Concurrent sarcoidosis and hemophagocytic lymphohistiocytosis: A case report

Abstract

BACKGROUND

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome driven by excessive cytokine release and uncontrolled immune activation. While HLH is commonly associated with infections, malignancies, and autoimmune diseases, its occurrence secondary to sarcoidosis is exceptionally rare. Sarcoidosis is a multisystem granulomatous disorder characterized by noncaseating granulomas, most frequently affecting the lungs and lymphatic system. Coexistence of these two conditions presents significant diagnostic and therapeutic challenges, particularly in adult populations in whom the established diagnostic criteria may be less sensitive.

CASE SUMMARY

We report the case of a 57-year-old man with a 2-year history of unexplained weight loss, recurrent nocturnal fever, generalized lymphadenopathy, and hepatosplenomegaly. His medical history included hypertension, type 2 diabetes mellitus, hyperlipidemia, and gout. Initial laboratory and imaging workup were inconclusive. Progressive clinical deterioration prompted further hematological evaluation, revealing pancytopenia with abnormal peripheral smear findings, although bone marrow biopsy was unremarkable. Serum angiotensin-converting enzyme levels were mildly elevated. Subsequent endoscopic ultrasound-guided fine needle aspiration of a subdiaphragmatic lymph node demonstrated florid noncaseating granulomatous inflammation consistent with sarcoidosis. Based on multidisciplinary team discussion and application of the HScore (174), a diagnosis of HLH secondary to systemic sarcoidosis was established. The patient was initiated on high-dose corticosteroid therapy, with a plan for gradual tapering and consideration of additional immunosuppressive therapy. Early recognition and prompt treatment were critical to prevent further clinical deterioration.

CONCLUSION

This case highlights a rare but important association between sarcoidosis and HLH, underscoring the need for maintaining a high clinical suspicion in patients presenting with systemic inflammatory features and granulomatous disease. Early multidisciplinary evaluation and timely initiation of immunosuppressive therapy are essential to improve outcomes in this potentially fatal condition.

Key Words: Sarcoidosis; Hemophagocytosis; Lymphohistiocytosis; Bone marrow; Splenomegaly; Case report

Core Tip: This case emphasizes the importance of considering sarcoidosis in adults presenting with unexplained hemophagocytic lymphohistiocytosis (HLH) after exclusion of infectious and malignant causes. Early use of the HScore facilitated prompt diagnosis and treatment initiation. Notably, the patient showed improvement with corticosteroid therapy alone, supporting a stepwise, individualized treatment approach in clinically stable sarcoidosis-associated HLH.

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening disorder characterized by systemic hyperinflammation due to excessive cytokine secretions[1]. Cytokine overproduction leads to excessive macrophage activation and phagocytosis of red blood cells (hemophagocytosis)[2]. This hyperinflammatory state can ultimately lead to severe tissue damage, multiorgan failure, and, occasionally, death. Clinically, patients can present with high-grade fever, hepatosplenomegaly, liver dysfunction, lymphadenopathy, and neurological symptoms. Laboratory findings frequently include pancytopenia and varying degrees of coagulopathy[2].

The diagnosis of HLH is mainly aided by the HLH-2004 diagnostic criteria, especially in pediatric populations, where they facilitate early identification of affected patients[1,2]. However, the application of the HLH-2004 criteria in adult populations carries several limitations. Despite advances in understanding the disease, the HLH-1994 protocol remains the main treatment algorithm for this condition.

One of the overlooked etiologies is viral infections such as those caused by the Epstein-Barr virus, coronavirus disease 2019, and parvovirus B19 infection[2]. Systemic sarcoidosis is one of the rare triggering factors of HLH. Although sarcoidosis itself does not typically affect the bone marrow, it may trigger HLH, which can subsequently manifest with hematologic and bone marrow abnormalities. Sarcoidosis mostly affects the lungs and intrathoracic lymph nodes, with over 90% of patients presenting with reticular lung opacities and bilateral hilar lymphadenopathy. However, sarcoidosis can also affect other organs and systems such as the skin, joints, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidneys, eyes, and central nervous system[3,4].

