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.

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.

Resolution of multiorgan sarcoid-like reaction after treatment of renal cell carcinoma.

Sarcoid -like reactions (SLRs) can occur in several malignancies adjacent to primary tumour location or the draining lymph nodes. The presence of peritumoural and intratumoural SLR in patients suffering from renal cell carcinoma (RCC) has been reported in few instances. However, the association of RCC with SLR in spleen, liver and other organs in the absence of systemic sarcoidosis is very rare.We present an unusual case of a gentleman in his 30s, who presented with a lesion in the left kidney along with non-specific lesions (likely granulomatous) in liver, spleen and lungs. Partial Nnephrectomy specimen confirmed conventional/clear cell RCC. The histopathology revealed an extensive epithelioid granulomatous reaction affecting both peritumoural and intratumoural areas. Follow-up images demonstrated an almost complete resolution of lesions in the spleen, liver and lungs. Our case supports the hypothesis that non-caseating granulomas of SLR could be a manifestation of an immunologically mediated antitumour response.

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.

Epithelial granuloma occurring on the staple-stump after segmentectomy for ovarian cancer lung metastasis.

When a mass occurs at the staple line following lung resection, it can be difficult to distinguish between local cancer recurrence and granuloma. We present a case of a staple-line granuloma with 18F-fluorodeoxyglucose-positron emission tomography uptake and elevated serum carbohydrate antigen 19-9 (CA19-9) in a patient with ovarian cancer lung metastasis. After granuloma resection, serum CA19-9 levels normalized, and CA19-9 positive cells were identified in the resected tumor. Therefore, serum CA19-9 elevation does not rule out a staple-line granuloma. Whereas granulomas on computed tomography (CT) scans tend to show smooth shadows along the staple line unilaterally, detailed CT evaluation may help diagnostic differentiation. Differentiation based on imaging and tumor markers has limitations. However, core needle biopsy has the risk of misdiagnosis and tumor cell dissemination, therefore surgical resection should be considered when comprehensive findings indicate a potential recurrence.

Proteomic analysis of granulomas from cattle and pigs naturally infected with Mycobacterium tuberculosis complex by MALDI imaging.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has recently gained prominence for its ability to provide molecular and spatial information in tissue sections. This technology has the potential to uncover novel insights into proteins and other molecules in biological and immunological pathways activated along diseases with a complex host-pathogen interaction, such as animal tuberculosis. Thus, the present study conducted a data analysis of protein signature in granulomas of cattle and pigs naturally infected with the Mycobacterium tuberculosis complex (MTC), identifying biological and immunological signaling pathways activated throughout the disease. Lymph nodes from four pigs and four cattle, positive for the MTC by bacteriological culture and/or real-time PCR, were processed for histopathological examination and MALDI-MSI. Protein identities were assigned using the MaTisse database, and protein-protein interaction networks were visualized using the STRING database. Gene Ontology (GO) analysis was carried out to determine biological and immunological signaling pathways in which these proteins could participate together with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Distinct proteomic profiles between cattle and pig granulomas were displayed. Noteworthy, the GO analysis revealed also common pathways among both species, such as "Complement activation, alternative pathway" and "Tricarboxylic acid cycle", which highlight pathways that are conserved among different species infected by the MTC. In addition, species-specific terms were identified in the current study, such as "Natural killer cell degranulation" in cattle or those related to platelet and neutrophil recruitment and activation in pigs. Overall, this study provides insights into the immunopathogenesis of tuberculosis in cattle and pigs, opening new areas of research and highlighting the importance, among others, of the complement activation pathway and the regulation of natural killer cell- and neutrophil-mediated immunity in this disease.

Why do a lung biopsy for benign lesions?

BACKGROUND: Transthoracic needle biopsy of lung lesions is a well-established procedure for the diagnosis of lung lesions. The literature focuses on the diagnosis of malignant lesions with an often reported accuracy rate of more than 90%. Experience showed that biopsy can identify sometimes incidentally, also benign lesions. There are many reasons why a biopsy is performed for a "benign lesion." First of all, it may be an unexpected diagnosis, as some benign pathologies may have misleading presentations, that are very similar to lung cancer, otherwise the reason is only to make a diagnosis of exclusion, which leads to the benign pathology already being considered in the differential diagnosis. METHODS: This study was designed as a retrospective single-center study. We selected from our database all the lung biopsies performed under CT guidance, from 2015 to 2019 and retrospectively analysed the histological data. We selected only benign lesions describing the imaging feature and differential diagnosis with lung malignancy. RESULTS: In our patient population, among the 969 of them that underwent biopsy, we identified 93 benign lesions (10%). Hamartomas, granulomas, slow-resolving pneumonia and cryptogenic organizing pneumonia are the pathologies that most frequently can misinterpratedas lung cancer. CONCLUSIONS: In this brief report we want to show the percentage and type of benign lesions that are found in our lung trans-thoracic biopsy population. Among these, we identified the three most frequent benign lesions that most frequently enter the differential diagnosis with lung malignant lesions describing the classic and atypical imaging findings.

