Sarcoidosis, first described by Caesar Boeck in 1899, is a chronic idiopathic multisystem granulomatous disease involving lungs and mediastinal lymph nodes in approximately 90% cases.1 Other sites commonly involved include nodal, cutaneous, ophthalmic and hepatic.2 Extrapulmonary involvement occurs in up to 30% cases but bone marrow sarcoidosis is rare.3 The isolated extrapulmonary sarcoidosis is seen only in less than 10% cases.4 Sarcoidosis affects middle aged patients and there is slight female predominance.5 The etiology of sarcoidosis is still unclear. Environmental antigens and genetic predisposition are important factors that modulate the incidence and clinical manifestations.2 Clinical manifestations are varied depending on the organ affected but a significant proportion of patients present with non- specific constitutional symptoms including fever, fatigue, weight loss, malaise, night sweats.6 Bone marrow sarcoidosis can present with signs and symptoms that overlap with other hematological diseases, thus making its diagnosis difficult.7 Patients with bone marrow involvement have higher frequency of extrapulmonary lesions, leukopenia, and anemia than those without bone marrow lesions.8 The diagnosis of sarcoidosis is based on exclusion of other possible causes, an explicable clinical presentation and presence of non-necrotizing granulomatous inflammation.9 The objective of this systematic review was to study the profile of bone marrow sarcoidosis.

The study comprises an analysis of other studies that have reported the profile of bone marrow sarcoidosis. We searched for the related full text articles in English language published between 2019 to 2024 in PubMed database. The search term/ key words used to identify the articles relevant to the research topic included “bone marrow sarcoidosis” which yielded 47 results. The abstracts of the located articles were carefully assessed for the quality and appropriateness of subject by examining aim, study design, results, discussion and conclusions of each selected article. The number of studies found relevant to research title were 25. The studies which documented the following points were included for systematic review: (i) Age and sex of patient, (ii) Evidence of biopsy proven bone marrow sarcoidosis, (iii) Whether associated with pulmonary sarcoidosis or not, (iv) The onset of clinical symptoms and clinical presentation, (v) Relevant investigations for diagnosis, (vi) Specific treatment strategies, (vii) Patient outcomes. Keeping in view these criteria, 15 studies were included for quantitative synthesis. Figure1 shows a PRISMA (Preferred Reporting Items for Systematic review and Meta analysis) flow diagram depicting the overall procedure for the literature search to data retrieval. The data collection process involved summarizing the findings of selected studies by focussing on the age, sex, clinical presentation, any underlying disease or history of disease, investigations done, other sites of extrapulmonary sarcoidosis besides bone marrow and whether pulmonary sarcoidosis was evident or not.

A total of 15 studies were included in the systematic review. Table 1 gives an overview about the studies that were selected at the end of the search process. The final set of articles consisted of case reports. Patient demographics, clinical manifestations and diagnosis: Out of 15 cases, the average age was 49.73yrs (range: 9yrs- 72yrs) and the majority were females (60%). Most cases were seen in the age groups above 50 years. A significant medical history/ preexisting disease was seen in 10 out of 15 cases. Some had two or more preexisting medical conditions. Majority of patients had multiple preexisting diseases. The most common conditions were cardiovascular diseases (6 cases) followed by diabetes mellitus (3 cases). Two patients had history of breast carcinoma. One patient besides having cardiovascular disease, also had major depressive disorder and generalized anxiety disorder. One patient had history