The incidence of sarcoidosis in adults varies significantly by ethnicity. The highest incidence has been reported among African Americans, ranging from approximately 17 to 35 cases per 100000 individuals per year, followed by White populations, with an incidence of approximately 5 to 12 cases per 100000 individuals per year. Lower incidence rates have been observed among Asians and Hispanics, estimated at around 1 to 3 cases per 100000 individuals per year. Sarcoidosis shows a female predominance, with the female-to-male prevalence ratio approaching 2:1 in African Americans[5]. The disease most commonly affects middle-aged adults between 35 years and 50 years of age. Typical symptoms include cough, dyspnea, and chest tightness. However, nearly half of patients with pulmonary sarcoidosis have no symptoms[5].

Serum angiotensin-converting enzyme (ACE) is elevated in approximately 60% of patients at the time of diagnosis and can reflect the volume of the total granuloma in the body[3]. Increased levels may also be detected in bronchoalveolar lavage fluid and cerebrospinal fluid. However, the diagnostic utility of serum ACE is limited because of its relatively low sensitivity and specificity of 60% and 70%, respectively[3]. Serum ACE levels have no clear prognostic value; hence, treatment decisions should not be based on ACE levels alone. Pulmonary function tests and a carbon monoxide diffusion capacity test may be useful for monitoring disease progression and treatment response during follow-up.

Sarcoid-related changes can be detected using multiple non-invasive imaging modalities, including chest radiography, cross-sectional imaging of the chest, and technetium-99m sestamibi scintigraphy[6]. For tissue acquisition, endobronchial ultrasound and transesophageal ultrasound facilitate access to targeted mediastinal lymph nodes[7].

The characteristic histopathologic feature of sarcoidosis is the presence of noncaseating granulomas with negative staining for Mycobacterium tuberculosis and fungi[2]. High-dose corticosteroid therapy remains one of the mainstays of initial treatment, followed by gradual dose tapering and transition to long-term immunosuppressive therapy when required[2]. Corticosteroid-refractory disease can be managed with alternative immune modulators or biologic therapy, including methotrexate, infliximab, and thalidomide. Among these agents, infliximab is very effective in extrapulmonary sarcoidosis and has been associated with more promising outcomes[8].

CASE PRESENTATION

Chief complaints

A 57-year-old man presented with unexplained weight loss, nocturnal pyrexia, and generalized fatigue.

History of present illness

Patient symptoms were progressively getting worse over a span of 2 years in addition to the left upper quadrant pain, which prompted further hematological assessment.

History of past illness

The patient had a history of well-controlled hypertension, hyperlipidemia, gout, and type 2 diabetes mellitus.

Personal and family history

The patient’s personal history was otherwise unremarkable. He reported no known family history of malignancy, autoimmune disease, or granulomatous disorders.

Physical examination

Clinical examination revealed hepatosplenomegaly. Cardiovascular examination identified an early diastolic murmur, which was later attributed to trivial aortic valve regurgitation. Respiratory examination revealed an incidental left-sided basal pleural effusion.

Laboratory examinations

Initial biochemical investigations were inconclusive. Hematologic evaluation demonstrated normocytic anemia, leukopenia, and thrombocytopenia. Initial peripheral blood smear analysis showed immature cells; repeat blood smear analysis revealed microcytosis, hypochromia, anisocytosis, and poikilocytosis.

Bone marrow aspiration and biopsy findings were unremarkable. Serum ACE levels were mildly elevated at 75.7 U/L (normal range: Approximately 8-52 U/L). Further laboratory findings are summarized in Table 1.

Table 1 Laboratory examinations during the patient’s disease course.