Modifications of surgical techniques in laparoscopic percutaneous extraperitoneal closure of inguinal ring for childhood inguinal hernia to achieve zero recurrence and zero subcutaneous stitch granuloma.

PURPOSE: To present our technical modifications of single incision laparoscopic percutaneous extraperitoneal closure (SILPEC) of the internal inguinal ring (IIR) for pediatric inguinal hernia (PIH). METHODS: The prospectively collected data of all children diagnosed with PIH undergoing SILPEC at our center from 2016 to 2023 were reviewed and divided into two groups for result comparison: Group A: before and Group B: after the implementation of full modifications. Our modifications included using a nonabsorbable monofilament suture, creating a peritoneal thermal injury at the internal inguinal ring (IIR), employing a cannula to ensure the suture at the IIR ligates only the peritoneum, and double ligation of the IIR in selected cases. RESULTS: 1755 patients in group A and in group B (1 month to 14 years old) were enrolled. There were no significant differences regarding baseline patient characteristics between the two groups. At a median follow-up of 40 months, the rate of recurrent CIH and subcutaneous stitch granuloma (SSG) was 2.3% and 1.5% in group A vs. 0% and 0% in group B (p < 0.001). There were no hydroceles, no ascended or atrophic testis. CONCLUSIONS: Our SILPEC technical modifications can achieve zero recurrence and zero SSG for PIH.

Ulcerative colitis: a diagnostic odyssey through cutaneous polyarteritis nodosa and granulomatous hepatitis.

SummaryUlcerative colitis (UC), a chronic inflammatory bowel disease, can cause extraintestinal manifestations (EIMs) in approximately 40% of individuals. This case report discusses the diagnostic procedure of a woman in her 20s who initially had non-specific symptoms. The patient underwent a thorough evaluation, which initially pointed towards tuberculosis (TB) due to necrotic lymphadenopathy and granulomatous hepatitis. However, no microbiological evidence of TB was found, and her symptoms worsened despite antitubercular therapy. The patient developed painful nodular-ulcerative skin lesions consistent with cutaneous polyarteritis nodosa (cPAN) on biopsy. Eventually, a definitive diagnosis of UC was made, revealing the true nature of her multisystemic manifestations. Cutaneous vasculitis, including leucocytoclastic vasculitis and cPAN, is a rare EIM of UC, with only five reported cases in the literature. This case report highlights the clinical implications of EIMs and contributes to the expanding knowledge of rare EIMs such as cPAN and granulomatous hepatitis.

Identification of apolipoprotein E-derived amyloid within cholesterol granulomas of leopard geckos (Eublepharis macularius).

Apolipoprotein E (ApoE) is involved in cholesterol transport among cells and also plays an important role in amyloid formation, co-depositing with amyloid fibrils in various types of amyloidosis. Although the in vivo amyloidogenicity of ApoE has not been previously demonstrated, this study provides evidence of ApoE amyloidogenicity in leopard geckos (Eublepharis macularius), belonging to the class Reptilia. Histologically, amyloid deposits were localized within cholesterol granulomas and exhibited positive Congo red staining, with yellow to green birefringence under polarized light. On mass spectrometry-based proteomic analysis, ApoE was detected as a dominant component of amyloid; of the full length of the 274 amino acid residues, peptides derived from Leu185-Arg230 were frequently detected with non-tryptic truncations. Immunohistochemistry with anti-leopard gecko ApoE antibody showed positive reactions of amyloid deposits. These results show that ApoE is an amyloid precursor protein within the cholesterol granulomas of leopard geckos. Although further investigations are needed, the C-terminal region of ApoE involved in amyloid formation is a lipid-binding region, and there should be a relationship between amyloidogenesis and the development of cholesterol granulomas in leopard geckos. This study provides novel insights into the pathogenesis of ApoE-related diseases.

Deciphering lung granulomas in HIV & TB co-infection: unveiling macrophages aggregation with IL6R/STAT3 activation.

Tuberculosis (TB) remains a leading cause of mortality among individuals coinfected with HIV, characterized by progressive pulmonary inflammation. Despite TB's hallmark being focal granulomatous lung lesions, our understanding of the histopathological features and regulation of inflammation in HIV & TB coinfection remains incomplete. In this study, we aimed to elucidate these histopathological features through an immunohistochemistry analysis of HIV & TB co-infected and TB patients, revealing marked differences. Notably, HIV & TB granulomas exhibited aggregation of CD68 + macrophage (Mφ), while TB lesions predominantly featured aggregation of CD20+ B cells, highlighting distinct immune responses in coinfection. Spatial transcriptome profiling further elucidated CD68+ Mφ aggregation in HIV & TB, accompanied by activation of IL6 pathway, potentially exacerbating inflammation. Through multiplex immunostaining, we validated two granuloma types in HIV & TB versus three in TB, distinguished by cell architecture. Remarkably, in the two types of HIV & TB granulomas, CD68 + Mφ highly co-expressed IL6R/pSTAT3, contrasting TB granulomas' high IFNGRA/SOCS3 expression, indicating different signaling pathways at play. Thus, activation of IL6 pathway may intensify inflammation in HIV & TB-lungs, while SOCS3-enriched immune microenvironment suppresses IL6-induced over-inflammation in TB. These findings provide crucial insights into HIV & TB granuloma formation, shedding light on potential therapeutic targets, particularly for granulomatous pulmonary under HIV & TB co-infection. Our study emphasizes the importance of a comprehensive understanding of the immunopathogenesis of HIV & TB coinfection and suggests potential avenues for targeting IL6 signaling with SOCS3 activators or anti-IL6R agents to mitigate lung inflammation in HIV & TB coinfected individuals.