of antituberculosis treatment. The most common presenting complaints were one or the other constitutional symptoms (fatigue, weakness, night sweats, unintentional weight loss) seen in 10 out of 15 cases. Two patients having simultaneous spinal cord involvement (myelopathy) had backache and numbness of lower limbs respectively. Three patients presented with bleeding episodes in the form of epistaxis, red coloured vomitus, gum bleeding, hemoptysis. Two patients had complaints related to hypercalcemia (increased thirst, fatigue, intermittent headache, myalgia, frequent urination). Multisystemic sarcoidosis was seen in all 15 cases and involvement of systems other than bone marrow was also seen. Pulmonary involvement was seen in 3 out of 15 cases. Besides bone marrow, the other systems involved were spleen (8 cases), lymph nodes (6 cases), liver and kidney (5 cases each), musculoskeletal system and skin (3 cases each), eye and nervous system (2 cases each). Cardiac involvement was seen in one case. Out of 15 cases, serum angiotensin converting enzyme (ACE) levels and serum calcium levels were documented in 11 and 9 cases respectively. ACE levels were raised in 9 cases and calcium levels were increased in 5 cases, in upper normal range in one case, within normal range in 2 cases and decreased in one case. One case with normal calcium levels showed hypercalciuria. Hematological investigations showed pancytopenia in 5 cases, bicytopenia in 2 cases, only anemia, leukopenia and thrombocytopenia in one case each. CRP was raised in all 6 reports that commented about it and ESR was raised in all 4 reports that documented its levels. Five cases reported raised serum IL-2 receptor (sIL-2R) levels. Also, 1, 25- dihydroxy Vitamin D3 levels were documented to be raised in 3 cases. Renal function test (RFT) and Liver function test (LFT) were impaired in 5 cases each. One or more radiological investigations including Ultrasonography (USG), Computed Tomography (CT) scan, Magnetic resonance imaging (MRI), Fluorine -18 fluorodeoxyglucose positron emission tomography (18F- FDG- PET) scan were done in all 15 cases and histopathological evidence of non-caseating granulomas (NCG) suggesting sarcoidosis on bone marrow biopsy was present in all 15 cases. In one case with pancytopenia, bone marrow biopsy showed myelofibrosis along with NCG. Fig.1: The overall process of study selection depicted in the form of a PRISMA flow chart Table 1: Studies selected at the end of the search process PET FDG (Fluorodeoxyglucose positron emission tomography), Bx (Biopsy), NCG (Non- caseating granuloma), LFT (Liver function test), RFT (Renal function test), CT (Computed tomography), MRI (Magnetic resonance imaging), EBUS (Endobronchial ultrasound), MRCP (Magnetic resonance cholangiopancreatography) S. No. Study Age Sex Presenting signs and symptoms Medical history/ Preexisting Disease Extrapulmonary sarcoidosis sites/ mainfestations Pulmonary involvement ACE (U/L) S. Calcium (mg/dl) Other Investigations Diagnosis 1 Meshram RM et al18; 2020 9 F Epistaxis, brown, red coloured vomitus, fever, loss of appetite, generalized weakness, pallor, stunted growth H/O Antituberculous treatment, past H/O nasal bleed, skin lesions (granuloma annulare) Bone marrow, Lymph node, ophthalmic, cutaneous, musculoskeletal, Hepatic, Splenic No 59 Pancytopenia USG and CT scan: Hepatosplenomegaly, Abdominal lymphadenopathy, B.M biopsy: NCG 2 Kontoghiorghes, CP et al17; 2023 45 F Malaise, poor appetite, and urinary frequency - Splenic, Renal, abdominal lymph nodes, bone marrow No - 13.2 Creatinine (2.4), ESR (47), 1,25 di hydroxy VitD (112), CRP (I), Pancytopenia CT Chest, Bone marrow Bx: NCG 3 Hunt S et al19; 2020 53 F Fatigue, self-detected splenomegaly - Splenic, Lymph node, Bone marrow, osseus No 262 - PET / CT: Mediastinal, Abdominal and iliac nodes, splenomegaly, B.M biopsy: NCG 4 Shah K et al13; 2024 50 F Chronic lower back pain Hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, major depressive disorder, generalized