Advances in cellular and tissue-based imaging techniques for sarcoid granulomas.

Sarcoidosis embodies a complex inflammatory disorder spanning multiple systems, with its origin remaining elusive. It manifests as the infiltration of inflammatory cells that coalesce into distinctive noncaseous granulomas within afflicted organs. Unraveling this disease necessitates the utilization of cellular or tissue-based imaging methods to both visualize and characterize the biochemistry of these sarcoid granulomas. Although hematoxylin and eosin stain, standard in routine use alongside cytological stains have found utility in diagnosis within clinical contexts, special stains such as Masson's trichrome, reticulin, methenamine silver, and Ziehl-Neelsen provide additional varied perspectives of sarcoid granuloma imaging. Immunohistochemistry aids in pinpointing specific proteins and gene expressions further characterizing these granulomas. Finally, recent advances in spatial transcriptomics promise to divulge profound insights into their spatial orientation and three-dimensional (3-D) molecular mapping. This review focuses on a range of preexisting imaging methods employed for visualizing sarcoid granulomas at the cellular level while also exploring the potential of the latest cutting-edge approaches like spatial transcriptomics and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), with the overarching goal of shedding light on the trajectory of sarcoidosis research.

Granuloma, vasculitis, and demyelination in sarcoid neuropathy.

BACKGROUND: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. METHODS: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. RESULTS: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. CONCLUSIONS: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

Sarcoid-like reaction and hypothyroidism induced by PD-1 inhibitor treatment in metastatic renal cell carcinoma: a case report and literature review.

BACKGROUND: Pembrolizumab is among the approved treatments for a variety of cancer types, including clear cell renal cell carcinoma (ccRCC). It has contributed to enhancing the prognosis of renal cell carcinoma. However, it is essential to be aware of the numerous potential immune-related side effects associated with its use. CASE PRESENTATION: A 69-year-old patient with a history of metastatic renal cell carcinoma has been undergoing treatment with Pembrolizumab, an immune checkpoint inhibitor. The medication has led to the development of a sarcoid-like reaction, initially misinterpreted as cancer recurrence and progression. Additionally, the patient has experienced new-onset hypothyroidism, which has been attributed to the immunotherapy. CONCLUSION: Clinicians, including oncologists, endocrinologists, and radiologists, should maintain a high level of suspicions and awareness regarding the potential adverse events associated with newly introduced immunotherapies like pembrolizumab. This knowledge is crucial for the accurate diagnosis and appropriate management of patients receiving these treatments.

Can FDG-PET Imaging Identify Cardiac Sarcoidosis Disease Phenotypes?

PURPOSE OF REVIEW: Despite the scarcity of data, most guidelines have advocated for the treatment of cardiac sarcoidosis with corticosteroids. However, there is heterogeneity in disease presentation and response to treatment, which can make treatment challenging. The ability to identify disease phenotypes to allow for tailored therapy is therefore highly desirable. This review will seek to outline the disease phenotypes of cardiac sarcoidosis and the role that FDG-PET imaging can play in identifying these phenotypes to optimize disease diagnosis and treatment management. RECENT FINDINGS: FDG PET can identify cardiac sarcoidosis and is being increasingly used to monitor therapeutic response to immunosuppressive therapy, to follow treatment response after discontinuation of corticosteroid therapy, and to evaluate for disease relapse. Modern quantitative techniques using FDG PET imaging may allow for even better phenotypic disease characterization and the ability to track the response to immunosuppression more accurately. FDG PET currently plays an important role in cardiac sarcoidosis diagnosis. However, it also affords us the opportunity to offer insights into cardiac sarcoidosis disease phenotypes to better understand the underlying disease process and in the future may allows us to tailor therapies accordingly.

Non-negligible ultrasonographic findings in sarcoid myositis: A case series and literature review.

Sarcoid myositis is a rare and often debilitating extrapulmonary manifestation of sarcoidosis that can be difficult to recognize without a prior sarcoidosis diagnosis. Sarcoidosis with muscle nodules or masses as the first symptom is the least common form, occurring in approximately 0.5%-2.3% of cases. This article presents four middle-aged female patients who initially sought medical attention for a lower limb mass. Ultrasound examinations revealed consistent characteristic changes indicative of myositis. All patients underwent ultrasound-guided muscle biopsy and were diagnosed with sarcoidosis. Therefore, ultrasonography plays a pivotal role as the primary diagnostic tool for the early detection of sarcoid myositis.

