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  Table of Contents    
REVIEW ARTICLE  
Year : 2022  |  Volume : 65  |  Issue : 5  |  Page : 125-134
Granulomatous diseases of the central nervous system: Approach to diagnosis


Department of Pathology and Lab Medicine, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana, India

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Date of Submission31-Oct-2021
Date of Decision06-Dec-2021
Date of Acceptance11-Dec-2021
Date of Web Publication11-May-2022
 

   Abstract 


Diagnosis of central nervous system (CNS) granulomas is challenging. The etiology may be infectious or non-infectious. The infectious causes are due to mycobacteria, fungi, parasites and rarely bacteria. The non-infectious causes include autoimmune diseases, diseases of uncertain etiology like sarcoidosis, those associated with neoplasms and reparative processes. Histologic evaluation of type of granuloma as necrotizing, non-necrotizing, fibrotic/calcific or foreign-body type, site of CNS involvement (leptomeninges/dura, brain/spinal cord) and identification of etiologic agent on histochemistry/culture/molecular methods resolves the diagnosis in a many a patient. Correlation with clinical and imaging features, risk factors and route of spread, geographical location and travel history are important. However, diagnosis may remain unresolved despite the application of all available techniques, highlighting the need for better diagnostic techniques.

Keywords: Central nervous system; granuloma; necrotizing granuloma; non-necrotizing granuloma; etiology; diagnosis

How to cite this article:
Challa S. Granulomatous diseases of the central nervous system: Approach to diagnosis. Indian J Pathol Microbiol 2022;65, Suppl S1:125-34

How to cite this URL:
Challa S. Granulomatous diseases of the central nervous system: Approach to diagnosis. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:125-34. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/125/345036





   Introduction Top


Granulomatous diseases of the central nervous system (CNS) have varied etiologies that include infections, autoimmune diseases, neoplastic conditions and reparative/reactive process.[1] Granuloma formation is a tissue response and it depends on the etiology, site of involvement and the immune status of the host. The granuloma may be necrotizing, non-necrotizing, suppurative, diffuse or foreign body (FB) type with a broad spectrum of etiologies within each category.[2] The common etiologies of CNS granuloma are listed in [Table 1].
Table 1: Common etiologies of central nervous system (CNS) granulomas

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Tuberculosis is the most common prototypical example of necrotizing granuloma, whereas sarcoidosis is the typical non-necrotizing granuloma. Fungal and parasitic infections usually have a suppurative granuloma. The tissue reaction pattern, site of involvement in the CNS (meninges/parenchyma; hemispheric/brainstem/cerebellum/spinal cord; ependyma/ventricle/choroid plexus; angiocentric/associated osteomyelitis; superficial cortical/deep white mater) help in making the diagnosis and guide clinical management. A brief review of the common granulomatous diseases followed by diagnostic approach will be presented to help in the identification of the etiology in the appropriate clinical context.


   Granulomas Due to Infections Top


Tuberculous granuloma

Tuberculosis, caused by Mycobacterium tuberculosis, occurs worldwide with a high prevalence of new/active cases in underdeveloped/developing countries.[3] CNS involvement occurs in about 1% of all and 5 to 10% of extra-pulmonary tuberculosis cases with a mortality of 60%.[4],[5] Children (those with malnutrition or with recent measles) and adult patients with immunosuppression (especially those infected with human immunodeficiency virus [HIV], those receiving immunosuppressive agents, patients with malignancy) are prone to develop tuberculous infections.[3],[6],[7],[8] Primary focus for CNS infection is either in the lung or gastrointestinal tract (GIT).Neuro-tuberculosis manifests as tuberculous meningitis (TBM), tuberculous encephalitis, intracranial tuberculoma, tuberculous abscess, or tuberculous vasculopathy.[3],[9] Tuberculomas constitute significant proportion of intracranial masses in TB-endemic areas, like India.[10] Clinical presentation of neuro-tuberculosis is often non-specific, and symptoms mainly depend on the location.[3],[11]

