Abstract
Background
Granulomas can be found in different tissues and are associated with a variety of processes. To understand the primary diagnoses is the aim of this study.
Materials and Methods
We retrospectively described a cohort of patients with a diagnosis of granulomas in histopathological samples over an 11-year period. Demographic characteristics, histopathological pattern and organ involved, diagnostic tests performed (microbiological, radiological and laboratory findings) and final diagnosis were analysed. The principal causes of granulomas were studied according to the organ involved, histopathological characteristics, and the patient’s origin. The techniques employed for diagnosis were evaluated.
Results
Six hundred twenty-six patients (median [IQR] age, 50 [33–64] years; 52% male) were analysed. Granulomas were non-necrotising in 56% (350) and necrotising in 24% (150) of cases. The main organ affected was gastrointestinal in 25% (157), ganglionic in 23% (142), pulmonary in 11% (71), hepatic in 10% (65) and skin tissue in 7% (44). The main aetiologies were infectious diseases (138; 22%), predominantly mycobacteria, followed by inflammatory bowel disease (IBD) (14%; 85), sarcoidosis (10%; 65), and neoplasms (9%; 56). In Western European patients, IBD was the main diagnosis (17% [78] vs 4% [7]; p < 0.001), whereas in foreign patients, it was tuberculosis (33% [56] vs 9% [41]; p < 0.001). Microbiological culture was performed in only 34% (210) of cases.
Conclusions
Infectious diseases were the primary cause of granulomas, followed by inflammatory diseases, sarcoidosis and response to neoplasms. The distribution of aetiologies varies according to the organ affected and the nationality of the patient. The implementation of a structured diagnostic algorithm may facilitate the evaluation and management of patients with granulomatous inflammation.
Keywords: Granulomas, granulomatous response, aetiologies, mycobacteria
Introduction
Granulomas are a distinct chronic response of the immune system to a range of antigenic stimuli. They are formed by an organised, multicellular structure of immune cells working together in a dynamic process including activated macrophages, dendritic cells, multinucleated and natural killer cells (at different stages of maturation of the granuloma), surrounded by a ring of T lymphocytes (the initial effectors). Antigen presentation to T helper lymphocytes (Th0) leads to different patterns of Th1, Th2, Th17 and Treg response, which in turn give rise to different granuloma phenotypes [1]. The production of proinflammatory cytokines (TNF-α, IFN-γ, IL-2) by Th1 cells induces an anti-fibrotic granuloma with a macrophage-rich core, typically observed in tuberculosis. Conversely, when Th2 is predominant in the response, a profibrotic phenotype is observed with a higher rate of release of anti-inflammatory cytokines (IL-4, IL-10). In both pathways, cytokines released by Th17 cells (IL-17a, IL-22) act as mediators of inflammation. It has been suggested that the function of granuloma formation is to achieve a balance between control of the exogenous trigger and destruction of local tissue, but this is still under investigation and review [2–4].
Granulomas can be found in several processes, including infections, immunological diseases, neoplasms, and foreign body reactions. They can also be found in different tissues and organs, depending on the underlying aetiology. The wide range of potential causes presents a challenge to the accurate diagnosis of these conditions in clinical practice [5]. Tissue staining techniques and microbiological examination of samples (primarily culture, but also molecular techniques) are essential in the diagnostic approach. However, in many cases, these methods are insufficient.
Although several studies have outlined the most common aetiologies associated with the development of tissue granulomas in specific organs [6–10] or specific diseases [11–13], there is a gap in the literature regarding the overall incidence of granulomas in tissue samples, their main aetiologies, and the diagnostic strategies employed [5]. For the optimal management of this diverse pathology, it is essential to have a comprehensive understanding of the aetiological factors that contribute most to the formation of granulomas in our environment, as well as the diagnostic procedures used to establish a definitive diagnosis. The aim of our study was to elucidate the aetiology of granulomatous processes in a large cohort of patients seen at our centre over an 11-year period. To this end, our approach included a detailed review of the diagnostic methodology employed in each case. As secondary endpoints, the aetiology was analysed according to the organ involved, the type of granuloma observed, and the origin of the patient.
Materials and methods
This retrospective study included all patients identified in the Anatomical Pathology Department database of our hospital over an eleven-year period (2013–2023) whose histopathological diagnosis contained the term “granuloma” and for whom clinical information was available. Each patient was considered a single episode, regardless of the total number of samples analysed (Figure 1). The hospital is a 1,300-bed acute-care teaching hospital that serves as a referral centre for a population of 550,000 inhabitants. Over the period of study, 382,262 biopsies were performed. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The requirement of informed consent was waived due to the retrospective design of the study and the use of anonymised data. This study was approved by the Ethics Committee of Hospital Universitario 12 de Octubre (CEIm imas12) (Approval No. 24/268).
Figure 1.
Flow diagram of case selection and diagnostic yield.
Descriptions from tissue samples were divided into four groups: no-necrotising granulomas (formed granuloma without central necrosis), necrotising granulomas (formed granuloma with central necrosis, both caseous or non-caseous), no-specified granulomas (formed granuloma without specification) and granulomatous response (granulomatous inflammation reaction without formed granuloma), based on the descriptions in the anatomopathological reports. The reports were prepared by various pathologists, with the choice of each pathologist depending on the specific type of organ and the designated study period. This approach is reflective of the nature of the workflow at our centre, whilst ensuring that the reports were consistently based on standard definitions (Figure 2).
Figure 2.
