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in-재발한 유육종증의 골수 침범 증례 보고 Bone Marrow Involvement in Relapsed Sarcoidosis: A Case Report

volvement and diagnostic techniques for a more precise clinical evaluation [3]. Bone marrow involvement is rare, accounting for < 10% of sarcoidosis organ involvement, and isolated extrapulmonary sarcoidosis occurs in less than 5% of cases [4]. In the present study, we report a case of bone marrow involvement in a patient with relapsed sarcoidosis. Because there is no pathognomonic laboratory test or histological appearance for sarcoidosis, its diagnosis is commonly overlooked [1]. Further, we review the differential diagnosis of bone marrow granuloma and its clinical char-acteristics, which could provide new insights into diagnosing bone marrow involvement in sarcoidosis by applying the WASOG instrument. This study was approved by the Korea University Guro Hospital Institutional Review Board (IRB No. 2020GRO414). Sarcoidosis can involve multiple organs and is characterized by non-caseating granuloma on biopsy, which is not pathognomonic of this disease. Therefore, diagnosis requires exclusion of other causes of granuloma, including malignant neoplasm, infections, autoimmune diseases, drug expo-sure, environmental causes, lymphoma, and tuberculosis. Herein, we present a rare case of a patient with a primary manifestation of sarcoidosis, with typical bilateral hilar adenopathy, and recurrence in the bone marrow. A 50-year-old female patient, who had been diagnosed with sarcoidosis at age 38, was admitted for petechia on both legs and pancytopenia. The patient was concluded to be “highly probable” for sarcoidosis, with at least 90 % likelihood, according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) organ assessment instrument. Moreover, the patient had a bone marrow biopsy positive for granulomatous inflammation. Hence, all findings supported the diagnosis of sarcoidosis. Because sarcoidosis is difficult to definitively diagnose, it will be useful to better understand the application, interpretation, and limita-tions of the WASOG instrument for bone marrow involvement assessment.


INTRODUCTION
Sarcoidosis is characterized by systemic, non-caseating epithelioid granulomas [1], which are resultant of an overactive immune system. Sarcoidosis commonly affects the lungs, with more than 90% of patients presenting pulmonary manifestations [2]. The World Association of Sarcoidosis and Other Granulomatous Disease (WASOG) created a new tool for sarcoidosis organ involvement assessment including newer diagnostic criteria for organ in-largement 5 days prior to admission, which subsidized without medication. The patient had a past medical history of sarcoidosis, which was incidentally found on chest radiography as bilateral hilar lymphadenopathy and para-aortic enlargement at the age of 38 years (year 2004). Bilateral hilar adenopathy on chest radiography, especially without symptoms such as fever, night sweats, or weight loss, suggests a diagnosis of sarcoidosis, even without tissue con rmation [5]. At the time, mediastinal and hilar lymph node and arm soft tissue biopsies were performed, all of which showed chronic, non-caseating granulomatous in ammation. To rule out lymphoma, sarcoidosis, and tuberculosis lymphadenopathy, several tests were performed, including tuberculosis test (TB-PCR), On the day of admission, multiple coin-sized violaceous to brownish papules and plaques over both extremities were observed ( Fig.   1). No peripheral lymphadenopathy or organomegaly was observed.
Moreover, serum haptoglobin was increased (266 mg/dL), reticulocyte count was decreased (0.20% of red blood cells), and plasma hemoglobin was normal, which ruled out a diagnosis of hemolytic anemia.
Further hematological studies revealed increased serum iron (227 µg/dL) and ferritin (477.10 ng/mL) levels, and decreased total iron binding capacity (243 µg/dL). ACE, Ca levels, coagulation tests, and liver function tests were within the normal limits. Other