Longitudinal pilot study examining the effect of punch biopsy on equine sarcoid growth dynamics.

BACKGROUND: Nonexcisional tissue biopsies facilitate pre-operative confirmation of equine sarcoid yet fear of lesion deterioration currently limits its use in the diagnostic workup. OBJECTIVES: To evaluate the effect of a single punch biopsy on tumour growth dynamics [thickness, area, circumference, viral load (VL) and Visual Analog Scale (VAS)]. ANIMALS: Six client-owned horses with 11 sarcoids of various classification. MATERIALS AND METHODS: Growth dynamics were recorded on a weekly basis, 12 weeks pre- and 24 weeks post-biopsy. The effect of a single punch biopsy on growth dynamics was estimated by linear mixed-effect models. Spearman's rank correlation coefficient (SRCC) was calculated to investigate correlations with the number of weeks before and after the intervention. RESULTS: While statistically significant post-biopsy changes were recorded for all parameters except VL, no parameter was consistently increased after the biopsy intervention. In two of 11 sarcoids, the VL correlation pattern revealed significant strong correlations: sarcoid 6 (pre: r = -0.66, p < 0.05; post: r = 0.81, p < 0.001), increased VL; and sarcoid 8 (pre: r = 0.85, p < 0.001; post: r = 0.17, p > 0.05), no further increase after biopsy. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results indicate that post-biopsy lesion deterioration is not a general concept that applies to all sarcoids, and both deterioration or improvement are possible outcomes over a 24-week period. Further clinical studies with a larger sample size are needed before a definitive conclusion can be made.

Radiotherapy in Equine Practice.

Radiotherapy is a valuable treatment option for equine tumors that have a high rate of recurrence or where complete surgical resection may damage vital structures. Teletherapy, brachytherapy, and plesiotherapy have been used successfully for the treatment of a variety of tumors and locations in the horse. Radiobiology, treatment protocols, side effects, and patient management are reviewed, with a focus on linear accelerator-based teletherapy. There is evidence of good success rates for treatment of periocular sarcoids and squamous cell carcinoma but teletherapy treatment is often limited to tumors on the head and distal extremities.

What Is the Evidence Behind Sarcoid Treatments?

Despite the ubiquitous nature of sarcoids, robust data regarding the selection of treatment modalities are scarce, with many treatments having little or no published data to support their use. Treatment options are numerous and vary with the location and type of sarcoid, treatment accessibility, and the financial status of the owner. Many treatments are expensive and time-consuming, and some have health and safety implications. It is this author's belief that, based on the limited evidence base, appropriate treatment options vary with the location and type of the sarcoid, and no one treatment is universally appropriate.

Sarcoid-like reaction of the orbit in diffuse large B-cell lymphoma.

Sarcoid-like reaction (SLR) has been reported in patients with solid tumor malignancies, lymphomas, and patients receiving immunotherapy. SLR is often incidentally found during positron emission tomography/computed tomography scans as hilar and/or mediastinal lymphadenopathy. SLR has also been found in the lung, spleen, bone marrow, and skin. Biopsy of these lesions shows noncaseating granulomas. When systemic criteria are not met for sarcoidosis, these noncaseating granulomas are termed SLR. We present the first case in the literature of a case of orbital SLR in a patient with concomitant diffuse large B-cell lymphoma and inverted papilloma of the maxillary sinus. This case highlights the importance of including malignancy in the differential for the presence of a noncaseating granuloma in the orbit.

Transcriptome and methylome sequencing reveals altered long non-coding RNA genes expression and their aberrant DNA methylation in equine sarcoids.

Recent publications confirmed that long non-coding RNAs (lncRNAs) perform an essential function in gene-specific transcription regulation. Nevertheless, despite its important role, lncRNA has not yet been described in equine sarcoids, the skin neoplasia of horses. Therefore, the aim of this study is to deepen the knowledge about lncRNA expression in the pathogenesis of equine sarcoids and provide new insight into the regulatory function of lncRNA in the bovine papillomavirus-dependent neoplasia of horse dermal tissues. RNA sequencing (RNA-seq) data from 12 equine sarcoid samples and the corresponding controls were reanalyzed in this study. A total of 3396 differentially expressed (DE) lncRNAs and 128 DElncRNA-DE genes (DEGs) pairs were identified. Differentially expressed lncRNAs predicted target genes were enriched in pathways associated with inter alia the extracellular matrix disassembly and cancer pathways. Furthermore, methylation data from the same samples were integrated into the analysis, and 12 DElncRNAs were described as potentially disturbed by aberrant methylation. In conclusion, this study presents novel data about lncRNA's role in the pathogenesis of equine sarcoids.