Spatial distribution of Mycobacterium tuberculosis mRNA and secreted antigens in acid-fast negative human antemortem and resected tissue.

BACKGROUND: The ability to detect evidence of Mycobacterium tuberculosis (Mtb) infection within human tissues is critical to the study of Mtb physiology, tropism, and spatial distribution within TB lesions. The capacity of the widely-used Ziehl-Neelsen (ZN) staining method for identifying Mtb acid-fast bacilli (AFB) in tissue is highly variable, which can limit detection of Mtb bacilli for research and diagnostic purposes. Here, we sought to circumvent these limitations via detection of Mtb mRNA and secreted antigens in human tuberculous tissue. METHODS: We adapted RNAscope, an RNA in situ hybridisation (RISH) technique, to detect Mtb mRNA in ante- and postmortem human TB tissues and developed a dual ZN/immunohistochemistry staining approach to identify AFB and bacilli producing antigen 85B (Ag85B). FINDINGS: We identified Mtb mRNA within intact and disintegrating bacilli as well as extrabacillary mRNA. Mtb mRNA was distributed zonally within necrotic and non-necrotic granulomas. We also found Mtb mRNA within, and adjacent to, necrotic granulomas in ZN-negative lung tissue and in Ag85B-positive bronchiolar epithelium. Intriguingly, we observed accumulation of Mtb mRNA and Ag85B in the cytoplasm of host cells. Notably, many AFB were negative for Ag85B staining. Mtb mRNA was observed in ZN-negative antemortem lymph node biopsies. INTERPRETATION: RNAscope and dual ZN/immunohistochemistry staining are well-suited for identifying subsets of intact Mtb and/or bacillary remnants in human tissue. RNAscope can identify Mtb mRNA in ZN-negative tissues from patients with TB and may have diagnostic potential in complex TB cases. FUNDING: Wellcome Leap Delta Tissue Program, Wellcome Strategic Core Award, the National Institutes of Health (NIH, USA), the Mary Heersink Institute for Global Health at UAB, the UAB Heersink School of Medicine.

Anti-TL1A monoclonal antibody modulates the dysregulation of Th1/Th17 cells and attenuates granuloma formation in sarcoidosis by inhibiting the PI3K/AKT signaling pathway.

Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.

Granulomatous Panniculitis as an Initial Manifestation of Sjögren Syndrome.

ABSTRACT: A 65-year-old woman presented with unexplained weight loss, recurrent fever, and a dermatosis with painful nodules on the extremities. Biopsies showed focal lobular panniculitis with neutrophilic microgranulomas. Comprehensive investigations ruled out infection and hematologic and solid organ neoplasms. Laboratory results showed anti-Ro/SSA and anti-La/SSB antibody positivity, and elevated inflammatory markers. Dry mouth and eye were confirmed. The diagnosis of Sjögren syndrome with cutaneous panniculitis was established. Prednisone treatment with 30 mg/d resulted in remission of fever and pain improvement. This case emphasizes Sjögren syndrome as an autoimmune disease with multiple cutaneous manifestations and highlights its association with granulomatous panniculitis.

An Unexpected Post-Egg-Free Influenza Vaccine Granulomatous Reaction.

ABSTRACT: A 53-year-old woman presented with a pruritic plaque on the left upper arm that appeared following an egg-free flu vaccine due to a history of reaction to the standard vaccine. The affected area enlarged over a several month period immediately following vaccine administration. Physical examination revealed an 8 × 4 cm coalescent pink plaque on the left upper arm. A shave biopsy of the lesion showed dermal "naked" granulomas, or granulomas with sparse lymphocytic infiltrate at the margins, as typically seen in sarcoidosis. No foreign material was seen in the granulomatous reaction, including with polarization. Special stains, including acid fast bacilli, Grocott methenamine silver, periodic acid-Schiff, and Gram, were negative for organisms. The diagnosis of granulomatous dermatitis was made. Subsequent imaging demonstrated no findings suggestive of sarcoidosis. While vaccine-associated hypersensitivity reactions occur frequently, these reactions are typically due to individual vaccine components, such as egg protein, and do not normally result in the formulation of granulomas. Vaccination-induced granulomas are more often associated with the use of aluminum as an adjuvant; however, this is not present in the egg-free influenza vaccine. Thus, a granulomatous reaction to the egg-free influenza vaccine is very unusual and, to our knowledge, not previously reported.