TBM and both intracranial and spinal tuberculomas show granulomatous response. Tuberculomas are focal intra-parenchymal granulomas that may be single or multiple, associated with or without TBM. Tuberculomas are more frequent in frontal and parietal lobes, in parasagittal areas. They are often supratentorial in adults and infratentorial (usually cerebellum), in children. They are located in the corticomedullary junction and periventricular areas.[11] They are usually firm, avascular and well demarcated. The adjacent brain parenchyma shows oedema and gliosis. In TBM, the exudate is thick and gelatinous and is basal, seen around the sylvian fissures, basal cisterns, brainstem, and cerebellum, particularly around the vessels of the circle of Willis. In TBM, intra-parenchymal granulomas are few and are located in the subpial/subependymal areas. Spinal tuberculomas are mostly dorsal. The complications include obstructive hydrocephalus, vasculitis and infarcts.[3],[11]

Histologically, three different types of granulomas are described: non-necrotizing, necrotizing (caseous), and suppurative. However, all three may be seen in same patient at the same time and likely represent different stages or spectrum of the same pathology.[5] Tuberculous granuloma consists of macrophages, epithelioid cells and Langhan's or FB- type giant cells around a central area of caseation.[12] The periphery of the granuloma in all types, is composed of B and T lymphocytes and plasma cells.[13]

The non-necrotizing granulomas are the smallest (0.1–0.5 mm) and the suppurative granulomas are the largest (up to 10 mm). The bacilli are nearly absent in non-necrotizing granulomas, with a very low load in caseous and a high load in the suppurative type. Reticulin is present throughout in the non-necrotizing granuloma, within the necrotic area also in the caseous granuloma, whereas it is completely absent in the suppurative type.[5]

Diagnosis of tuberculoma remains a challenge as mass lesions due to other etiologies like fungal infections, sarcoidosis, cysticercosis, toxoplasmosis or neoplasms like gliomas and metastases, are difficult to differentiate on clinical and imaging features. Neuroimaging with computed tomography (CT)/magnetic resonance imaging (MRI), is very important in the diagnostic evaluation. Magnetization transfer imaging analysis is helpful to differentiate tuberculoma from brain tumors.[14] Every effort should be made to find an extra-neural focus of TB to facilitate a safer diagnostic sampling. In CNS tuberculoma, granulomatous encasement precludes detection of the bacilli in serum or cerebrospinal fluid (CSF) samples. A definite diagnosis can be made with stereotactic biopsy and histopathology; however, it should be considered only when other less invasive methods are inconclusive.[15] If associated with TBM, Ziehl-Neelsen (Z-N) stain and culture of CSF may be done but the yield is low. Culture of tissue, immunohistochemistry (IHC) for mycobacterial antigen, polymerase chain reaction (PCR) for detection of mycobacterial DNA (Cartridge-based nucleic acid amplification test (CBNAAT)) improve diagnosis and are also useful for testing drug resistance.[15],[16]

CNS tuberculosis in immune suppressed patients: Tuberculosis is one of the most important opportunistic infections in patients with HIV and transplant recipients. It increases the risk for CNS involvement, alters the clinical picture and is associated with high mortality. Infections with atypical mycobacteria, Mycobacterium avium intracellulare (MAC) are also reported in patients with acquired immunodeficiency syndrome.[11] TBM occurs in 5-8% patients with HIV; in these patients, the basal exudates are less frequent, thinner and serous, show fewer lymphocytes, epitheloid cells and Langhan's type of giant cells but show large number of tuberculous bacilli.[17],[18],[19] Obstructive hydrocephalus is less frequent; however, tuberculous arteritis/phlebitis, abscess, cerebral and brainstem infarcts were more frequent in HIV-positive patients.[18],[19] Tuberculous abscesses are more common in the stage of severe immunosuppression; the granulomas tend to be multiple, <1cm and poorly formed with necrosis, higher bacillary load and neutrophilic and macrophage infiltration with prominence of plasma cells.[19],[20],[21] Spinal mass lesions show dispersed granulomas with lymphocytes and macrophages throughout the granuloma rather than at the periphery and also increase in plasma cells.[22] Though MAC infections are widely disseminated, granulomas, lymphocytes, and tissue destruction are rare. A high index of clinical suspicion, presence of disseminated disease on imaging, CD4 counts <100/μl, culture/demonstration of tuberculous bacilli in CSF/tissue are important for diagnosis.[19]

Other bacterial infections that produce CNS granuloma: Very few bacterial infections cause typical granulomas and these include Brucellosis, Syphilis, Nocardiosis and Actinomycosis; however, these are rare.