Symptomatic myopathies in sarcoidosis: disease spectrum and myxovirus resistance protein A expression.

OBJECTIVES: Symptomatic myopathy in sarcoidosis patients is not always due to sarcoid myopathy (ScM). We investigated the clinical and pathological spectrum including myxovirus resistance protein A (MxA) expression among sarcoidosis patients. METHODS: We reviewed the Mayo Clinic database (May 1980-December 2020) to identify sarcoidosis patients with myopathic symptoms and pathological evidence of myopathy. RESULTS: Among 5885 sarcoidosis patients, 21 had symptomatic myopathy. Eight carried a diagnosis of sarcoidosis 5.5 years (median) prior to myopathy onset. Eleven patients had ScM. The remaining had non-sarcoid myopathies (five IBM, one immune-mediated necrotizing myopathy, one non-specific myositis, two non-specific myopathy and one steroid myopathy). Estimated frequency of IBM is 85 per 100 000 sarcoidosis patients. The following features were associated with non-sarcoid myopathies (P < 0.05): (i) predominant finger flexor and quadriceps weakness, (ii) modified Rankin scale (mRS) >2 at time of diagnosis, (iii) creatine kinase >500 U/l, and (iv) absence of intramuscular granulomas. Sarcoplasmic MxA expression was observed in scattered myofibres in three patients, two of whom were tested for DM-specific autoantibodies and were negative. Immunosuppressive therapy led to improvement in mRS ≥1 in 5/10 ScM, none of the five IBM, and 3/3 remaining patients with non-sarcoid myopathies. DISCUSSION: Symptomatic myopathy occurred in 0.36% of sarcoidosis. IBM was the second most common cause of myopathies after ScM. Frequency of IBM in sarcoidosis is higher than in the general population. Recognition of features suggestive of alternative aetiologies can guide proper treatment. Our findings of abnormal MxA expression warrant a larger study.

Utility of 68Ga-DOTANOC PET/CT in therapeutic monitoring of cardiac sarcoidosis.

Cardiac sarcoidosis usually occurs as a manifestation of systemic sarcoidosis, even though isolated cardiac involvement is not uncommon. The usefulness of 68Ga-DOTANOC PET/CT in the diagnosis of CS has been previously documented in the literature. We present a case of cardiac sarcoidosis, where 68Ga-DOTANOC PET/CT was used for monitoring response to therapy.

Comparison of cardiac magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in the assessment of cardiac sarcoidosis: Meta-analysis and systematic review.

AIM: Fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) and cardiac magnetic resonance (CMR) are frequently used advanced cardiac imaging to diagnose cardiac sarcoidosis (CS). We conducted a meta-analysis and systematic review to compare diagnostic parameters of FDG-PET and CMR in the diagnosis of cardiac sarcoidosis (CS). METHODS: We searched PubMed, EMBASE, and Scopus databases from their inception to 9/30/2021 with search terms "cardiac sarcoidosis" AND "cardiac magnetic resonance imaging" AND "positronemission tomography". We extracted patient characteristics, results of the FDG-PET and CMR, and adverse outcomes from the included studies. Adverse outcomes served as a reference standard for the evaluation of FDG-PET and CMR. RESULTS: We included 4 studies in the meta-analysis which provided adverse outcomes and all patients underwent FDG-PET and CMR. There were 237 patients, 60.3% male, and ages ranged from 50-53 years. There were 45 events in 237 patients from four studies included in the meta-analyses. The pooled sensitivity (95% confidence interval-CI) and specificity (CI) of CMR in predicting an adverse event were 0.94 (0.79-0.98) and 0.49 (0.40-0.59), respectively. The pooled sensitivity (CI) and specificity (CI) of FDG-PET in predicting an adverse event were 0.51 (0.26-0.75) and 0.60 (0.35-0.81), respectively. CONCLUSION: CMR was more sensitive but less specific than FDG-PET in predicting adverse events; however, the study population and definition of a positive test need to be considered while interpreting the results.

A rare case of extensive biventricular cardiac sarcoidosis with reversible torrential tricuspid regurgitation.

Reversal of torrential tricuspid regurgitation is rarely seen. We describe a case in which effective immunosuppression alongside conventional heart failure therapies lead to reversibility of torrential tricuspid regurgitation in a patient with cardiac sarcoidosis. We also discuss the diagnostic challenge in distinguishing cardiac sarcoidosis from other myocardial diseases in a patient presenting with biventricular failure.