Histopathological features of representative case selection (H&E). (A) Lung showing a well-formed non-necrotising granuloma composed of epithelioid histiocytes with occasional multinucleated giant cells (×100), in a case of sarcoidosis. (B1) Lymph node showing necrotising granulomatous inflammation with central eosinophilic necrosis at low power (×20). (B2) Panoramic view of the lymph node demonstrating multiple confluent necrotising granulomas extensively involving the tissue, both from a patient with IgG4-related disease. (C1) Liver showing a granuloma with irregular central necrosis surrounded by epithelioid histiocytes and a peripheral lymphocytic infiltrate (×100). (C2) Low-power view of the liver showing diffuse necrotising granulomatous inflammation with poorly defined necrotic areas (×20), both from a case of tuberculosis.
The data were obtained from electronic medical records and the laboratory database and included the following information: demographic characteristics (age, sex and country of origin), histopathological pattern and organ involvement, microbiological results of interferon gamma release assay (IGRA), purified protein derivative (PPD) skin test, cultures and molecular tests on the specimen (such as polymerase chain reaction, PCR), serological tests, radiological findings, autoantibodies and serum angiotensin-converting enzyme (ACE). Some of this data was only collected when the clinical presentation suggested a specific differential diagnosis. The primary endpoint of the analysis was the final diagnosis established by the treating physicians, based on clinical presentation, diagnostic procedures, and complete follow-up monitoring, as reflected in the diagnosis algorithm (Figure 3). Foreign-body reaction was diagnosed when granulomatous inflammation with multinucleated giant cells of the foreign-body type was identified on histopathological examination. Latent tuberculosis infection (LTBI) was defined according to World Health Organisation (WHO) recommendations as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifest activity [14]. A diagnosis of tuberculosis was considered appropriate when an active disease state due to M. tuberculosis was confirmed. Sarcoidosis was classified as a separate entity from inflammatory diseases because it represents a major and distinct cause of granulomatous diseases.
Figure 3.
Diagnostic workflow for the evaluation of granulomatous disease. The algorithm illustrates a structured multidisciplinary approach to the evaluation of patients with granulomatous inflammation identified on histopathology. Following initial clinical assessment and identification of involved organ systems, patients undergo either targeted confirmatory testing when a specific aetiological suspicion is present or a systematic multidisciplinary diagnostic workup when no clear aetiology is identified. Diagnostic outcomes are classified as confirmed diagnosis, probable diagnosis based on established clinicopathological criteria, or undiagnosed granulomatous disease requiring longitudinal follow-up and reassessment.
The cause of the granulomatous reaction was assessed for the whole cohort, as well as according to the main organ involved. The paediatric population was defined as individuals 16 years of age or younger. Simultaneous involvement of more than one organ was recorded and analysed. The different techniques used to arrive at the registered diagnosis, as described above, were studied and compared between the different aetiologies. Follow-up was not evaluated as a study endpoint, since the objective was to describe the diagnostic process and the distribution of aetiologies. Nevertheless, follow-up data were reviewed in undiagnosed cases to confirm that the diagnosis remained unchanged over time, and the state and date of the last clinical review were recorded.
Data analysis was performed using the STATA 15.1 statistical software package. The Student’s t-test was used for continuous variables with a normal distribution, the Wilcoxon rank-sum test for variables with a non-normal distribution, and the chi-squared test or Fisher’s exact test for categorical variables, as appropriate. Confidence intervals were set at 95%, with a significance level of p < 0.05 for all tests. Variables associated with the diagnosis were assessed using multivariable logistic regression. Results are reported as odds ratios with 95% confidence intervals.
Results
A total of 743 biopsies (0.19% of all biopsies throughout the period of study) were reviewed, corresponding to an average annual incidence of 10.4 patients with granulomas per 100,000 inhabitants. After the exclusion of patients with incomplete data in the electronic medical record and typographic errors in diagnosis (Figure 1), the analysis was conducted on 626 patients with any type of granulomatous response pattern in histopathological samples and all available information on diagnostic tests and demographic characteristics. Fifty-two percent (325) were male, and the median age was 50 years (IQR 33–64). Granulomas were non-necrotising in 56% (350) of cases, necrotising in 24% (150), not specified in 9% (58), foreign body associated in 8% (49), and granulomatous reactions in 3% (19). Organ involvement was gastrointestinal in 25% (157), ganglionic in 23% (142), pulmonary in 11% (71), hepatic in 10% (65), skin and soft (S&S) tissue in 7% (44), breast in 5% (29), pleural in 4% (25), reno-ureteral in 3% (18), genital in 3% (17), prostatic in 2% (12), osteoarticular in 2% (10), bone marrow in 2% (10), and central nervous system (CNS) involvement in only 0.3% (2). The remaining 4% (24) involved other organs. The main aetiologies were infectious diseases (138; 22%), mainly tuberculosis and non-tuberculosis mycobacteria (NTM), followed by inflammatory bowel disease (IBD) (85; 14%), sarcoidosis (65; 10%), and neoplasms (56; 9%). In 29% (181) of cases, a definitive diagnosis could not be established following a median follow-up period of 4 years (IQR 2–8), during which no new clinical evidence altered the ultimate diagnosis. All aetiologies are listed in Table 1.
Table 1.