Neurobrucellosis: Brucellosis is a multisystem zoonotic disease; CNS involvement occurs in 5%–10% with meningoencephalitis being the most common. Mass lesions are uncommon and show a perivascular non-necrotizing granuloma.[23],[24] Antibodies against Brucella spp. in CSF and PCR help in making a diagnosis.[23],[24]

Neurosyphilis: Neurosyphilis, caused by Treponema pallidum is a sexually transmitted disease. Involvement of the CNS is rare; however, the incidence is on the rise due to HIV.[25] Syphilitic gumma usually occurs in tertiary syphilis and is seen as single or multiple dural based masses that show granulomas with a large number of plasma cells, lymphocytes, eosinophils, epithelioid cells and fibroblasts, with central necrosis. T. pallidum can be demonstrated using immune-fluorescence or silver staining.

Diagnosis is based on clinical and imaging features along with CSF serology. The serology tests include venereal disease research laboratory (VDRL) which is specific but less sensitive, fluorescent treponemal antibody (FTA) detection test or the fluorescent treponemal antibody absorption (FTA-Abs) test, which are more sensitive but less specific and PCR.[25],[26],[27],[28]

Mycotic granuloma

Fungal infections of CNS usually occur in immune suppressed hosts, manifesting as abscess/infarct/hemorrhage. However, a number of fungi can cause intracranial granulomas, especially in immune competent hosts.[29] Aspergillus granuloma is the most common mycotic granuloma in India, followed by cryptococcoma. Dematiaceous fungi can cause suppurating granuloma/mycetoma.Granulomas are uncommon with Mucorales and Candida spp.[30] Coccidioidomycosis, paracoccidioidomycosis, blastomycosis and histoplasmosis can cause granulomas but are geographically restricted. Identification of etiologic agent on hematoxylin and eosin (H&E) and fungal stains [periodic acid-Schiff (PAS) or Gomori methenamine silver (GMS)] is important. Histopathology and culture can be complemented with non-culture based diagnostic techniques to improve the diagnosis.[31],[32]

Aspergillus Granuloma: CNS aspergillosis is rare and constitutes 10-20% of invasive aspergillosis. In immune suppressed hosts, it usually occurs due to hematogenous spread from lung. However, in immune competent hosts, it occurs by contiguous spread from sinus, ear or orbit. The etiologic agent is usually A. flavus and the most common pathology is granuloma. The environmental conditions and constant exposure to high inoculums of pathogen are implicated in the pathogenesis of intracranial aspergillus granuloma in countries like India, Pakistan, Sudan and Saudi Arabia.[29],[33],[34] Aspergillus granulomas are usually located in frontal or temporal regions (due to contiguous spread from sinus or ear respectively). The granulomas may be extracerebral in continuity with sinus lesion or completely intra-parenchymal with no lesion in the sinus. There may be associated skull bone involvement or basal meningitis.[35],[36]

Histology is a non-caseating granuloma, composed of lymphocytes, plasma cells, eosinophils and numerous FB-giant cells. The stroma shows extensive fibrosis. Fungal hyphae are difficult to identify on H and E stain and may be seen as negative staining structures within giant cells and in the stroma; however, PAS and GMS stains, highlight the slender septate, acute angle branching hyphae, which is the characteristic morphology of Aspergillus spp.[35],[36]

Diagnosis is made by histopathology and culture on excised tissue. The aspergillus granulomas need to be differentiated from tuberculomas in countries endemic for tuberculosis. Presence of lesion in sinus, extracerebral location, extensive fibrosis, minimal necrosis with prominence of FB-giant cells along with appropriate fungal stains help in differentiating aspergillus granuloma from tuberculous granuloma.[35],[36] The morphology on histopathology alone cannot differentiate Aspergillus spp hyphae from Fusarium spp, Scedosporium spp, Mucorales and others.[31] The diagnostic tests include direct microscopy, culture, serology and molecular tests. Culture is considered gold standard but may be negative/not available. In the absence of culture, diagnostic yield on histopathology can be increased by combining with other ancillary techniques.[31]