Equine sarcoids: A clinicopathologic study of 49 cases, with mitotic count and clinical type predictive of recurrence.

Sarcoids are common mesenchymal neoplasms of horses. Although there are few studies in which sarcoids have been followed over a long period of time, sarcoids are considered locally invasive and have been reported to frequently recur following surgical excision. Currently, no histological features have been identified to predict which sarcoids will recur after excision. The present study comprised 49 sarcoids for which histology sections were available and in which the recurrence status of the case was known. Each sarcoid was excised from a different horse. Overall, 12 of the 49 (24%) sarcoids recurred after surgical excision. Mitotic count (MC), cellularity, necrosis, nuclear pleomorphism, and inflammation of the sarcoids were evaluated histologically. Of these, MC correlated with recurrence. Four of 5 (80%) sarcoids with an MC ≥ 20 in 2.37 mm2 recurred, which was a significantly higher recurrence rate than that of sarcoids with an MC < 20, 8 of 44 cases recurred (18%), P = .0051. Clinical type was also found to correlate with recurrence. Three of 4 (75%) fibroblastic types recurred, which was a significantly higher recurrence rate than that of sarcoids with other clinical types, 9 of 45 cases (18%), P < .001. In addition, univariate Cox regression analysis confirmed fibroblastic type and MC ≥ 20 as significant predictors for recurrence (P = .016 and P = .005, respectively). To the authors' knowledge, this is the first large study examining recurrence rates in sarcoids, and the first time that histological features have been correlated with recurrence.

Clinical significance of serum autoantibodies in patients with sarcoidosis.

BACKGROUND: The association between sarcoidosis and autoimmunity has been reported for years. However, the significance of autoantibodies in the pathophysiology and clinical management of sarcoidosis is not well understood. No autoantibodies that can be used as serologic biomarkers to diagnose the disease, monitor the state of the disease, and predict the prognosis of patients are established. METHODS: We performed a comprehensive analysis of serum autoantibodies and analyzed their associations with clinical features of sarcoidosis. RESULTS: Patients with systemic autoimmune rheumatic diseases-associated autoantibodies had a higher prevalence of advanced radiographic stage and consolidations in high-resolution computed tomography than patients without autoantibodies (p < .05). Age, sex, clinical history, pulmonary function tests, serum angiotensin-converting enzyme levels, rheumatoid factor, and the number of involved organs were not significantly different between the two groups. CONCLUSIONS: There may be an association between autoantibodies and more advanced pulmonary lesions in patients with sarcoidosis. Further investigations are needed to establish the significance of autoantibodies.

Unusual features of neurosarcoidosis: A 18-year retrospective.

BACKGROUND: Neurosarcoidosis (NS) is a challenging diagnosis for clinicians and pathologists. NS most often presents with leptomeningeal involvement where it mimics infectious or neoplastic meningitis, and in up to half of cases, systemic signs of sarcoidosis are lacking. Rare presentations include dural-based mass(es) (mimicking meningioma), hypothalamic/sellar-based lesions (mimicking pituitary adenoma), or as myelopathy (mimicking tumor or neurodegenerative condition). For pathologists, the morphological effects of prior therapy are not well documented. NS as an unsuspected cause of demise today is even less well known. METHODS: Search of departmental databases and personal files, 2004-2022, for NS cases, with focus on the subset with features of interest to pathologists. RESULTS: 22 cases were identified (8 M: 14F, 13-66 years), in 11 of which the CNS specimen represented first diagnosis of sarcoidosis. 20 were surgical and 2 were autopsy cases. Focus of the study revolved around 2 surgical cases with NS granulomas intimately admixed with tumor (1 meningoma, 1 gonadotroph pituitary adenoma/pituitary neuroendocrine tumor (PitNET). One surgical and one autopsy case each had decrease in lymphocytes and well-formed granulomas, with increased fibrosis and hemosiderin in post-treatment tissues. We speculate, but cannot prove, that this may be due to prior steroid therapy. Both autopsy cases were women (38, 43-years), both with cauda equina syndrome/ progressive weakness as first presentation, and extensive spinal cord/nerve root sarcoidosis at demise. First diagnosis of NS/sarcoidosis was at autopsy in the 38-year-old. CONCLUSIONS: Unusual features for pathologists are that NS can co-exist within benign tumors, prior therapy alters histological features, and even in the modern era, may be first diagnosed at autopsy.