Global distribution of aetiologies and distribution by organ involved.
| Diagnosis | All patients, n (626) | Intestine, n (157) | Lymph node, n (142) | Lung, n (71) | Pleura, n (25) | Liver, n (65) | UG, n (47) | S&S, n (44) | Breast, n (29) | Bone & joint, n (10) | Bone marrow, n (10) | Miscellaneous, n (26)* |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No diagnosis | 181 (28.9%) | 43 (27.4%) | 40 (28.0%) | 21 (30.0%) | 1 (4.0%) | 17 (26.0%) | 18 (38.0%) | 17 (39.0%) | 16 (55.0%) | 1 (10.0%) | 3 (33.0%) | 4 (15.4%) |
| Infectious diseases | 138 (21.9%) | 13 (8.3%) | 42 (29.8%) | 12 (17.0%) | 24 (96.0%) | 9 (13.8%) | 9 (19.0%) | 7 (16.3%) | 3 (10.3%) | 4 (40.0%) | 5 (50.0%) | 10 (38.5%) |
| IBD | 85 (13.5%) | 83 (52.9%) | – | – | – | – | 1 (2.0%) | 1 (2.3%) | – | – | – | – |
| Sarcoidosis | 65 (10.3%) | 1 (0.6%) | 34 (24.0%) | 18 (25.0%) | – | 6 (9.0%) | – | 2 (5.0%) | 1 (3.4%) | 1 (10.0%) | 1 (10.0%) | 1 (3.8%) |
| Solid neoplasm | 56 (8.9%) | 2 (1.3%) | 17 (12.0%) | 12 (17.0%) | – | 8 (12.0%) | 7 (15.0%) | 3 (7.0%) | 4 (14.0%) | – | – | 3 (11.5%) |
| Foreign body reaction | 40 (6.4%) | 12 (7.6%) | 1 (0.7%) | – | – | 4 (6.0%) | 8 (17.0%) | 9 (20.0%) | 2 (7.0%) | 1 (10.0%) | – | 3 (11.5%) |
| Inflammatory diseases | 38 (6.0%) | 2 (1.3%) | 2 (1.4%) | 4 (5.6%) | – | 15 (23.0%) | – | 5 (11.6%) | 3 (10.0%) | 3 (30.0%) | – | 4 (15.4%) |
| Pharmacologic | 9 (1.4%) | 1 (0.6%) | – | – | – | 4 (6.0%) | 4 (9.0%)** | – | – | – | – | – |
| Lymphoma | 7 (1.1%) | – | 3 (2.0%) | 1 (1.4%) | – | 2 (3.0%) | – | – | – | – | 1 (10.0%) | – |
| Pneumoconiosis | 5 (0.8%) | – | 2 (1.4%) | 3 (4.2%) | – | – | – | – | – | – | – | – |
| Histiocytosis | 2 (0.3%) | - | 1 (0.7%) | – | – | – | – | – | – | – | – | 1 (3.8%) |
Miscellaneous includes pericardium (2), peritoneum (5), retroperitoneum (1), spleen (2), pancreas (1), gallbladder (2), CNS (2), thyroid (4) and other head and neck tissues (6). **All the pharmacological cases in the urogenital area were due to BCG instillation. Other pharmacologic agents were metformin in the intestinal sample, and immunotherapy, non-steroidal anti-inflammatories, and two unknown agents in hepatic samples.
IBD: inflammatory bowel disease; S&S: skin and soft tissues; UG: urogenital.
All percentages are based on column totals.
With respect to country of origin, seventy-two percent (448) of the patients were born in Spain, 17% (108) in Latin American countries, 5% (30) in Africa (mainly Morocco), 3% (18) in Eastern Europe, and 3% (16) in Asia. The remaining six patients were born in countries in Western Europe other than Spain (1%). The main diagnosis in patients born in Western Europe (including Spain) versus other origins was IBD (17% [78] vs 4% [7]; p < 0.001), followed by neoplasms (10%), sarcoidosis, tuberculosis and foreign body reaction (8–9% each). In foreign patients, tuberculosis was the principal aetiology (33% [56] vs 9% [41]; p < 0.001), followed by sarcoidosis (13% [23], p = 0.179) and neoplasms (6% [11], p = 0.233). Table 2 shows the global distribution of the data according to nationality.
Table 2.
Distribution of aetiologies according to the nationality of patients.
| Diagnosis | Western Europe, n (454) | Other nationalities*, n (172) | p |
|---|---|---|---|
| Non diagnosis | 140 (30.8%) | 41 (23.8%) | |
| Infectious diseases | 69 (15.2%) | 68 (39.5%) | <0.001 |
| Tuberculosis | 41 (9.0%) | 56 (32.6%) | <0.001 |
| NTM | 8 (1.8%) | 2 (1.2%) | |
| CMV | 2 (0.4%) | 1 (0.6%) | |
| Histoplasma | 0 (0.0%) | 2 (1.2%) | |
| Q fever | 0 (0.0%) | 2 (1.2%) | |
| Leishmania spp | 0 (0.0%) | 1 (0.6%) | |
| Bartonella spp | 1 (0.2%) | 0 (0.0%) | |
| Toxoplasma gondii | 1 (0.2%) | 0 (0.0%) | |
| Hydatid disease | 1 (0.2%) | 0 (0.0%) | |
| Other bacterial causes | 9 (2.0%) | 4 (2.3%) | |
| Other fungal causes | 5 (1.1%) | 0 (0.0%) | |
| Other viral causes | 1 (0.2%) | 1 (0.6%) | |
| IBD | 78 (17.2%) | 7 (4.1%) | <0.001 |
| Sarcoidosis | 42 (9.0%) | 23 (13.4%) | |
| Solid neoplasm | 45 (9.9%) | 11 (6.4%) | |
| Foreign body reaction | 36 (7.9%) | 4 (2.3%) | 0.010 |
| Inflammatory diseases | 26 (5.7%) | 12 (7.0%) | |
| CBP | 7 (1.5%) | 1 (0.6%) | |
| Rheumatoid arthritis | 6 (1.3%) | 0 (0.0%) | |
| Vasculitis | 1 (0.2%) | 2 (1.2%) | |
| IgG4 disease | 2 (0.4%) | 1 (0.6%) | |
| Other autoimmune diseases | 10 (2.2%) | 8 (4.7%) | |
| Pharmacological | 9 (2.0%) | 0 (0.0%) | |
| Lymphoma | 5 (1.1%) | 2 (1.2%) | |
| Pneumoconiosis | 2 (0.4%) | 3 (1.7%) | |
| Histiocytosis | 2 (0.4%) | 0 (0.0%) |
Eastern Europe, Asia, Africa, Central America and South America.
p-values not statistically significant or too small to be calculated are not shown in the table.