Cryptococcoma: Granulomatous meningoencephalitis or cryptococcoma occurs in immune competent hosts, mostly due to Cryptococcus gatti. Granulomas may be seen in the meninges, parietal lobe, basal ganglia, pons, cerebellum and rarely in spinal cord. The granulomas may be necrotizing or fibrotic and inflammation may be intense mimicking inflammatory pseudotumor.[37],[38],[39] In cryptococcomas, the budding yeast forms are seen within the giant cells and in the mucoid stroma.[40] Rarely, cryptococcomas are reported in HIV-negative, immune suppressed patients.[41]

CNS phaeohyphomycosis: It is caused by melanized/dematiaceous fungi which are neurotropic. Infections are most often due to Cladophialophora bantiana and occur in immune competent hosts.The most common manifestation is as brain abscess; however, granulomas are reported in 48% cases with FB giant cells containing pigmented hyphae.[30],[34],[37],[42],[43]

Parasitic granuloma: The most common parasitic disease involving the CNS is neurocysticercosis (NCC). Protozoans, Acanthamoeba spp, Toxoplasma gondii, Plasmodium falciparum and others mostly cause encephalitis. Neuro-schistosomiasis, toxocariasis and echinococcosis are uncommon, but in endemic areas, these infections also need to be considered in the differential diagnosis.Immigration and international travel cause some of these infections in non-endemic geographic regions also.[44]

Neuro-cysticercosis (NCC): NCC is caused by the larvae of Taenia solium. It is endemic in developing countries like India, particularly in rural areas. The lesions vary in size and location.[45] NCC is parenchymal or extra-parenchymal; however, parenchymal location is the most frequent, with seizures being the most common manifestation.[46],[47] Co-infection with HIV is frequently associated with multiple cysts.[48]

Viability of the parasite is important in disease progression. Cysticerci remain viable (vesicular stage) in the CNS with no inflammation but after a variable period, the cyst involutes and degenerates; granuloma forms around the cyst (granular-nodular stage). A fibrous wall forms around the granuloma and the remnants of the parasite become calcified (calcified stage).[49],[50] Histologically, the granuloma is composed of FB-giant cells, macrophages, microglia, T and B lymphocytes, plasma cells, neutrophils, mast cells and eosinophils.[47],[51],[52] The surrounding brain parenchyma shows reactive gliosis, microglial proliferation, edema, and perivascular lymphocytes.[49],[50]

Meningeal cysticerci induce an intense inflammatory response. Large or multiple small cysticerci may obstruct the ventricles/CSF pathway resulting in hydrocephalus. Granular ependymitis can also contribute to dense adhesion and obstruction. Entrapment of vessels in the thick fibrous exudates leads to arteritis and lacunar infarcts.[49],[50]

Diagnosis of NCC is based on clinical, epidemiological, imaging, histological and serologic criteria (enzyme-linked immune-electro-transfer blot assay). Histological identification of the parasite on tissue provides an unequivocal diagnosis of NCC. Serological tests are useful to suggest the diagnosis but cannot be used alone to make the diagnosis. PCR is a more sensitive diagnostic tool.[53]

Other CNS parasitic granulomas: Infection with Toxocara canis is common worldwide. Infection occurs due to exposure with soil contaminated by the eggs of dog roundworm. It usually involves liver, lungs, eyes.[54] CNS involvement is rare and is caused by visceral larva migrans, causing eosinophilic meningitis, encephalitis and myelitis. The lesions may be single/multiple, located in sub-cortical/cortical/white matter, involving the cerebrum/cerebellum or spinal cord. The reaction to migrating larvae is minimal; however, the dying larvae release antigen and elicit a granulomatous response in brain/spinal cord. A large number of eosinophils and neutrophils are seen with perivascular lymphocytes. The larvae may not always be found on histologic examination as the larvae migrate by burrowing through brain parenchyma and produce other inflammatory foci. These produce characteristic track-like lesions on imaging and histology. The granulomas eventually become fibrotic and calcify. Diagnosis is established by a high titre of anti-Toxocara antibody and eosinophilia in the serum/CSF. Clinical/imaging improvement may be seen after anti-helminthic treatment.[55]

Cerebral and spinal schistosomiasis are rare but increasingly being recognized due to immigration and international travel. Granulomatous reaction occurs around the eggs of Schistosoma spp. Sometimes, adult worms migrate to CNS via vertebral venous plexus and elicit inflammatory response. Travel history along with identification of eggs in the granuloma are important for diagnosis.[56]

Echinococcosis is endemic and may involve both brain and spinal cord with minimal inflammatory response.