Diagnostic efficacy of elevated serum angiotensin-converting enzyme and lymphopenia between presumed sarcoid uveitis and presumed tubercular uveitis.

PURPOSE: To evaluate the diagnostic efficacy of elevated serum angiotensin-converting enzyme (sACE) and lymphopenia in presumed sarcoid and tubercular uveitis. METHODS: A single-centre retrospective study was conducted on a cohort of 755 adult patients with uveitis between January 2019 and June 2020. Demographic, clinical and laboratory data were retrieved from our hospital database. Measurements of serum angiotensin-converting enzyme (sACE) and lymphocyte counts were analysed. RESULTS: The mean age of the patients was 41 ± 13 years. Presumed sarcoid uveitis was diagnosed in 50 (7%) patients, presumed tubercular uveitis in 222 (29.4%) and other uveitic entities noted in 483 (64%). Intermediate and posterior uveitis were the most common anatomical diagnosis in presumed sarcoid uveitis (59% and 20%, respectively) and in presumed tubercular uveitis (46% and 38%, respectively). Elevated sACE was noted in 76% of presumed sarcoid uveitis and 46% in presumed tubercular uveitis. The combination of high serum angiotensin-converting enzyme along with lymphopenia was only in 17% in presumed sarcoid uveitis and 9.7% in presumed tubercular uveitis. sACE was found to be a significant risk factor for presumed sarcoid uveitis with an odds ratio of 3.603 (p < 0.002), and in presumed tubercular uveitis odds ratio was not significant with odds ratio of 1.19. Lymphopenia was not found to be a significant factor in both groups. CONCLUSION: Elevated sACE activity was an independent risk factor for presumed sarcoid uveitis over lymphopenia alone or in combination with lymphopenia.

Dactylitis Due to Subcutaneous Sarcoidosis as a Manifestation of Sarcoidosis. / Dactilitis producida por sarcoidosis subcutánea como presentación de sarcoidosis.

Dactylitis, or sausage fingers or toes, refers to the swelling of 1 or more digits. Sarcoid dactylitis is an uncommon form that tends to be caused by granulomatous bone involvement in the underlying phalanges. Sarcoid dactylitis can, however, clinically resemble subcutaneous sarcoidosis with finger or toe involvement. We describe 5 patients with dactylitis due to subcutaneous sarcoidosis of the fingers. In all cases, the proximal phalanges were involved; sarcoid dactylitis, by contrast, tends to affect the medial and distal phalanges. Differential diagnosis is important, as dactylitis due to bone involvement tends to be much more persistent and is generally seen in chronic forms of sarcoidosis.

Granulomas associated with renal neoplasms: A multi-institutional clinicopathological study of 111 cases.

AIMS: Formal depiction of granulomatous inflammation associated with renal neoplasms has mainly consisted of case reports. Herein, we investigate the clinicopathological features and potential significance of granulomas associated with renal tumours from a large multi-institutional cohort. METHODS AND RESULTS: One hundred and eleven study cases were collected from 22 institutions, including 57 partial nephrectomies and 54 radical nephrectomies. Patient ages ranged from 27 to 85 years (average = 60.1 years; male = 61%). Renal neoplasms included clear cell renal cell carcinoma (RCC; 86%), papillary RCC (8%), chromophobe RCC (3%), clear cell papillary RCC (1%), mixed epithelial stromal tumour (1%) and oncocytoma (1%). Granulomas were peritumoral in 36%, intratumoral in 24% and both in 40% of cases. Total granuloma count per case ranged from one to 300 (median = 15) with sizes ranging from 0.15 to 15 mm (mean = 1.9 mm). Necrotising granulomas were seen in 14% of cases. Histochemical stains for organisms were performed on 45% of cases (all negative). Sixteen cases (14%) had a prior biopsy/procedure performed, and eight patients had neoadjuvant immunotherapy or chemotherapy. Eleven patients (10%) had a confirmed diagnosis of sarcoidosis, including five in whom sarcoidosis was diagnosed after nephrectomy. CONCLUSION: Based on this largest case-series to date, peri-/intratumoral granulomas associated with renal neoplasms may be more common than initially perceived. The extent of granulomatous inflammation can vary widely and may or may not have necrosis with possible aetiologies, including prior procedure or immunotherapy/chemotherapy. Although a clinical association with sarcoidosis is infrequent it can still occur, and the presence of granulomas warrants mention in pathology reports.