granulomas, histiocytic response with no granulomas. The necrotizing and non-necrotizing granulomas are called immune granulomas. Necrotizing granulomas distinctly have central necrosis with a lymphohistiocytic reaction and a collar of chronic inflammation. The most common etiology of necrotizing granulomas is Mycobacteria species. Non-necrotizing granulomas are characterized by the collection of epithelioid histiocytes and giant cells with minimal peripheral chronic inflammation, the prototypical example being sarcoidosis [7].

The granulomatous lesions are classified based on infections, vasculitis, immunological aberrations, leucocyte oxidase defects, hypersensitivity pneumonitis, chemicals, neoplasia, and other miscellaneous infections. Infections are the most common cause of disseminated granulomatous disease. Granulomatous fungal infections mimic sarcoidosis, hence fungal infections need to be excluded and distinguished from sarcoidosis [2]. Other non – infectious causes that commonly induce granulomatous inflammations are sarcoidosis, foreign bodies, Wegener’s granulomatosis, and Crohn's disease [8].

In countries that have a high incidence of tuberculosis (TB), it is considered primarily in the differential diagnosis of granulomatous diseases [8]. Mycobacterium tuberculosis granulomas are classically characterized by the presence of caseous necrosis in the center that is referred to as a tubercle. Typically, there is a central area of amorphous caseating granular debris along with loss of cellular detail. This area is encircled by epithelioid cells, lymphocytes, histiocytes, fibroblasts, and occasionally Langhans' giant cells. Ziehl- Neelsen stain demonstrates acid-fast bacilli. These histologic features of the granuloma are characteristic and they allow the exact diagnosis of tuberculosis [3].

Inhalation of Mycobacterium bacilli initiates a histologic granulomatous response mediated by similar cytokine-mediated mechanisms within the lung as described. Chronic granulomatous response limits the extent of inflammation, activates histiocytes, and forms a collar of histiocytes and peripheral lymphocytes around a necrotic center called Ghon’s focus. Mycobacterium tuberculosis can affect any tissue by the direct inoculation or by the hematogenous spread such as miliary tuberculosis or as the localized cavitary form [7].

India has the world’s largest TB cases which are

• Water washed, air-dried, dehydrated, and mounted.

For Fite- Faraco (FF) staining 5% sulphuric acid was used for decolorizing.

Statistical analysis: Data was entered in the excel spreadsheet. Results were expressed as frequencies and percentages for comparison.

Ethical committee clearance was obtained from the institutional ethical committee.

Results

Out of total 3623 histopathology specimens, 61 (1.7%) were granulomatous lesions of which 28 (45.9%) were AFB (Acid-fast bacilli) positive (+ ve). The most common granulomatous lesion in the present study was granulomatous lymphadenitis accounting for 20 cases (32.7%), out of which 12 (19.6%) were positive for AFB. (Table 1 and Table 2)

Out of 13 granulomatous skin lesions, 2 (3.3%) each of tuberculosis verruca cutis (TVC), and granuloma annulare were noted, 3 (4.9%) were tuberculoid leprosy, 6 (9.8%) were borderline tuberculoid leprosy.

4 (6.5%) out of these 13 cases showed AFB positivity. Among them 3 were Fite- Faraco stain positive, 1 (1.6%) out of 2 (3.3%) tuberculosis verrucosa cutis was Ziehl- Neelsen stain positive.

6 (9.8%) cases of granulomatous mastitis (1 was AFB + ve), 4 (6.5%) cases of granulomatous synovitis (2 were AFB + ve), 3 (4.9%) cases of granulomatous endometritis (2 were AFB + ve) were seen. 2 (3.3%) cases each of granulomatous epididymitis and appendicitis were noted. AFB positivity was seen in 1 (1.6%) case of granulomatous epididymitis and 2 cases of appendicitis (3.3%).

1 (1.6%) case of HIV positive hysterectomy specimen showed granulomas in endometrium and cervix and was concurrently positive for AFB.

1 (1.6%) case each of granulomatous lesions was found at other uncommon sites like a salivary gland, thyroid, testis, parietal pleura, nasal septum, suture granuloma of the fallopian tube (FT), lipoma with foreign body granuloma (LFBG), sinus tract, intestine, and omentum. Acid-fast bacilli positivity was seen in each case of granulomatous lesions of a sinus tract, parietal pleura, and intestine.

Fig-1: Tuberculosis verrucosa cutis, H and E, 10X.

Fig-2: Borderline tuberculoid leprosy, H and E, 10X.

Fig-3: Granulomatous mastitis, H and E, 10X.

