were determined in the lungs, liver, spleen, and adipose tissue using bacteriological, histopathological, and immunohistochemical techniques. The results indicate that implantation of <50 bacteria can establish a progressive disease in the lungs that transmits to other tissues over time. The disease pathology in organs correspondingly increased with the bacterial load. A distinct spatial distribution of T cells, macrophages, and natural killer cells were noted in the lung granulomas. The kinetics of spatial immune cell distribution were consistent with the disease pathology in the lungs. Thus, the novel humanized model recapitulates several key features of human pulmonary TB granulomatous response and can be a useful preclinical tool to evaluate potential anti-TB drugs and vaccines.

Transthyretin-derived amyloid (ATTR) and sarcoidosis: Does ATTR deposition cause a granulomatous inflammatory response in older adults with sarcoidosis?

This study aimed to assess the frequency and association between transthyretin-derived (ATTR) amyloidosis and sarcoidosis in a large autopsy cohort including many cases of sudden cardiac death (SCD). We identified 73 sporadic ATTR amyloidosis cases and 11 sarcoidosis cases, among which we found two cases with concomitant ATTR amyloidosis and sarcoidosis (2.4% of all cases; 2.7% within the sporadic ATTR group). The first case involved a 92-year-old man who experienced SCD. In this patient's heart, we observed ATTR deposition and noncaseating epithelioid granulomas consistent with sarcoidosis. Focally, ATTR deposits and granulomas co-localized, with histiocyte phagocytosis of transthyretin-immunoreactive fragments. However, in most lesions, they were distributed independently. The second case was that of an 86-year-old woman who also experienced SCD. In this patient, we detected ATTR deposition in the heart and lung, while noncaseating epithelioid granulomas were only observed in the lung, liver, kidney, and thyroid. Furthermore, no co-localization of the two lesions was observed. Based on these findings, we concluded that the coexistence of ATTR amyloidosis and sarcoidosis was likely coincidental. Nevertheless, despite the rarity of the combination of these two diseases, it should be recognized as a potential cause of SCD, especially among elderly people.

CRDet: A circle representation detector for lung granulomas based on multi-scale attention features with center point calibration.

Lung granuloma is a very common lung disease, and its specific diagnosis is important for determining the exact cause of the disease as well as the prognosis of the patient. And, an effective lung granuloma detection model based on computer-aided diagnostics (CAD) can help pathologists to localize granulomas, thereby improving the efficiency of the specific diagnosis. However, for lung granuloma detection models based on CAD, the significant size differences between granulomas and how to better utilize the morphological features of granulomas are both critical challenges to be addressed. In this paper, we propose an automatic method CRDet to localize granulomas in histopathological images and deal with these challenges. We first introduce the multi-scale feature extraction network with self-attention to extract features at different scales at the same time. Then, the features will be converted to circle representations of granulomas by circle representation detection heads to achieve the alignment of features and ground truth. In this way, we can also more effectively use the circular morphological features of granulomas. Finally, we propose a center point calibration method at the inference stage to further optimize the circle representation. For model evaluation, we built a lung granuloma circle representation dataset named LGCR, including 288 images from 50 subjects. Our method yielded 0.316 mAP and 0.571 mAR, outperforming the state-of-the-art object detection methods on our proposed LGCR.

Correlation Between Proinflammatory Cytokine Expression and Clinical Data in Apical Granuloma.

INTRODUCTION: This study was intended to evaluate the expression of inflammatory cytokines commonly secreted by CD4+ T cells (IL-2, IL-5, IL-17, TGF-ß, TNF-α, and IFN-γ) in apical granulomas and correlate with the clinical conditions and time elapsed since root canal treatment. METHODS: Eighteen biopsy specimens obtained by periradicular surgery of teeth with post-treatment apical periodontitis and diagnosed as apical granuloma were available from the oral pathology laboratory. Silanized slides containing paraffin sections were used for immunohistochemical reactions. Images were analyzed by using an optical microscopy and each slide was subdivided into 5 fields at high magnification. RESULTS: IFN-γ and TGF-ß were the cytokines with the highest expression levels. There were statistically significant differences when comparing IL-2 and IFN-γ (P < .05), and IL-2 and TGF-ß (P < .05). Comparison between the detected cytokines and clinical data and time of treatment demonstrated significant correlation (P < .05) between lower expression of IL-2 and the presence of painful symptoms, absence of sinus tract, and treatments performed more than 4 years before. It was also possible to observe a significant correlation between lower expression of IL-5 and treatments performed less than 4 years before (P < .05). CONCLUSION: IFN-γ and TGF-ß were highly expressed in apical granulomas. However, only IL-2 and IL-5 levels were associated with clinical data and time since previous root canal treatment.

Xanthogranulomatous Epithelial Tumors and Keratin-Positive Giant Cell Rich Tumors of Soft Tissue and Bone: Two Sides of the Same Coin.

Xanthogranulomatous epithelial tumor is a recently described soft tissue tumor characterized by subcutaneous location, partial encapsulation, a xanthogranulomatous inflammatory cell infiltrate, and keratin-positive mononuclear cells. It shares some morphologic features with keratin-positive, giant cell-rich soft tissue tumors. Both have recently been shown to harbor HMGA2::NCOR2 fusions. The relationship between these tumors and their differential diagnosis with other osteoclast-containing soft tissue tumors is discussed.

Evaluation of the antiparasitic and antifibrotic effects of gallic acid on experimental hepatic schistosomiasis mansoni.

Schistosomiasis afflicts approximately 120 million individuals globally. The hepatic pathology that occurs due to egg-induced granuloma and fibrosis is commonly attributed to this condition. However, there is currently no efficacious treatment available for either of these conditions.Our study aimed to investigate the potential antifibrotic and antiparasitic properties of different doses of gallic acid (GA) in experimental schistosomiasis mansoni. In addition, we investigated the outcomes of co-administering it with the standard anti-schistosomiasis treatment, praziquantel (PZQ).In experiment I, Schistosoma mansoni-infected mice were administered GA at doses of 10, 20, or 40 mg/kg. Their effectiveness was evaluated through parasitological (worm and egg loads, granuloma number and diameter), pathological (fibrosis percentage and H-score of hepatic stellate cells (HSCs)), and functional (liver enzymes) tests. In experiment II, we investigated the optimal dosage that yielded the best outcomes. This dosage was administered in conjunction with PZQ and was evaluated regarding the parasitological, pathological, functional, and immunological (fibrosis-regulating cytokines) activities.Our findings indicate that the administration of 40 mg/kg GA exhibited the highest level of effectiveness in experiment I. In experiment II, it exhibited lower antiparasitic efficacy in comparison to PZQ. However, it surpassed PZQ in other tests. It showed enhanced outcomes when combined with PZQ.In conclusion, our findings reveal that GA only slightly increased the antischistosomal activity of PZQ. However, it was linked to decreased fibrosis, particularly when administrated with PZQ. Our pilot study identifies GA as a natural antifibrotic agent, which could be administered with PZQ to mitigate the development of fibrosis.