Fever of unknown origin as the primary manifestation of extrapulmonary sarcoidosis with bone marrow involvement: a rare clinical scenario

ABSTRACT

Isolated bone marrow involvement in sarcoidosis is a rare condition, mostly manifested by cytopenia, hypercalcemia and/or hypercalciuria. We present the case of a 48-year-old man with a prolonged fever meeting the criteria for fever of unknown origin, in whom a suspicion of sarcoidosis only emerged after non-necrotizing granulomas were identified in the bone marrow, one year after the onset of the disease. The patient exhibited only mild anemia, moderate leukocytosis, thrombocytosis, and increased erythrocyte sedimentation rate, C-reactive protein levels. Other potential causes of fever of unknown origin and bone marrow non-necrotizing granulomas were ruled out. Although serum angiotensin-converting enzyme levels were elevated, they did not reach diagnostic thresholds. The diagnosis of sarcoidosis was confirmed by newly detected intra-abdominal lymphadenopathy on computed tomography and whole-body 18F-fluorodeoxyglucose positron emission tomography with computed tomography, along with the presence of multiple sarcoid-type non-necrotizing granulomas in the intra-abdominal lymph nodes. Treatment with prednisolone normalized the patient’s body temperature, improved laboratory-inflammatory profile, and enhanced the patient’s quality of life. In cases where fever of unknown origin is present and sarcoidosis is suspected, a bone marrow biopsy may be considered, even in the absence of cytopenia, hypercalcemia, or hypercalciuria.

INTRODUCTION

Sarcoidosis is a multisystem inflammatory disease characterized by a wide range of clinical manifestations, the morphological substrate of which is non-necrotizing granulomas (NNGs). Lung damage with involvement of intrathoracic lymph nodes and/or parenchyma is observed in more than 90% of cases. In approximately one-third of patients, other organs and systems may also be affected.^1-3 Among such organs may be bone marrow (BM), although the frequency of its damage is not high (0–12.1%).^4-7 Exclusively extrapulmonary sarcoidosis is uncommon, occurring in only 2–8.3% of cases^3,4, and isolated BM involvement is even rarer, typically manifested by cytopenia.⁸ We present a diagnostically challenging case of sarcoidosis with BM involvement, where the leading manifestation was prolonged fever.

CASE PRESENTATION

A 48-year-old man, with no aggravated epidemiological or professional history, was admitted to the hematology department with a complaint of persistent fever, reaching 39.5 °C, that had lasted for one year. Initially, the fever was attributed to an exacerbation of chronic purulent bronchitis. The patient experienced an improvement in symptoms and a normalization of body temperature during antibacterial therapy. However, after discontinuing the antibiotics, his fever returned, rising again to 39 °C. Subsequent investigations revealed no evidence of tuberculosis or other known infectious diseases.

Four months prior to the current admission, the patient was examined in the rheumatology department. The physical examination was unremarkable. Laboratory tests, however, revealed leukocytosis at 11*10⁹/L (normal range, 4–9*10⁹/L), an increased erythrocyte sedimentation rate (ESR) of 79 mm/hour (normal range, 1–10 mm/hour), and a C-reactive protein (CRP) level of 128 mg/L (normal range, 0.1–8.2 mg/L). A chest computed tomography scan revealed no focal or infiltrative changes (Fig. 1). Additionally, a contrast-enhanced computed tomography of the abdominal organs, along with esophagogastroscopy and colonoscopy, did not reveal any pathology.

Fig. 1.

Chest CT scan showing no abnormalities in the lung or mediastinum

CT: computed tomography

No convincing data were obtained to support a diagnosis of systemic connective tissue diseases or systemic vasculitis. The patient underwent a trial of prednisolone at 30 mg per day for one month, which resulted in normalization of body temperature. He was discharged without a definitive underlying diagnosis. However, after discontinuation of prednisolone, the fever resumed, general weakness increased, and the general blood test showed an ESR of 78 mm/hour, leukocytosis at 11.4*10⁹/L, and thrombocytosis at 529*10⁹/L (normal range, 180–400*10⁹/L).

At presentation, the patient had a body temperature of 38.5 °C. Physical examination revealed no abnormalities, with a heart rate of 88/min and blood pressure of 130/80 mm Hg. Laboratory results were as follows:

1. Complete blood count: hemoglobin was 98 g/L (normal range, 130–160 g/L), normochromia, normocytosis; leukocytes were 11*10⁹/L; platelets were 480*10⁹/L; the leukocyte formula was unchanged, and ESR was 86 mm/h.