Liver function test	Reference range/Unit	August 31, 2025	September 13, 2025	December 14, 2025
Total bilirubin	< 21.0 μmol/L	7.00	9.30	7.03
Direct bilirubin	≤ 5.0 μmol/L	4.54	5.60	4.13
Alkaline phosphatase	35-104 U/L	220	212	120
Alanine aminotransferase	< 35 U/L	22.9	15.60	31.60
Aspartate aminotransferase	< 35 U/L	28.50	21.00	18.30
Albumin	35.0-52.0 g/L	37.00	37.10	40.70
Protein	64-83 g/L	84.60	70.20	71.20
Complete blood count	Reference range/unit	September 13, 2025	January 4, 2026	March 18, 2026
Hematocrit	37%-47%	24.3	35.4	34.7
Nucleated red blood cells	0-0.6/100 WBC	0.2	0.1	0.1
Red cell distribution width	12.1%-16.2%	18.2	20.2	15.8
Mean platelet volume	7.4-11.4 fL	8.6	8.7	9.1
Basophils	0-0.1 × 103/μL	0.0	0.0	0.0
Eosinophils	0-0.5 × 103/μL	0.1	0.0	0.0
Hemoglobin	12.5-16.3 g/dL	7.6	11.3	11.6
Lymphocytes	1-3.2 × 103/μL	0.6	2.00	1.0
Mean corpuscular hemoglobin	23.8-33.4 pg	24.6	24.6	29.2
Mean corpuscular hemoglobin concentration	32.5-36.3 g/dL	31.3	31.8	33.5
Mean corpuscular volume	73.0-96.2 fL	78.4	77.3	87.2
Monocytes	0.3-1.10 × 103/μL	0.4	0.3	0.1
Neutrophils	1.70-7.60 × 103/μL	2.00	4.80	3.9
Platelet count	150-410 × 103/μL	138	110	101
Red cell count	4.06-5.63 × 103/μL	3.11	4.58	3.97
White cell count	3.6-10.2 × 103/μL	3.1	7.2	5.1
Additional hematological tests. Absolute reticulocyte count (August 31, 2025). Absolute reticulocyte count (December 14, 2025)	39-57 × 109/L; 39-57 × 109/L	97; 84
Prothrombin time	11.7-15.3 seconds	14.5
International normalized ratio	0.80-1.20	1.08
Activated partial thromboplastin time	28.6-40.0 seconds	37.8
Other laboratory tests	Reference range	Result
Procalcitonin	< 0.05 mg/mL	0.17-0.52
Ferritin	30-250 ng/mL	425
D-dimer	0.27-0.60 µg/mL	2.05
Angiotensin-converting enzyme	20-70 U/L	75.7
Leishmania screening	Negative	Negative
Viral serology	Negative	Negative
Malarial antigen (Plasmodium falciparum)	Negative	Negative
Parvovirus B19 IgG and IgM	Negative	IgG positive: 29.4 IU/mL; IgM negative
QuantiFERON-TB gold test	Negative	Negative

WBC: White blood cell; IgG: Immunoglobulin G; IgM: Immunoglobulin M.

Imaging examinations

Prior transabdominal ultrasound and cross-sectional imaging demonstrated hepatosplenomegaly and generalized lymphadenopathy, seen in Figure 1. Additionally, a left-sided basal pleural effusion was identified.

Figure 1 Contrast-enhanced computed tomography image. A: The abdomen shows enlarged liver and spleen, and a cluster of lymph nodes (white arrow); B: The abdomen shows mesenteric lymphadenopathy (white arrow).

Endoscopic ultrasound with fine-needle aspiration targeting a pathological subdiaphragmatic lymph node revealed changes in keeping with non-caseating granuloma seen in Figures 2 and 3.

Figure 2 Endoscopic ultrasound image demonstrates left gastric territory lymph nodes (orange arrow).

Figure 3 Histopathological image demonstrates noncaseating granulomatous inflammation with multinucleated giant cells, consistent with sarcoidosis. A: White arrow pointing at noncaseating granuloma; B: Magnified picture of histopathological slide.