anxiety disorder Cutaneous, Bone marrow, Renal, Lymph node Yes 10 15.1 Anemia, Leukopenia, creatinine 1.6 Chest CT, Liver scan, Bone marrow Bx: NCG 5 Adhikari B et al7; 2023 62 F Bilateral leg weakness, fatigue, unintentional weight loss Diabetes, Hypertension Bone marrow, Osseus No 111 13.4 Anemia, Alkaline phosphatase: 227 (I), 25-OH Vit D: 24.4 (D), 1,25- di(OH) Vit D 80 (I), ESR (40), CRP (42.1) CT scan Chest, abdomen, pelvis, Bone marrow Bx: NCG 6 Brugnaro P et al20; 2022 60 M Dyspnoea, fatigue and abdominal tenderness - Hepatic, Bone marrow, renal No 82 (I) 11 Impaired LFT, RFT, Low Vit D (12.3) Chest CT, FDG PET, Liver and Bone marrow Bx: NCG 7 Sugai M et al10; 2020 67 M Fatigue, weight loss, fever, loss of appetite Cerebral infarction, aortic valve stenosis, internal carotid artery stenosis, overactive bladder, hyperlipidemia Renal, Hepatic, Bone marrow No 34.1 (I) 8.5 Pancytopenia, Impaired LFT, RFT, Sil-2 R: 7835 (I), Lysozyme: 29.8 (I) CT Chest and abdomen, Bone marrow Bx: NCG 8 Matsuda N et al21; 2021 51 M Fever, joint pain, night sweats, nausea, fatigue Dilated Cardiomyopathy, Type 2 DM, AV Block, Hyperthyroidism Bone marrow, splenic, renal Yes 37.2U/L (8.3- 21.4U/L) Pancytopenia, Deranged LFT, RFT, s IL-2R: 3890U/ml, CRP: 0.92mg/dl 18F-FDG PET/CT , B.M Bx: NCG 9 Weeraddana P et al22; 2023 72 F Intermittent nose, gum, rectal bleeding, skin rash COPD, H/O Breast cancer, Pulmonary sarcoidosis, Liver cirrhosis Bone marrow Yes 10 Bicytopenia, low 25- OH Vit D: 23 USG abdomen, CT chest, Head, B.M Bx: NCG 10 Iwata M et al23; 2021 69 F Fever, weight loss, night sweats Hypertension, hyperlipidemia Bone marrow and hepatic No 15.8 10.3 ESR (64), CRP (60.2), Raised Liver enzymes, IL-2R (4030) (I) FDG- PET scan, Liver and B.M Bx: NCG 11 Brandão Calçada M et al3; 2021 37 M Back pain - Spinal and ganglionic, splenic and bone marrow No 91.2 10.1 ESR(56), Hypercalciuria (351mg/day) FDG- PET scan, B.M Bx: NCG 12 Raymond C et al24; 2022 35 M Hematochezia, hemoptysis - Lymph node, splenic No - - Pancytopenia B.M Bx: NCG with moderate myelofibrosis 13 Braun T et al28; 2021 40 M Numbness lower limbs, flu-like symptoms Arterial hypertension, Gout Bone marrow, spinal cord (myelopathy), Cardiac No Leukopenia, CRP (I) MRI, PET- CT 14 Chikamori F et al25; 2021 68 F Weight loss, Malignant lymphoma, H/O breast cancer, Hepatic, splenic, Bone marrow No 29.3 (I) Thrombocytopenia, CRP (I),s IL-2R: 3365U/ml, lysozyme: 18.3µg/ml FDG- PET/ CT: progressive malignant lymphoma, B.M Bx: NCG 15 Sta. Maria I P et al12; 2023 28 F Increased thirst, fatigue, intermittent headaches, myalgias, nausea, and unintentional weight loss Uveitis Cutaneous, ocular, splenic, abdominal lymph node, and bone marrow No 120 16.31 High 24 hr urine calcium (416), 1,25 di hydroxy VitD (416), IL-2 (3654.5) CT chest, abdomen, pelvis, PET scan, Bone marrow and Skin Bx: NCG

Sarcoidosis is a systemic granulomatous disease which can involve multiple systems. Lung and mediastinal lymph nodes are involved in over 90% cases.10 The clinical course may range from spontaneous remission, relapse and persistent disease activity.11 Most patients undergo remission with immunosuppressive therapy, but the clinical course depends on several factors such as age, sex, ethnicity, preexisting diseases and the systems involved by sarcoidosis.12 Etiology of sarcoidosis remains unclear. It has a heterogenous clinical presentation due to multisystemic involvement and it can mimic neoplastic, inflammatory and infectious conditions.13 It is a diagnosis of exclusion and relies on a compatible clinical presentation, findings of non-necrotizing granulomatous inflammation in tissue samples and exclusion of other causes of granulomatous disease.14 The disease mostly affects young to middle age adults and female preponderance is seen.15 In this review, the mean age was 49.73 years, maximum cases were seen in the age groups above 50 years and 60% patients were females. Extrapulmonary manifestations of sarcoidosis can be seen both