2. Blood biochemistry: total protein—75.9 g/L (normal range, 64–83 g/L), albumin—39.2 g/L (normal range, 33–50 g/L), total calcium—2.48 mmol/L (normal range, 2.0–2.7 mmol/L), creatinine—77 μmol/L (normal range, 62–115 μmol/L), ultra-sensitive CRP—228.65 mg/L (normal range, 0.1–8.2 mg/L), potassium—5.04 mmol/L (normal range, 3.5–5.1 mmol/L), sodium—139 mmol/L (normal range, 136–145 mmol/L), uric acid—281 μmol/L (normal range, 210–419 μmol/L), urea—3.3 mmol/L (normal range, 3.2–7.3 mmol/L), procalcitonin—0.435 ng/mL (normal, <0.5 ng/mL).

Urinalysis was unremarkable. β2-microglobulin was within normal limits at 1.8 μg/mL. No microflora growth was detected in blood, urine, or throat cultures. Both the tuberculin skin test and interferon gamma release assay were negative.

A magnetic resonance imaging of the brain with intravenous contrast, echocardiography, esophagogastroduodenoscopy, and colonoscopy were performed. These investigations revealed no evidence of specific diseases, oncological conditions, pulmonary hypertension, or infective endocarditis.

A trepanobiopsy showed the following findings: erythropoiesis was slightly narrowed, granulocytopoiesis was expanded and rejuvenated, with a large number of eosinophils present. Among the megakaryocytes, mononuclear and anuclear cells were observed. Granulomas without caseous necrosis were identified, consisting of macrophages, epithelioid cells, and multinuclear giant cells (Fig. 2). No fungal elements or bacterial colonies were detected.

Fig. 2.

Histological images of bone marrow showing granulomas without caseous necrosis, consisting of macrophages, epithelioid cells, and multinuclear giant cells

Fig. 2A: Low magnification (50x)

Fig. 2B: High magnification (400x)

A repeat computed tomography scan of the abdominal organs revealed lymphadenopathy in the hepatopancreatoduodenal and paragastric groups, with lymph nodes measuring up to 14 mm along the short axis.

18F-fluorodeoxyglucose positron emission tomography with computed tomography showed numerous lymph nodes in the porta hepatis and around the celiac trunk, measuring up to 16x28 mm, with increased metabolic activity (SUVmax 11.99). There was a heterogeneous increase in metabolic activity in the bone marrow, mainly in the iliac bones and sacrum (SUVmax 5.09), without structural changes. No pathological radiopharmaceutical accumulation or structural changes were observed in the soft tissues.

A laparoscopic biopsy of the hypermetabolic lymph nodes at the level of the liver porta was performed, but the histopathological examination was not informative. Thus, no convincing evidence of lymphoproliferative disease was found. Due to persistent, unexplained fever, leukocytosis, elevated ESR, CRP, and the potential infectious nature of the bone marrow’s NNGs, empirical therapy with piperacillin tazobactam (4.5 g three times a day) and valganciclovir (450 mg twice a day) was initiated in the third week and continued for 12 days. During this time, acute phase indices and body temperature normalized. The patient was discharged and continued taking valganciclovir.

However, shortly after, the patient experienced a recurrence of general weakness and an increase in body temperature to 39.5 °C. Four weeks later, he was re-hospitalized in the hematology department. Blood chemistry revealed an ultra-sensitive CRP of 222.4 mg/L, procalcitonin of 0.467 ng/mL, and an angiotensin-converting enzyme level of 100 U/L (normal range, 20–70 U/L).

A repeat whole-body 18F-fluorodeoxyglucose positron emission tomography with computed tomography scan was performed, with the results consistent with the previous scan.

A second lymph node biopsy revealed multiple non-necrotizing epithelial cell granulomas with multinucleated giant cells (Fig. 3), without signs of tumor growth.

Fig. 3.

Histological image of an intra-abdominal lymph node

Multiple epithelial cell granulomas without necrosis with giant multinucleated cell surrounded by a moderate number of lymphocytes; some granulomas show signs of sclerosis.

The detection of NNGs composed of epithelioid and giant cells in the BM trephine biopsy, along with similar granulomas in enlarged hypermetabolic intra-abdominal lymph nodes, and elevated angiotensin-converting enzyme levels in the absence of other identifiable diseases in a patient with prolonged fever, led to the diagnosis of extrapulmonary sarcoidosis with involvement of the bone marrow and intra-abdominal lymph nodes.