   Granuloma Due to Uncertain Etiology Top


Neuro-sarcoidosis: Sarcoidosis is a multi-system disease of unknown etiology. It usually affects lungs and mediastinal lymph nodes.CNS involvement occurs as part of systemic disease or is isolated (1%); however, CNS involvement is reported to be 25% in autopsies.[57] It may involve the brain, spinal cord, peripheral nerves and muscles.[57],[58] The clinical syndromes include leptomeningitis, cranial neuropathy, myelopathy, sellar disease, parenchymal masses, encephalopathy, peripheral neuropathy and myopathy.[58] The involvement may be diffuse or localized. The basal cisterns, optic chiasm, convexity of brain, choroid plexus and ependymal lining of ventricles and spinal arachnoid are most commonly involved. The pathology is a discrete non-caseating and non-necrotizing granuloma composed of epithelioid cells, giant cells and lymphocytes surrounded by fibroblasts at the periphery.[58] The granulomas tend to cluster in peri-vascular/peri-ventricular areas. The mass lesions are usually seen in brain in the region of hypothalamus and pituitary or dural based mass in the brain/spinal cord. The lesions may measure few mm to cm, coalescing and are rarely necrotizing but not caseating.[58],[59]

The diagnosis is established by correlating the clinical, imaging and histopathological findings, and excluding other causes of granulomatous disease.[58],[60] Biopsy from leptomeninges or mass lesion may be considered for diagnosis. Stains for tuberculous bacilli/fungi, and culture of tissue should be done to exclude infectious etiologies.[61] Biopsy from peripheral sites like lung/lymph node/salivary gland are helpful. The main differential diagnosis is tuberculosis and other granulomatous diseases.[57],[58],[61]

IgG4-related disease (IgG4-RD): It is a condition of unknown etiology that affects many organs; however, CNS involvement is rare.[62],[63] The CNS involvement is in the form of hypertrophic pachymeningitis, cranial neuropathy or inflammatory mass lesions of the pituitary or orbit and the most commonly affected locations are skull base and calvarium. Histologically there is an infiltrate that is rich in IgG4-positive plasma cells, lymphocytes and eosinophils. There is also obliterative phlebitis and a storiform pattern of fibrosis.[62],[63] Serology shows elevated IgG4 levels. Diagnosis is often delayed and multiple biopsies may be required to stablish the diagnosis. Response to steroid treatment, highlights the importance of early diagnosis.[62],[63]


   Granulomatous Hypophysitis Top


Hypophysitis may be lymphocytic, granulomatous (GH) or xanthomatous and is relatively rare.[64] The clinical features of GH are due to mass lesion and endocrine abnormalities.[65] GH can occur as primary, or secondary. The secondary causes include tuberculosis, sarcoidosis, syphilis, pituitary adenoma, Langerhans cell histiocytosis, granulomatosis with polyangiitis and rupture of Rathke's cleft cyst. The diagnosis of idiopathic GH is made following exclusion of secondary causes. GH is characterised by histiocytes, lymphocytes, multinucleated giant cells with variable amounts of fibrosis.[64],[65]


   Granulomas Due to Autoimmune Diseases Top


Primary angiitis of CNS (PACNS): PACNS is defined as a non-infectious CNS vasculitis.[66] Patients may present with encephalopathy or mass lesion with relapsing and remitting course.[67],[68] MRI is abnormal and sensitive, but angiography is neither sensitive nor specific.[66],[69] CSF often shows pleocytosis but not specific. A positive brain or meningeal biopsy is diagnostic.[66] Sensitivity of brain biopsy compared with autopsy diagnosis as gold standard, is 75%.[70] Sampling the leptomeninges and cortex from a radiographically abnormal area, particularly in the presence of abnormal enhancement increases the diagnostic yield. In the absence of focal lesions, biopsy from the tip of temporal lobe of non-dominant hemisphere, which contains vessels of 250-300μm size is recommended.[66],[70]