in the presence and absence of pulmonary disease. Isolated extrapulmonary sarcoidosis is a rare entity seen in less than 10% cases.16 Bone marrow sarcoidosis is very rare and is seen in less than 5% cases of extrapulmonary sarcoidosis.10 It is possible that bone marrow involvement may be more common than reported as it may go underreported as most patients do not receive a bone marrow biopsy.17 In this review, pulmonary involvement was seen in only 3 out of 15 cases. The patients mostly presented with constitutional symptoms (fatigue, weakness, unintentional weight loss, night sweats) and other complaints including chronic back pain, bleeding episodes and skin rash.7,10,13,17-25 Patients with spinal cord involvement presented with back pain, numbness of limbs.3,28 Two patients presented with symptoms related to hypercalcemia such as increased urinary frequency, increased thirst, intermittent headaches, myalgias and fatigue.7,12 Most patients in this review, presented with one or the other haematological abnormality. Pancytopenia was seen in 5 cases, bicytopenia in 2 cases, only anemia, leukopenia and thrombocytopenia were seen in one case each. Hematologic abnormalities in sarcoidosis may be secondary to hypersplenism, bone marrow suppression or due to autoimmune mechanisms.27 Bone marrow sarcoidosis may present with cytopenia, lymphadenopathy and hypersplenism.17 Unexplained cytopenias may be a solitary finding of bone marrow sarcoidosis and clinician should keep a high index of suspicion.28 Thus, a complete blood count is recommended to assess bone marrow involvement.29 Anemia and/or leukopenia may be the initial sign of sarcoidosis resulting from bone marrow infiltration.13 Thrombocytopenia is extremely rare extrapulmonary manifestation of sarcoidosis.30 Weeraddena P et al22 reported a case of severe thrombocytopenia with a platelet count of less than 10,000/cmm. The patient had presented with bleeding from gums, nose, petechial rash and intracerebral hemorrhage (ICH). This was a case of relapsed sarcoidosis after being in remission for 15 years. The occurrence of granulomas in bone marrow biopsies has been estimated to be low, ranging from 0.3 to 2.2% in various studies.13 Sarcoidosis account for a significant proportion of these cases and as per a retrospective review by Brackers et al31, the bone marrow sarcoidosis was as high as 21%. There could be a possibility that bone marrow involvement is more common than reported as most patients do not undergo a bone marrow biopsy.17 The differential diagnoses for granulomas in bone marrow include malignant tumors such as lymphoma, tuberculosis, other infectious diseases caused by fungi and viruses, drugs and autoimmune disorders.10 Adhikari B et al7 described a case of 62 year old women whose presenting complaints closely resembled multiple myeloma. There has been a continuous dilemma of diagnosis and management between tuberculosis and sarcoidosis. Most clinicians in high tuberculosis prevalence settings tend to prescribe anti- tubercular drugs to such patients.18 Sarcoidosis can affect multiple organs, with 26% of patients experiencing splenomegaly, increasingly with other extrapulmonary lesions.13 Multisystemic sarcoidosis was seen in all 15 cases of bone marrow sarcoidosis and spleen was the most frequently involved organ (8 cases) followed by lymph nodes (6 cases), liver and kidney (5 cases each), musculoskeletal system and skin (3 cases each), eye and nervous system (2 cases each). Cardiac involvement was seen in one case. In bone marrow sarcoidosis, neurological symptoms are rare and typically linked to spinal cord compression.13 James et al32 reported that bone marrow involvement occurred more frequently in those with non-pulmonary sarcoidosis (12.1%) compared to those with pulmonary sarcoidosis (6%). In this review, 12 out of 15 cases did not have evidence of pulmonary sarcoidosis. Meshram et al18 described a case of early onset childhood sarcoidosis with bone marrow involvement. The 9 years old