All percentages are based on column totals.
Chest X-ray was available in 68% (424) of cases, PPD in 39% (245), IGRA in 26% (160), and an ACE determination in 25% (159) of cases. Microbiological culture was performed in only 34% (210) of cases, while serological tests and autoantibodies were diagnostic in only about 5% (13 and 17 cases, respectively) (Table 3). Among patients with ACE determination, 57% (91) had high levels, which were significantly higher in sarcoidosis patients (median 80 µg/L [IQR 55–157] vs 51 µg/L [IQR 31–80]; p = 0.004). Diagnostic yield is summarised in Supplementary Table 1, and demographic characteristics of the disease cohort are presented in Supplementary Table 2.
Table 3.
Distribution of diagnosis tests: overall and by organ affected.
| Diagnostic tests | Overall, n (626) | Intestine, n (158) | Lymph node, n (142) | Lung, n (71) | Pleura, n (25) | Liver, n (65) | Urogenital, n (47) | Skin and soft tissues, n (44) | Breast, n (29) | Bone & Joint, n (10) | Miscellaneous*, n (35) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Microbiological study | 210 (33.6%) | 29 (18.4%) | 66 (46.5%) | 31 (43.7%) | 18 (72.0%) | 10 (15.4%) | 7 (14.9%) | 10 (22.7%) | 14 (48.3%) | 5 (50.0%) | 20 (57.1%) |
| Tuberculosis PCR | 74 (11.8%) | 11 (7.0%) | 29 (20.4%) | 11 (15.5%) | 3 (12.0%) | 7 (10.8%) | 2 (4.3%) | 2 (4.6%) | 1 (3.5%) | 2 (20.0%) | 6 (17.1%) |
| IGRA | 160 (25.6%) | 57 (36.1%) | 35 (24.7%) | 20 (28.2%) | 2 (8.0%) | 18 (27.7%) | 5 (10.6%) | 3 (6.8%) | 7 (24.1%) | 1 (10.0%) | 12 (34.3%) |
| PPD | 245 (39.1%) | 78 (49.4%) | 53 (37.3%) | 20 (28.2%) | 13 (52.0%) | 28 (43.1%) | 13 (27.7%) | 14 (31.8%) | 14 (48.3%) | 3 (30.0%) | 9 (25.7%) |
| Chest X-ray | 424 (67.7%) | 88 (55.7%) | 119 (83.8%) | 67 (94.4%) | 25 (100.0%) | 37 (56.9%) | 20 (42.6%) | 21 (47.7%) | 14 (48.3%) | 8 (80.0%) | 25 (71.4%) |
| ACE | 159 (25.4%) | 29 (18.4%) | 58 (40.9%) | 29 (40.9%) | 3 (12.0%) | 16 (24.6%) | 2 (4.3%) | 9 (20.5%) | 7 (24.1%) | 1 (10.0%) | 5 (14.3%) |
ACE: angiotensin converting enzyme; IGRA: interferon gamma release assay; PCR: polymerase chain reaction; PPD: purified protein derivative.
Miscellaneous include bone marrow, pericardium, peritoneum, retroperitoneum, CNS, thyroid and other head and neck tissues.
All percentages are based on column totals.
Performance of specific staining techniques for fungi and mycobacteria by the pathologist was variable and rarely diagnostic (0.04%). Microbiological studies were more frequently performed in infectious granulomas (100/138; 72.5%) than in non-infectious ones (110/488; 22.5%) (p < 0.001), and in only 10/38 (26.3%) of inflammatory disease cases and in 45/181 (24.9%) of non-diagnostic cases. Patients who underwent microbiological studies (culture, molecular tests, serologies and/or TST/IGRA) differed significantly from those who did not, being younger (p < 0.001), born outside Western Europe and having a final diagnosis more frequently (p < 0.001), mainly an infectious disease (p < 0.001) (Supplementary Table 3).
Sub-analysis according to organ involvements
The distribution of aetiologies was recorded according to the organ involved (Table 1). The infectious and autoimmune causes of granulomas by organ involved are shown in Tables 4 and 5, respectively. In 8% (48) of patients, a second organ was involved at the time of diagnosis: in 4% (24), it was a ganglion (mainly in sarcoidosis, tuberculosis and solid neoplasms) and in 2% (11), it was the lung (also typically in tuberculosis and sarcoidosis).
Table 4.
Description of infectious causes of granulomas.