Fig-6 b: Granulomatous cervicitis, AFB +VE, ZN stain, 100X.

Fig-7: Granulomatous orchitis, H and E, 40X.

Fig-8: Granulomatous thyroiditis, AFB +VE, ZN stain, 100X.

granulomatous inflammation seen elsewhere with the presence of epithelioid histiocytes, multinucleated giant cells, and a lymphohistiocytic collar. Granulomas can persist for 18 months after treatment [7]. Granuloma annulare (GA) is a dermatosis most commonly presenting on the extremities of female patients as an isolated erythematous papule or arcuate plaque. GA may be seen in association with many autoimmune, neoplastic, and drug-induced states including sarcoidosis, Alagille’s syndrome, thyroid disease, hepatitis B and C, Epstein Barr virus (EBV), mycosis fungoides, Hodgkin and non-Hodgkin lymphomas (NHL), gastrointestinal stromal tumors (GIST), adenocarcinomas, allopurinol, amlodipine, and TNF-alpha inhibitors [7].

Breast tuberculosis is a rare disease that accounts for 3% of all surgically treated lesions in developing countries and is less common than carcinoma of the breast. It presents with non-specific clinical, radiological, and histological findings and closely looks like carcinoma of the breast and pyogenic inflammatory disease [12]. In the present study 6 (9.8%) cases of granulomatous mastitis were diagnosed and one case showed positivity for acid-fast bacilli. Other cases of granulomatous mastitis were found to have no significant clinical, radiological history towards any infectious etiologies and thus were considered to be idiopathic in nature. Granulomatous lesions in the breast include other infections like sarcoidosis, granulomatous reaction to the tumor, and foreign body reaction [12] (Figure 3).

According to a study done by Vijay PM, tuberculous synovitis was one of the commonest causes of inflammatory synovial lesions constituting 18.07% [13] and in the present study, 2 (3.3%) out of 4 granulomatous synovitis were positive for AFB (Figure 4). 30% of skeletal TB involves the joints and knee being the third most commonly affected joint after the spine and the hip. The involvement of the musculoskeletal system by tuberculosis is by hematogenous spread often from a primary focus in the lungs. As the bone and joint tuberculosis are paucibacillary, the Ziehl-Nielsen test may yield a negative result. In such cases Lowenstein culture would be an essential tool for the diagnosis of tubercular etiology [14].

The incidence of granulomatous inflammation in the appendix is around 1.3 to 2.3% in developing countries. Diagnostic criteria for granulomatous appendicitis are similar to those of the intestinal

The probable causes could be trauma, an autoimmune reaction to sperms, and urinary tract infection. The differential diagnosis of non-caseating granulomas mainly includes sarcoidosis. The granulomas in sarcoidosis are seen in the interstitium whereas in granulomatous orchitis they are confined to seminiferous tubules. Tuberculous infections primarily involve the epididymis [18]. The clinical and ultrasound findings of the disease often simulate malignancy and histopathology plays an important role in diagnosing granulomatous lesion [19] (Figure 7).

Abdominal TB is associated with significant morbidity and mortality because of its late diagnosis due to non-specific clinical symptoms. Approximately 15% - 25% of cases with abdominal TB have associated pulmonary TB. In the areas with high prevalence, a high index of suspicion is an important factor in early diagnosis. The most common site of gastrointestinal TB is the ileocecal region (ileocecal TB) followed by jejunum and colon. Oesophagus, stomach, and duodenum are rarely involved [10]. In the present study a case of granulomatous lesion of intestine was noted which was positive for AFB. Abdominal TB also involves other sites like peritoneum, lymph nodes, and solid viscera [10]. Crohn’s disease is the other commonest cause of granulomatous disease of the gastrointestinal tract [2].

One case (1.6%) of granulomatous thyroiditis was noted in the present study. The incidence of granulomatous thyroiditis is 0.16% of all primary thyroid diseases. Areas of thyroid tissue show intrafollicular cellular infiltration with partial or complete loss of colloid from infiltrated follicles and partial or complete distraction of their lining epithelium. This leads to granuloma formation along with fibrosis and inflammatory cell infiltration in the interstitium [20] (Figure 8).

One (1.6%) case of granulomatous lesion of the nasal septum was noted in the present study which showed negativity for ZN staining. Granulomatous diseases are rare causes of sinonasal inflammatory disease. They are categorized under inflammatory, infective, and neoplastic lesions [21]. In immunocompromised patients fungi may cause granulomatous lesion of the nasal septum. Inflammatory diseases that may affect the nasal septum include sarcoidosis, reparative granuloma, and granulomatosis with polyangiitis (Wegener granulomatosis) [22].

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