DISCUSSION
Sarcoidosis is characterized by non-caseating granulomas in multiple organs, including the lungs, lymph nodes, skin, and eyes.
It is a rare systemic in ammatory disorder of unknown etiology.
Sarcoidosis is exceedingly rare in Korea, with studies in Japan and Korea reporting a relatively low incidence of sarcoidosis, accounting for 0.13-1.01% per 100,000 population [6]. Bone marrow involvement in relapsed sarcoidosis is extremely rare, accounting for 0.3% of cases [7].
The diagnosis of sarcoidosis is not de nitive [5]. Sarcoidosis organ involvement may not cause any signi cant clinical symptoms and is often underdiagnosed [8]. Judson suggested a multistep process involving the comprehensive collection of clinical information, histologic examination of tissue for the presence of granulomatous in ammation, exclusion of other known causes of granuloma formation, and documentation that granulomatous in ammation is present in at least two organs [5].
The WASOG organ assessment instrument, developed in 2014, assesses various clinical manifestations of the probability of sarcoidosis organ involvement. Two criteria are required to apply this assessment: 1) histologic evidence of granulomatous in ammation of unknown cause in an organ that is not being assessed; 2) alternative causes for the clinical manifestation being addressed other than sarcoidosis have been reasonably excluded [9]. For all organs, a biopsy showing granulomatous in ammation where alternative causes were reliably excluded was considered "highly probable," and the likelihood of sarcoidosis was at least 90% [9]. A "highly probable" clinical manifestation of the lung was bilateral hilar adenopathy, perilymphatic nodules, and symmetrical hilar/ mediastinal adenopathy in imaging studies, which our patient manifested in 2004, in addition to the histologic evidence of granulomatous in ammation. For the WASOG assessment of bone marrow involvement in sarcoidosis, a "highly probable" criteria includes PET displaying diffuse uptake [9]. Moreover, a complete blood count has been suggested as an adjunct to determine bone marrow involvement [9].
In our case, a history of sarcoidosis, skin manifestation, and pancytopenia were considered strong indicators of bone marrow involvement. Papules/plaques and subcutaneous nodules are the most common sarcoidosis-speci c skin lesions [10]. Subcutaneous nodules are caused by granulomatous in ammation of adipose tissue underneath the skin and are commonly found on the extremities [10]. In addition, unexplained anemia, leukopenia, and thrombocytopenia are considered de nite clinical ndings in the clinical criteria for extrapulmonary sarcoidosis organ involvement [5]. High incidences of anemia, leukopenia, and extrapulmonary involvement have been reported in bone marrow involvement in sarcoidosis [12]. Anemia (hemoglobin <11 g/dL) occurs in 4-20% of patients with sarcoidosis, and leukopenia occurs in 40% of patients [13].
Leukopenia alone may be the initial presentation of sarcoidosis secondary to bone marrow in ltration or lymphocyte redistribution [7]. Unexplained cytopenia, although nonspeci c, may be a solitary nding and marker; thus, clinicians should maintain a high index of suspicion [7,12]. Granulomatous in ltration of the bone marrow is the cause of cytopenia [11]. According to the WA-SOG instrument, pancytopenia is considered an adjunct to determine bone marrow involvement [9].
The presence of non-caseating granuloma on biopsy is not pathognomonic of sarcoidosis because several other diseases can cause similar histopathologic changes [13]. This statement points to the complementary clinical information needed to make the diagnosis of sarcoidosis and that pathological ndings of a granuloma are insuf cient [5]. The estimated incidence of granulomas in bone marrow biopsies is low, accounting for 0.3-2.2% of all bone marrow biopsies. Sarcoidosis accounts for up to 21% of these cases [7]. Bone marrow granulomas have been reported in malignant neoplasms, tuberculosis, infectious mononucleosis, infectious causes such as brucellosis, typhoid fever, Q fever, tuberculosis, acquired immunodeficiency syndrome, Rickettsial disease, drug use, and autoimmune diseases [14]. The diagnosis of sarcoidosis requires that all these diseases should be excluded to a reasonable degree, which at least requires special staining and culture of the specimen for mycobacteria and fungi [5]. Malignant neoplasms have been reported as the cause of bone marrow granulomas in 20-25% of cases, most of which are malignant lymphomas of the Hodgkin's and non-Hodgkin's types [14]. If medical history suggests a possible alternative diagnosis, additional tests may need to be performed. In our case, we performed bone marrow cultures and stains to exclude fungal and mycobacterial infections. Lymphomas were excluded by ow cytometry.
This study has some potential limitations. Our diagnosis process may not have been thorough. Unfortunately, the most signicant limitation was that regarding time and cost, we were only able to evaluate more commonly occurring diseases that can cause granulomas such as tuberculosis and lymphoma; therefore, there was a lack of information available when excluding diseases with similar histopathologic changes. Second, the patient did not agree to further follow-up visits and investigations, and the treatment response remains unknown.
In conclusion, this case demonstrates a rare presentation of relapsed sarcoidosis with bone marrow involvement. Clinical presentations of sarcoidosis are diverse and may mimic several other diseases, posing diagnostic challenges for clinicians [10]. The diagnosis of sarcoidosis relies on the following: (1) the presence of non-caseating granulomas on histopathologic examination, (2) compatible clinical presentation, and (3) exclusion of other causes of granulomatous in ammation [10].
According to the WASOG sarcoidosis organ assessment instrument, our patient was concluded to be "highly probable," likeli-

Conflicts of Interest
None declared.