| Diagnosis | All patients, n (626) | Intestine, n (157) | Lymph node, n (142) | Lung, n (71) | Pleura, n (25) | Liver, n (65) | UG, n (47) | S&S, n (44) | Breast, n (29) | Bone & Joint, n (10) | Bone marrow, n (10) | Miscellaneous, n (26) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Infectious diseases | 138 (21.9%) | 13 (8.3%) | 42 (29.8%) | 12 (17.0%) | 24 (96.0%) | 9 (13.8%) | 9 (19.0%) | 7 (16.3%) | 3 (10.3%) | 4 (40.0%) | 5 (50.0%) | 10 (38.5%)* |
| Tuberculosis | 97 (15.4%) | 9 (5.7%) | 34 (24.0%) | 6 (8.0%) | 23 (92.0%) | 2 (3.0%) | 6 (13.0%) | 4 (9.0%) | 1 (3.4%) | 4 (40.0%) | 1 (10.0%) | 7 (26.9%) |
| NTM | 10 (1.6%) | 5 (4.0%) | 1 (1.4%) | 1 (4.0%) | 1 (1.5%) | 1 (2.3%) | 1 (10.0%) | |||||
| Pyogenic unaffiliated | 6 (1.0%) | 2 (4.0%) | 2 (7.0%) | 2 (7.7%) | ||||||||
| CMV | 3 (0.5%) | 1 (0.6%) | 2 (3.0%) | |||||||||
| Histoplasma | 2 (0.3%) | 1 (1.4%) | 1 (10.0%) | |||||||||
| Q fever | 2 (0.3%) | 1 (1.5%) | 1 (10.0%) | |||||||||
| Polymicrobial | 2 (0.3%) | 1 (0.7%) | 1 (1.4%) | |||||||||
| Chlamydia trachomatis | 2 (0.3%) | 2 (1.3%) | ||||||||||
| Fungal unaffiliated | 2 (0.3%) | 1 (1.4%) | 1 (2.0%) | |||||||||
| Leishmania spp | 1 (0.2%) | 1 (10.0%) | ||||||||||
| Bartonella spp | 1 (0.2%) | 1 (1.5%) | ||||||||||
| Toxoplasma gondii | 1 (0.2%) | 1 (0.7%) | ||||||||||
| Hydatid disease | 1 (0.2%) | 1 (1.5%) | ||||||||||
| H. pylori | 1 (0.2%) | 1 (0.6%) | ||||||||||
| Klebsiella pneumoniae | 1 (0.2%) | 1 (2.3%) | ||||||||||
| Actinomyces spp | 1 (0.2%) | 1 (2.3%) | ||||||||||
| Candida spp. | 1 (0.2%) | 1 (3.8%) | ||||||||||
| Mucormycosis | 1 (0.2%) | 1 (1.4%) | ||||||||||
| Scedosporium spp | 1 (0.2%) | 1 (1.4%) | ||||||||||
| HCV | 1 (0.2%) | 1 (0.7%) | ||||||||||
| EBV | 1 (0.2%) | 1 (1.5%) |
Miscellaneous includes: pericardium (1), peritoneum (4), spleen (1), gallbladder (1), CNS (2), and other head and neck tissues (1).
CMV: cytomegalovirus; EBV: Epstein-Barr virus; HCV: hepatitis C virus; NTM: non-tuberculous mycobacteria; S&S: skin and soft tissues; UG: urogenital.
All percentages are based on column totals.
Table 5.
Description of inflammatory causes of granulomas.
| Diagnosis | All patients, n (626) | Intestine, n (157) | Lymph node, n (142) | Lung, n (71) | Pleura, n (25) | Liver, n (65) | UG, n (47) | S&S, n (44) | Breast, n (29) | Bone & joint, n (10) | Bone marrow, n (10) | Miscellaneous*, n (26) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Inflammatory diseases | 38 (6.0%) | 2 (1.3%) | 2 (1.4%) | 4 (5.6%) | – | 15 (23.0%) | – | 5 (11.6%) | 3 (10.0%) | 3 (30.0%) | – | 4 (15.4%) |
| PBC | 8 (1.3%) | 8 (12.0%) | ||||||||||
| Rheumatoid arthritis | 6 (1.0%) | 1 (1.4%) | 3 (7.0%) | 2 (20.0%) | ||||||||
| Autoimmune hepatitis | 4 (0.6%) | 4 (6.2%) | ||||||||||
| Vasculitis | 3 (0.5%) | 2 (2.8%) | 1 (2.3%) | |||||||||
| IgG4 disease | 3 (0.5%) | 2 (1.4%) | 1 (3.8%) | |||||||||
| Immunotherapy | 3 (0.5%) | 1 (0.6%) | 2 (3.1%) | |||||||||
| Granulomatous mastitis | 3 (0.5%) | 3 (10.0%) | ||||||||||
| Eosinophilic oesophagitis | 1 (0.2%) | 1 (0.6%) | ||||||||||
| PFAPA syndrome | 1 (0.2%) | 1 (3.8%) | ||||||||||
| Gouty arthritis | 1 (0.2%) | 1 (10.0%) | ||||||||||
| Seronegative autoimmune cholangiopathy | 1 (0.2%) | 1 (1.5%) | ||||||||||
| Lymphocytic thyroiditis | 1 (0.2%) | 1 (3.8%) | ||||||||||
| Granulomatous folliculitis | 1 (0.2%) | 1 (2.3%) | ||||||||||
| Unclassified dysimmune | 2 (0.3%) | 1 (1.4%) | 1 (3.8%) |
Miscellaneous includes retroperitoneum (1), thyroid (1) and other head and neck tissues (1).
IgG4: immunoglobulin G4 (subclass): PBC: primary biliary cirrhosis; PFAPA: Periodic Fever, Aphthous stomatitis; Pharyngitis and Adenopathy; S&S: skin and soft tissues; UG: urogenital.
All percentages are based on column totals.
For some organs, there was a strong association with a particular diagnosis. For example, the presence of granulomas in gastrointestinal samples was associated with IBD in more than 50% (83) of cases. Mycobacterial infection and sarcoidosis were the most common diagnoses in patients with granulomas of the ganglion (n = 142), although tuberculosis was only tested in 50% (71) of cases and ACE levels were determined in only 41% (58) of patients. It was noted that up to 15% (21) of cases were tumour-related.
As with lymph node involvement, infectious diseases and sarcoidosis were the main aetiologies found in lung biopsies. When the pleura was examined (n = 25), the cause was mycobacterial infection in 96% (24) of cases. Mycobacterial culture was performed in 72% (18) of these patients and was positive in 39% (7). The diagnosis of infection in patients with negative results was based on indirect results considering the whole clinical picture.