Histologically, PACNS is focal or segmental and involves small leptomeningeal and intracerebral vessels. PACNS may be granulomatous, necrotizing, lymphocytic or mixed. Granulomatous vasculitis is characterized by transmural, well-formed granulomas. In about 50% of the patients, β-amyloid deposition may be seen. In lymphocytic type, the infiltrate is composed of lymphocytes and plasma cells. In the necrotizing type, fibrinoid necrosis of the vessel wall is seen. Acute lesions may co-exist with chronic lesions. Large or small vessel thrombosis may occur.[71],[72] PACNS is a diagnosis of exclusion and infections like tuberculosis, sarcoidosis, systemic autoimmune diseases, neoplasia like Hodgkin lymphoma and drug related causes that can cause granuloma need to be excluded. Stains and culture of the biopsy should be done to rule out infectious causes. PACNS-like illnesses are described with Varicella-Zoster, Cytomegalovirus and HIV.[66],[71],[72]

ANCA associated vasculitis (AAV): It mainly includes granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. CNS is affected in <15% of patients and disease limited to CNS represents a distinct subset.[73],[74] Pituitary, dura, CNS vasculature (small to medium sized vessels) are primarily involved and isolated parenchymal masses are extremely uncommon. Cranial neuropathy, orbital and sinus disease are usually associated with CNS involvement. Histopathology is the gold standard for diagnosis but not mandatory; correlation of clinical, imaging and serological features often helps in making a diagnosis. Biopsy from affected organs (kidney or skin) or brain (dura, parenchyma or the overlying leptomeninges) may be obtained. Necrotizing vasculitis with fibrinoid necrosis is characteristic. The granulomas may be palisading, poorly formed, focal or confluent, and non-caseous or necrotizing. The infiltrate is usually composed of lymphocytes, monocytes, plasma cells, eosinophils, neutrophils and occasional giant cells. Due to segmental involvement of the vessel, a negative biopsy does not exclude the diagnosis.[75]

Common variable immunodeficiency (CVID): It is characterized by recurrent infections and hypo-gammaglobulinemia (though not always). It involves multiple sites (lungs, skin, liver, spleen, kidneys, eyes, lymph nodes, intestines). CNS involvement is rare (8-22%) and may be the initial manifestation.[76],[77] CNS involvement is as mass lesion, leptomeningeal or white matter lesions.[76],[77] Histopathology shows angiocentric (50%) non-caseating granulomas or vasculitis without granulomas or lymphocytic meningitis. Diagnosis is established by correlating clinical features of multisystem involvement with histology of non-caseating granulomas. Infectious etiology should be excluded. Genetic evaluation may be necessary for an underlying monogenic disorder.[78]


   Granuloma Due to Inherited Disorder Top


Chronic granulomatous disease (CGD): It is an inherited disorder of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in which phagocytes are defective in generating reactive oxidants. CGD may be autosomal recessive or X-linked.[79] It causes recurrent, life-threatening bacterial and fungal infections with granulomatous reaction. The organs involved include skin, lung, lymph nodes, GIT, liver, brain, eyes and bones. The common etiologic agents include Staphylococcus aureus, Aspergillus spp, Nocardia spp, Actinomyces spp, Burkholderia cepacia, Serratia marcescens and Salmonella spp.Though CNS involvement is rare, CGD should be considered in the differential diagnosis of recurrent infections in children.[80]


   Granulomas in Neoplastic Conditions Top


Germinoma with granuloma: Intracranial germinoma may be associated with sarcoid-like granuloma. While evaluating limited tissue with stereotactic biopsy or cytology, it needs to be differentiated from tuberculosis or sarcoidosis by appropriate IHC and special stains.[81],[82]

Langerhans cell histiocytosis (LCH): LCH may affect almost any organ. In CNS, hypothalamus and pituitary are most commonly involved, followed by meninges, pineal gland and choroid plexus.[83],[84] The clinical presentation is usually with diabetes insipidus and anterior pituitary hormone deficiency. The pathology is as multiple small nodules or as space occupying lesions in the meninges/choroid plexus/brain parenchyma. The lesions are sharply demarcated and consist of a mixture of histiocytes, foamy macrophages, multinucleated giant cells, lymphocytes, plasma cells and eosinophils.[83] Diagnosis is by clinical, radiological and histopathological features along with IHC (CD68+, CD1a+, S-100+).