female child had presented with bleeding manifestations, skin rash, uveitis and arthritis. Hypercalcemia results from increased PTH independent conversion of 25 hydroxyvitamin D to 1,25- dihydroxy vitamin D by 1- alpha hydroxylase expressed by activated macrophages within granulomas.33 This leads to subsequent increase in activated vitamin D causing increased calcium absorption from intestines and resorption from bones.34 In this review, 1, 25- dihydroxy Vitamin D3 levels were documented to be raised in 3 cases. Hypercalcemia can have a variety of clinical manifestations including constipation, nausea, vomiting, dysrhythmias, dehydration, polyuria, nephrolithiasis, acute renal injury, weakness, muscle pain, behavioural changes, anxiety and various other neurological abnormalities.35 In this review, two patients had complaints related to hypercalcemia (increased thirst, fatigue, intermittent headache, myalgia, frequent urination).Serum calcium levels were documented in 9 reports and were found to be increased in 5 cases, in upper normal range in one case, within normal range in 2 cases and decreased in one case. One case with normal calcium levels showed hypercalciuria. There is no ideal pathognomonic biomarker to confirm the diagnosis of sarcoidosis though serological biomarkers such as serum angiotensin converting enzyme (ACE), soluble IL- 2R, chitotriosidase, lysozymes, serum amyloid A protein have been examined for potential roles in diagnosing or monitoring disease activity.36 Serum ACE, produced by the epithelioid cells of the sarcoid granuloma is presently the most well-known biomarker.12 Serum ACE levels are elevated in 75% of untreated cases of sarcoidosis. However, its diagnostic utility is limited due to poor sensitivity and specificity.23 In this series, serum ACE levels were raised in 60% cases. Serum soluble IL-2R has been suggested as a useful marker for identifying extrapulmonary involvement in sarcoidosis patients.36 Radiological imaging plays an important role in diagnosing extrapulmonary sarcoidosis. Computed Tomography (CT) scan, Magnetic resonance imaging (MRI), Fluorine -18 fluorodeoxyglucose positron emission tomography (18F- FDG- PET) are indispensable in the assessment of lesions in various organs affected by extrapulmonary sarcoidosis.37 Extrapulmonary sarcoidosis management is based on disease modifying drugs aimed at controlling the granulomatous process, organ specific treatments and supportive treatments to provide holistic, personalized and effective treatment.38 No double blind randomized controlled trials are available for comparing treatment approaches for sarcoidosis.13 Corticosteroid is considered first line of therapy for sarcoidosis. But steroids have dose dependent negative impact on quality of life. So, steroid sparing agents, Methotrexate, Azathioprine, Leflunomide and Mycophenolate mofetil may be used. Infliximab and biosimilars are used in patients having experience of second line treatment failure or bad tolerance. The fourth line therapy though used in exceptional cases, target the mTOR, IL-6 or JAK/STAT pathways.38 Methotrexate is used cautiously in bone marrow sarcoidosis due to its potential cytotoxic effects.13

Extrapulmonary sarcoidosis is a masquerade due to varied presentations and multisystem involvement. Bone marrow sarcoidosis is a rare form of extrapulmonary sarcoidosis, more frequently seen in women. Careful evaluation of clinical symptoms, serum biomarkers and other laboratory and radiological investigations and histopathological examination is necessary to rule out infectious, inflammatory and neoplastic conditions that mimic sarcoidosis. Though bone marrow sarcoidosis usually has nonspecific and varied clinical presentation, unexplained cytopenias might be the only finding, hence a high level of suspicion must be exercised to establish the diagnosis. If the diagnosis is missed or delayed, patients can experience debilitating consequences.

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