Granulomatous responses in the liver were secondary to a wider range of conditions. Autoimmune causes accounted for 25% (16) of cases, but were also seen in response to drugs, infectious diseases, and solid neoplasms. Pharmacological causes related to the urogenital system were mainly associated with BCG treatment (9%, 4). In S&S tissue (n = 44), the foreign body reaction was the primary cause, with tuberculosis representing the second most common cause. Diagnosis of cases was based on positive culture in 2 patients, tuberculosis molecular detection in one patient, and a positive PPD in the remaining patient. Only 34% (15) of cases were tested for tuberculosis infection.
The rate of definitive diagnosis was higher when the affected organ was bone or joint (n = 10), where tuberculosis was responsible for 40% (4) of cases. The main aetiologies were only one case of sarcoidosis and one of lymphoma; the remaining cases were undiagnosed.
Of the less represented organs, the peritoneum, thyroid and head and neck tissues were the most frequently biopsied. The main aetiology in peritoneum (4/5), pericardium (1/2) and CNS (2/2) was tuberculosis. Neoplasms were the principal cause in thyroid (3/4) and pancreas (1/1), and IgG4 disease in retroperitoneal samples (1/1).
Three specific entities were analysed separately:
Granulomatous appendicitis. Of 13 episodes, all in the context of acute appendicitis, only one was characterised as a foreign body reaction-related, with no alternative diagnosis in the other 12. In forty-six percent of patients (6), tuberculous infection was studied by PPD or IGRA test, with a positive result in 15% (2) of cases, but no diagnosis of tuberculous disease was made.
Granulomatous mastitis. The no-diagnosis rate for this tissue was high (55%, 16 patients). Screening for tuberculous infection and microbiological cultures were performed in 48% (14) of cases each. Other studies performed included serum ACE in 24% (7), serological tests in 20% (6) and autoimmunity tests in 14% (4).
Granulomatous prostatitis. Based on an examination of 12 specimens, a diagnosis was made in 50% of the cases: three were associated with BCG treatment, 2 were cases of neoplasms and one was a bacterial infection. None of the tissue samples was cultured, and only two cases were tested for LTBI, with no positive results.
Necrotising and non-necrotising granulomas
The type of granuloma has historically been associated with a specific aetiology. Table 6 shows the principal aetiologies of necrotising and non-necrotising granulomas. Our analysis revealed the overall predominance of non-necrotising granulomas (350 vs 150), particularly in immunological diseases (CBP, IBD, etc) and in cases where the cause was undetermined. In addition, 92% (60) of cases with sarcoidosis presented non-necrotising granulomas. In neoplasms, a considerable proportion of the granulomas exhibited evidence of necrosis (71.4% [30] no-necrotising granulomas vs 28.6% [12] necrotising granulomas; p = 0.833). In fungal and mycobacterial diseases, however, necrotising granulomas predominated, notably in 72% (70) of tuberculosis cases. When necrotising granulomas were compared with other non-necrotising granulomatous reactions, the difference in patterns persisted across some aetiologies (Supplementary Table 4). Necrotising granulomas were predominantly found in infectious diseases, while non-necrotising responses were observed in sarcoidosis, IBD, lymphoma and foreign body reaction.
Table 6.
Granulomatous diseases by granuloma type.
| Diagnosis | Necrotizing granulomas, n (150) | No-necrotizing granulomas, n (350) | P |
|---|---|---|---|
| No diagnosis | 39 (27.8%) | 101 (72.1%) | |
| Infectious diseases | 84 (63.6%) | 48 (36.4%) | < 0.001 |
| IBD | 14 (14.5%) | 71 (83.5%) | < 0.001 |
| Sarcoidosis | 4 (6.3%) | 60 (93.8%) | < 0.001 |
| Neoplasm | 12 (28.6%) | 30 (71.4%) | |
| Foreign body reaction | 1 (16.7%) | 5 (83.3%) | |
| Inflammatory diseases | 6 (20.7%) | 23 (79.3%) | |
| Pharmacological | 2 (33.3%) | 4 (66.7%) | |
| Lymphoma | 0 (0.0%) | 4 (100.0%) | |
| Pneumoconiosis | 0 (0.0%) | 3 (100.0%) | |
| Histiocytosis | 1 (50.0%) | 1 (50.0%) |
IBD: inflammatory bowel disease.
Percentages are based on row totals.
Paediatric population
Forty-two patients were paediatrics with a median age of 7 years-old (IQR 3–12), predominantly females (59.52%). Eighty-six percent (36) were born in Spain, 7% (3) were from Morrocco, and one case each from Colombia, Ecuador and the Dominican Republic. The main organ affected in this subpopulation was gastrointestinal (45%, 19), followed by ganglion (21%, 9) and S&S tissue (14%, 6). In five percent of cases (2 each), the organ affected was the lung, the liver, the spleen and other head and neck tissues. There were no specimens from pleura, urogenital, breast, osteoarticular nor bone marrow. The diagnostic was not achieved in 35.7% (15) of paediatrics patients. IBD was the most prevalent diagnostic (28.6%, 12), followed by infectious diseases (23.8%, 10), which was represented mainly by mycobacterial diseases (2 cases of tuberculosis and 4 cases of NTM) (Table 7).
Table 7.