Juvenile xantho-granuloma: It involves the brain, spine or nerve roots with or without cutaneous involvement and occurs in children. Histologically, it is composed of round to spindled vacuolated histiocytes, FB/Touton type of giant cells, lymphocytes and occasional eosinophil. On IHC, the cells are positive for CD68, CD11c and are negative for S-100 and CD1a.[85]

Hodgkin lymphoma (HL) associated with granuloma: HL may be associated with non-caseating granuloma and about 5% HL may develop spinal cord compression, and rarely as the initial presentation.[86],[87] HL with granuloma needs to be differentiated from tuberculosis in endemic countries. Associated lymphadenopathy and presence of Reed-Sternberg cells along with eosinophilic and lymphomononuclear infiltrate help in the diagnosis. Confirmation is by IHC.[86],[87]

Lymphomatoid granulomatosis (LYG): LYG is a rare disease involving the lungs (most frequently), kidneys, skin and CNS. It is Epstein-Barr virus-driven B-cell lymphoproliferative disease. CNS involvement is seen in approximately one-third of cases as focal intra-parenchymal (most common) or cranial nerve and leptomeningeal lesions.[88] Spinal LYG is rare, and sometimes, isolated involvement of CNS or spine is seen.[89] Histology shows infiltration by lymphocytes, plasma cells and histiocytes forming angiocentric and angio-destructive granulomas with varying degrees of coagulative necrosis.[89],[90]


   Reparative Process Associated with Granuloma Top


A granuloma may develop following hemorrhage, especially in choroid plexus with cholesterol crystals and FB-giant cells or following implantation of any device after surgery.


   Approach to Diagnosis Top


Etiologic diagnosis of CNS granuloma for a pathologist starts with the type of granuloma, its location and the type of cellular infiltrate [Figure 1] and [Figure 2]. Necrotizing granuloma, coalescing, with caseous necrosis, Langhan's or FB-type giant cells and lymphomononuclear infiltrate in the meninges/brain/spinal cord is the commonest histology in tuberculosis. Such morphology of granuloma is highly suggestive of tuberculosis in countries like India, where tuberculosis is endemic. The yield on Z-N stain/culture is variable. Caseous/non-necrotizing/fibrotic granuloma with predominance of plasma cells, either with pachymeningitis/dural based mass should alert for a possibility of syphilis (though rare). Extracerebral/intraparenchymal fibrotic granuloma with FB-giant cells, lymphocytes, plasma cells and eosinophils may indicate aspergillus granuloma and should prompt to look for a lesion in sinus/ear/skull bone and evaluation with fungal stains. A suppurating granuloma with necrosis, neutrophils and FB giant cells should be evaluated for immune status along with Z-N stain, PAS, GMS for the presence of tuberculosis/parasite/fungi. Non-necrotizing granulomas, though typically suggest sarcoidosis, can occur in tuberculosis, autoimmune diseases and brucellosis. Angiocentric granulomas suggest PACNS or AAV. Correlation with immune status, risk factors, geographical location, clinical syndrome and imaging are essential for further diagnostic tests. Extra cranial sites of involvement provide not only useful clues for diagnosis but also provide option for sampling. Optimal use of tissue for histology, culture and molecular methods is essential for diagnosis and therapeutic decisions. [Table 2] summarizes the diagnostic approach.
Figure 1: Photomicrographs showing (a) Non-necrotizing granulomas composed of epitheloid cells with lymphocytes in the periphery (H and E x100); (b) Necrotizing granuloma with central caseation surrounded by epitheloid cells, Langhan's giant cells, lymphocytes and plasma cells (H and E x 100);(c) Suppurative granuloma with necrosis, neutrophils, lymphocytes, eosinophils, plasma cells and foreign-body type of giant cells (H and E x100); (d) Fibrotic granuloma (H and E x100); (e) Calcified granuloma (H and E x100); (f) Fibrotic wall delineating from adjacent brain parenchyma (Masson trichrome x100); (g) Gliosis around healed granuloma (Glial fibrillary acidic protein x100)