The patient was prescribed prednisolone at a dose of 20 mg, which he has been taking for 5 months. His body temperature has steadily normalized, the angiotensin-converting enzyme level has normalized (43 U/L), and his ability to work has been restored. A follow-up whole-body 18F-fluorodeoxyglucose positron emission tomography with computed tomography is planned, and treatment adjustments are being considered.

DISCUSSION

The diagnosis of sarcoidosis remains unstandardized and is especially difficult in isolated extrapulmonary localization of sarcoidosis.⁹ One reason to suspect extrapulmonary sarcoidosis is the presence of fever of unknown origin.^10,11

We report a case of a patient with prolonged fever meeting the fever of unknown origin criteria,¹² where sarcoidosis was only suspected after the detection of NNGs during a histopathological examination of the BM, one year after the onset of the disease. Prior to this, there were no obvious reasons for BM examination. Apart from fever, the patient exhibited only non-specific laboratory signs, such as mild anemia, moderate leukocytosis, thrombocytosis, increased ESR, and CRP levels. There were no perilymphatic foci in the lungs or lymphadenopathy on CT scans. At the stage of the diagnostic search within the fever of unknown origin, no evidence was found to support common infections, systemic connective tissue diseases, systemic vasculitis, inflammatory bowel diseases, or solid tumors. It was during the current hospitalization that a histopathological examination of the BM revealed non-necrotizing granulomas, the genesis of which required further clarification. Granulomas in BM biopsies are rare, occurring in approximately 0.5–1.4 cases per 100 biopsies.¹² The primary causes include infections, particularly tuberculosis, malignant neoplasms, autoimmune disorders, and sarcoidosis.¹² In our patient, most of the listed possible causes of the identified BM granulomas were excluded. Given the absence of predisposing factors, less common causes, such as drug-induced sarcoidosis-like reactions, diffuse granulomatous reactions to foreign substances, and chronic beryllium disease, were also considered unlikely.¹² Although the patient had an elevated serum angiotensin-converting enzyme level, it did not reach a diagnostically significant threshold for sarcoidosis.⁹ As a result, lymphoma, which is documented among the causes of granulomatous inflammation in lymph nodes and BM, was highly suspected.¹³ The key diagnostic breakthrough came from a repeat biopsy and histological examination of newly identified lymph nodes with increased metabolic activity from the porta hepatis region. This allowed us to exclude lymphoma and confirm the presence of sarcoid-type NNGs.⁹ Thus, the identification of multiple NNGs in the lymph nodes and bone marrow, combined with the exclusion of other potential causes, led to the definitive diagnosis of sarcoidosis.⁹

The history of our patient raises questions about the current assessment of the frequency of BM lesions in sarcoidosis, which is likely underestimated. This underestimation may be due to the absence of distinctly pathognomonic clinical and laboratory manifestations that typically prompt BM examination.¹⁴

This case highlights that such a disease development scenario should be taken into account in clinical practice and can be considered as favorable, in terms of the impact on the prognosis, but not on the quality of life. Consequently, thorough screening for sarcoidosis and the initiation of prednisolone treatment, which improved both the laboratory-inflammatory profile and the patient’s quality of life, in this case can be considered as justified and appropriate measures.¹

To date, only a few reports of isolated BM sarcoidosis have been published. In the vast majority of these cases, patients presented with persistent cytopenia and/or hypercalcemia/hypercalciuria, which could indirectly indicate either BM lesion or sarcoidosis. This facilitated a faster diagnosis and the initiation of pathogenetic treatment.

What makes this case unique is that the patient did not exhibit these typical signs. Even intra-abdominal lymphadenopathy, which might have earlier suggested hemoblastosis and prompted BM investigation, did not appear until 8 months after the onset of the disease.

Diagnosing extrapulmonary sarcoidosis, particularly with isolated BM involvement, is extremely challenging due to the lack of specific clinical and laboratory manifestations, which can lead to significant delays in the initiation of treatment. In cases of prolonged fever where common causes such as infections, malignancies, and autoimmune disorders have been excluded, a high index of suspicion for extrapulmonary sarcoidosis should be maintained. BM biopsy should be considered in such cases, even in the absence of cytopenia, hypercalcemia, or hypercalciuria, unless there are specific reasons to justify otherwise.

INFORMED CONSENT

Informed consent was obtained from the patient; our institutional policy does not require formal ethical approval for case reports.

CONFLICTS OF INTEREST

The authors declare that they have no conflict of interest.

Abbreviations

NNGs

non-necrotizing granulomas

BM

bone marrow

ESR

erythrocyte sedimentation rate

CRP

C-reactive protein