Paediatric population: distribution of aetiologies by organ affected.
| Diagnosis | n (42) | % | Intestine, n (19) | Lymph node, n (9) | Skin & soft tissues, n (6) | Lung, n (2) | Liver, n (2) | Spleen, n (2) | Head & neck**, n (2) |
|---|---|---|---|---|---|---|---|---|---|
| No diagnosis | 15 | 35.7 | 5 (26.2%)* | 4 (44.4%) | 4 (66.7%) | 1 (50.0%) | 1 (50.0%) | ||
| Infectious diseases | 10 | 23.8 | |||||||
| Tuberculosis | 2 | 4.8 | 1 (5.3%) | 1 (11.1%) | |||||
| NTM | 4 | 9.5 | 4 (44.4%) | ||||||
| CMV | 1 | 2.4 | 1 (50.0%) | ||||||
| Histoplasma | 1 | 2.4 | 1 (50.0%) | ||||||
| Fungal unaffiliated | 1 | 2.4 | 1 (50.0%) | ||||||
| EBV | 1 | 2.4 | 1 (50.0%) | ||||||
| IBD | 12 | 28.6 | 12 (63.2%) | ||||||
| Foreign body reaction | 2 | 4.8 | 2 (33.3%) | ||||||
| Inflammatory diseases | 2 | 4.8 | |||||||
| Eosinophilic oesophagitis | 1 | 2.4 | 1 (5.3%) | ||||||
| PFAPA syndrome | 1 | 2.4 | 1 (50.0%) | ||||||
| Histiocytosis | 1 | 2.4 | 1 (50.0%) |
1 case from appendix.
One case from tonsils and other from auricular pavilion.
CMV: cytomegalovirus; EBV: Epstein-Barr virus; IBD: inflammatory bowel disease; NTM: non-tuberculous mycobacteria; PFAPA: Periodic Fever, Aphthous stomatitis; Pharyngitis and Adenopathy.
All percentages are based on column totals.
Temporal trends in diagnosis
In a multinomial logistic regression analysis evaluating the association between year of diagnosis and the different diagnostic categories, no significant temporal changes were observed (p = 0.055). However, the proportion of tuberculosis decreased from 19.4% in 2013–2016 to 10.0% in 2021–2023 (OR 0.46, 95% CI 0.25–0.83; p = 0.010) (Figure 4). Moreover, the use of certain diagnostic techniques increased significantly, including IGRA (OR 1.25; 95% CI 1.17–1.33; p < 0.001), tuberculosis PCR (OR 1.12; 95% CI 1.04–1.22; p = 0.004) and ACE (OR 1.10; 95% CI 1.04–1.16; p = 0.001) (Figure 5).
Figure 4.
Distribution of diagnoses across study periods. Bars represent the percentage distribution of diagnoses within each 3-year study period. IBD, inflammatory bowel disease.
Figure 5.
Temporal trends in the use of diagnostic tests (IGRA, TB molecular assays and serum ACE measurement).
Risk factors associated with the most common granulomatous diagnoses
To identify factors independently associated with the most common granulomatous diagnoses, separate multivariable logistic regression models were performed. Variables included age, sex, nationality, affected organ, multisystem involvement, and histological pattern. After adjustment for potential confounders, distinct clinicopathological profiles emerged for the most frequent diagnoses.
Infectious diseases were independently associated with non-Western European origin (aOR 4.0, 95% CI 2.3–7.1), pleural involvement (aOR 89.1, 95% CI 10.3–770.8), and the presence of necrotising granulomas (aOR 10.2, 95% CI 5.6–18.5) (all p < 0.001), whereas pulmonary involvement was negatively associated with an infectious aetiology (aOR 0.36, 95% CI 0.16–0.84). In contrast, sarcoidosis was negatively associated with S&S involvement, intestinal involvement, hepatic involvement, and necrotising granulomas, with the latter showing the strongest inverse association (aOR 0.05, 95% CI 0.02–0.15; p < 0.001). Patients with IBD were younger (aOR 0.97, 95% CI 0.95–0.99; p < 0.001) and less likely to be of non-Western European origin (aOR 0.29, 95% CI 0.10–0.80; p = 0.017). Intestinal involvement was strongly associated with the diagnosis (aOR 15.0, 95% CI 2.0–132.0), whereas necrotising granulomas were uncommon (aOR 0.06, 95% CI 0.01–0.61). Finally, increasing age was the only independent factor associated with neoplastic diagnoses (aOR 1.04 per year, 95% CI 1.02–1.06).
Discussion
The aetiological classification of granulomatous diseases is a complex process that encompasses a wide range of causes depending on factors related to the patient, the organ involved and differential anatomopathological features. The aim of this study was to describe the causes identified in a heterogeneous population of patients over a 11-year period in a tertiary hospital in Madrid (Spain). Our hospital serves a population with a high proportion of non-Western European nationals, as reflected in their representation in the cases described (28%), which increases the diversity of causes and extends them to different environments. In the overall cohort, infectious diseases were the primary cause of granulomas and the majority of cases were related to mycobacterial infections, although bacterial, viral, parasitic and fungal infections were also found. This has been described in previous studies on pulmonary granulomas, granulomatous interstitial nephritis, causes of bone marrow granulomas and paediatric lymphadenopathies [6,9,15,16], but differs from the only global series published in the USA in 1982, where the most common cause was sarcoidosis [17]. This underlines the importance of a thorough microbiological examination of the sample. It is worth noting that in our cohort, microbiological specimens were collected and tested in only one third of cases, and that PPD (39%) or IGRA (26%) testing rates were low. The heterogeneity in the performance of microbiological studies probably reflects de pre-test likelihood of a given diagnosis depending on the specific site of disease (e.g. mycobacterial infection in pleural granulomas). Still, given that certain diagnoses, such as sarcoidosis, are inherently made by exclusion of other conditions, it seems reasonable to assume that the diagnostic work-up is often underdeveloped. In a previous study examining the granulomatous process in specific organs [18], the underlying aetiology remained unidentified in 29% of cases. To address this issue, Mukhopadhyay et al. conducted a review of diagnoses from a database of pulmonary granulomatous processes [15]. Their findings showed that the establishment of a diagnostic algorithm could rescue the diagnosis of 60% of undiagnosed cases. Our study suggests that patients who underwent a more comprehensive diagnosis workup, including microbiological investigations, were more likely to receive a definitive diagnosis (Supplementary Table 3). Although our diagnostic algorithm was applied solely to validate established diagnoses and cases without a final diagnosis were not systematically reassessed, the proportion of undiagnosed cases was similar to that reported in previous studies [18]. Moreover, the absence of a definitive diagnosis did not appear to significantly affect patient outcomes or clinical evolution. This observation may reflect the natural course of many granulomatous disorders and is supported by the prolonged follow-up period available in our cohort.