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Figure 2: Photomicrographs showing different types of granulomas (a-d) in neurotuberculosis: (a) Non-necrotizing granuloma (H and E x100); (b) Coalescing granulomas (H and E x100); (c) Caseating granuloma with epitheloid cells, Langhan's giant cells, lymphocytes and plasma cells (H and E x100); (d) Suppurating granuloma with abscess-like necrosis surrounded by neutrophils, macrophages and lymphocytes (H and E x100), Inset shows numerous acid-fast bacilli (Ziehl-Neelsen stain x 1000); (e) Multiple discrete non-necrotizing granulomas composed of epitheloid cells with lymphocytes in the periphery in sarcoidosis (H and E × 100); (f) Aspergillus granuloma with foreign-body giant cells containing negative staining septate hyphae, lymphocytes, plasma cells and few neutrophils in a fibrotic stroma (H and E x100), Inset: slender, septate hyphae with acute angle branching (Gomori methenamine silver x400); (g) Cryptococcoma with lymphoplasmacytic infiltrate and capsulated yeast forms (H and E x100), Inset: Capsulated budding yeast forms (Periodic acid-Schiff x400); (h) Cysticercal granuloma with cyst wall surrounded by intense inflammatory infiltrate composed of lymphocytes, plasma cells and foreign-body giant cells (H and E x100); Primary central nervous system angiitis (i and j) with (i). Non-necrotizing angiocentric granuloma (H and E x100); (j). Necrotizing angiocentric granuloma (H and E x100); (k). Juvenile xantho-granuloma with infiltrate of histiocytes, eosinophils and occasional giant cell (H and E x100); (l). Xantho-granuloma with foreign-body giant cell reaction around cholesterol clefts along with histiocytes and lymphocytic infiltrate (H and E x100)

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Table 2: Central nervous system granuloma: etiology, risk factors, extracranial sites of involvement, CNS involvement, histology and diagnosis

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   Conclusion Top


Tuberculosis is the most common cause of granulomatous disease in the CNS; however, the etiology of granulomatous inflammation is broad and includes many infectious or non-infectious causes. Histological evaluation with histochemical stains and culture resolves the diagnosis in a number of infectious diseases. The diagnostic yield can be improved by application of molecular techniques. The histologic type of granulomatous inflammation, whether non- necrotizing or necrotizing along with the site of CNS involved is helpful in the diagnosis and differential diagnosis of etiology. The diagnosis of non-infectious diseases is more difficult. Careful evaluation of clinical, imaging features, risk factors and extracranial sites of involvement provide clues to diagnosis. Despite application of modern molecular techniques, the etiologic diagnosis may remain unresolved in about a third of patients with CNS granulomas, highlighting challenge and limitation of currently available methods.

Abbreviations

CNS: central nervous system; HIV: human immunodeficiency virus; GIT: gastrointestinal tract; TBM: tuberculous meningitis; Z-N: Ziehl-Neelsen; IHC: immunohistochemistry; PCR: polymerase chain reaction; CSF: cerebrospinal fluid; VDRL: venereal research laboratory; FTA: fluorescent treponemal antibody; FTA-Ab: fluorescent treponemal antibody absorption; ACE: angiotensin converting enzyme; PNS: paranasal sinus; PAS; periodic acid-Schiff; GMS: Gomori methenamine silver; ISH: in-situ hybridization; ICSOL: intracranial space occupying lesion; FB: foreign body; PACNS: primary angiitis of CNS; SALL-4: Sal-like protein 4; PLAP: placental alkaline phosphatase; LCH: Langerhans cell histiocytosis; JXG: juvenile xanthogranuloma.

Acknowledgements

Faculty, residents and staff of department of Pathology, Nizam's Institute of Medical Sciences are gratefully acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Sundaram Challa
Sr Consultant and Advisor, DNB Pathology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, 500 034 Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_1067_21

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