The next most frequently observed causes were inflammatory diseases, including sarcoidosis, and response to neoplasms. These conditions often involved multiple organs, exhibiting a broader clinical spectrum and affecting patients with comorbidities, which poses significant challenges for management. Advances in imaging techniques, including 18 F-FDG PET/CT and MRI, as well as the use of biomarkers, should be incorporated into updated diagnostic algorithms [19,20]. In addition, recent evidence suggests that inborn errors of immunity, including STAT1 gain-of-function and other disorders of immune regulation, may underlie a subset of unexplained granulomatous diseases. Accordingly, genetic testing is increasingly being considered in selected patients with atypical, multisystemic, recurrent, or microbiologically negative granulomatous presentations [21].
It is important to note that the distribution of aetiologies varied according to the organ affected and the country of origin of the patient. Our results are broadly similar to other published studies of organ-specific granulomatosis. Immunological diseases have been more frequently found in intestinal and hepatic samples [22], whereas infectious diseases were more likely when the granuloma was found in the serosa or bone marrow. With respect to inflammatory bowel diseases, it is interesting to note that Crohn’s disease is the focus of almost all the published literature, with some references to its differential diagnosis with tuberculosis [23]. On the other hand, lymph node and lung involvement can have a wide range of causes, making the diagnosis even more complex. Granulomatous mastitis is an uncommon entity (4.6% of our cohort) with a relevant impact on women’s quality of life and a challenging diagnosis. It may be classified as specific when an infectious or autoimmune cause is identifies, or idiopathic, including cystic neutrophilic granulomatous mastitis associated with Corynebacterium spp [24]. Imaging findings are often non-specific and differentiation from breast cancer is difficult, making histology the diagnostic gold standard [25]. However, identification of the underlying aetiology remains challenging, and microbiological studies are essential given the implications for management [24,26–28].
In Western European patients, the aetiologies of granuloma were relatively evenly balanced between neoplasms, inflammatory and infectious diseases. In the other origins group, however, tuberculosis was identified as the cause in about a third of cases. A recent review of published data on granulomas in bone marrow biopsies highlighted that neoplasms were the predominant cause in the USA and Australia, whereas infectious diseases were the most common aetiology in other countries [9,29,30].
Finally, as expected, necrotising granulomas were more commonly observed in cases of mycobacterial infections, while non-necrotising granulomas were predominantly associated with IBD and sarcoidosis. This was also described for necrotising granulomas in the lung [18] and epithelioid granulomas in the renal interstitium [31]. For the remaining causes, the type of granuloma was less specific.
The main limitations of this study are its single-site, retrospective design, which limits the generalisability of the findings. It must be noted that certain organs are underrepresented in the cohort (CNS, bone marrow); as a result, findings should be considered merely exploratory. In addition, diagnoses were based on heterogeneous assessments by individual clinicians, and different pathologists without the possibility of a central pathology re-review of the samples. Cases were identified through a search strategy based on the presence of the term “granuloma” in the final pathology report. As a result, biopsies in which granulomatous inflammation was present but incorporated into a definitive pathological diagnosis without explicit mention of granulomas in the final report may not have been captured. This could introduce a theoretical selection bias and may have led to the underrepresentation of selected diagnosis categories (e.g. lymphoma). However, the study reflects real-world clinical practice by focusing on granulomatous lesions, i.e. the subset of specimens that clinicians actually receive and interpret for differential diagnosis. This likely reflects the lack of standardised diagnostic pathways over the study period. Despite these limitations, to the best of our knowledge, this is the first study since 1982 to provide a comprehensive assessment of granulomatous diseases [17]. In addition, we proposed a diagnostic algorithm that may assist clinicians in the diagnostic evaluation of these challenging entities. The findings, derived from a heterogenous patient population in an advanced medical facility, serve to corroborate the information available on the subject [6,13,15]. Our study has identified potential causes of certain entities (e.g. granulomatous mastitis) that warrant further exploration in future research. It also highlighted specific aspects of diagnosis that require improvement, such as microbiological studies and handling of samples for laboratory shipment, which will help to improve clinical practice and optimise the diagnostic approach in this heterogeneous pathology.
Conclusions
Granulomatous responses are observed in diverse aetiological contexts, exhibiting variable prevalence contingent on organ specificity and geographical origin of the patient. In our setting, the most frequent cause is infectious, primarily due to mycobacteria. The optimisation of diagnostic algorithms and the systematisation of the microbiological study in these entities will facilitate diagnosis. Further prospective studies are required to validate and refine these diagnostic algorithms.
Supplementary Material
Acknowledgements
We are grateful to Janet Dawson for reviewing the English version of the manuscript. Conceptualization, methodology, investigation, resources, writing—review and editing, and visualization: P.H.-J., M.M.-L., M.S.F., J.M.P., J.M.B., A.G.G., D.R.O., J.M.H.-M., P.L.-R., A.B.E.V., and J.L.-T.; software, validation, formal analysis, and data curation: P.H.-J., M.M.-L., and J.L.-T.; writing—original draft preparation, supervision, project administration, and funding acquisition: P.H.-J. and J.L.-T. All authors have read and agreed to the published version of the manuscript.
Funding Statement
P.H.-J. was supported by a research contract ‘Río Hortega’ (Instituto de Salud Carlos III, Expte CM23/00259).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
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Supplementary Materials
Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.