MULTIDISCIPLINARY EXPERT CONSULTATION

The case was discussed during a multidisciplinary team meeting involving specialists in gastroenterology, hematology, and radiology. After a comprehensive evaluation of clinical, laboratory, and histopathological findings, a consensus diagnosis was established.

FINAL DIAGNOSIS

Systemic sarcoidosis presenting with secondary HLH, supported by an HScore of 174, which exceeded the diagnostic cutoff value of ≥ 169[9].

TREATMENT

The patient was initiated on high-dose corticosteroid therapy at 1 mg/kg/day, with a plan for gradual tapering and consideration of additional immunomodulatory therapy if required.

OUTCOME AND FOLLOW-UP

The patient demonstrated clinical and biochemical improvement following corticosteroid therapy, with subsequent stabilization of symptoms. Ongoing follow-up was arranged to monitor treatment response and assess the need for additional immunosuppressive therapy.

DISCUSSION

Sarcoidosis-associated HLH, particularly in adults, presents with prolonged constitutional symptoms and hematologic abnormalities that can be clinically challenging. Only a few reports on sarcoidosis-associated HLH exist in the literature, most of which involved patients already diagnosed with sarcoidosis. To the best of our knowledge, there are currently no published reports on HLH as the initial presentation of sarcoidosis.

In the present case, the diagnosis of systemic sarcoidosis was considerably delayed, mainly owing to uncoordinated medical care across multiple hospitals.

In cases of suspected HLH, infectious triggers must be rigorously excluded. Visceral leishmaniasis is a well-established cause of secondary HLH and may closely mimic sarcoidosis both clinically and histologically. Visceral leishmania can similarly present with prolonged pyrexia, weight loss, fatigue, anemia and thrombocytopenia. As part of affecting the reticuloendothelial system, splenomegaly and hepatomegaly are mostly present[10].

Parvovirus B19 is another important but underrecognized trigger of HLH, particularly associated with severe anemia and bone marrow suppression. Cases of parvovirus B19-associated HLH have also been reported in immunocompetent adults[11,12]. Additionally, post-coronavirus disease 2019 hyperinflammatory syndromes have emerged as recognized precipitants of HLH, with delayed immune dysregulation occurring weeks after acute infection[13,14]. Therefore, comprehensive viral serologic testing and parasitic screening should be performed to rule out possible infectious etiologies. In the present case, the patient had a negative parasite and viral serology, which supported the eventual diagnosis of systemic sarcoidosis-associated HLH.

Further invasive diagnostic evaluation was therefore warranted. Endoscopic ultrasound-guided fine-needle aspiration of the targeted lymph node showed noncaseating granulomatous inflammation. When interpreted alongside the patient’s clinical presentation and the exclusion of alternative diagnoses, these histopathological findings supported systemic sarcoidosis as the most likely diagnosis.

Serum ACE levels were initially thought to be specific for sarcoidosis and disease activity following studies published in 1975. However, recent studies have demonstrated that serum ACE has a sensitivity of as low as 40% and poor specificity, with false-positive rates of approximately 15%[15-17].

Chest computed tomography is another diagnostic modality that may support the diagnosis of sarcoidosis. One of its characteristic radiological features is the “1-2-3 pattern”, also known as the Garland triad or “pawnbroker’s sign”, which is characterized by bilateral hilar and right paratracheal lymphadenopathy. In sarcoidosis, hilar lymphadenopathy is typically prominent and is especially recognized by its clear separation from the cardiac border[18].

Another radiological feature that may be observed in sarcoidosis is the crazy-paving pattern. Although nonspecific, its presence may further support the diagnosis. This pattern is described as a superimposed linear network on areas of ground-glass opacity, producing an appearance resembling irregularly shaped paving stones, hence the term “crazy paving”[19].

Lymph node biopsy is not routinely required in asymptomatic patients with clinically suspected sarcoidosis. However, in cases where the diagnosis remains uncertain or in symptomatic patients, endoscopic ultrasound-guided fine-needle aspiration is recommended. This approach is less invasive than mediastinoscopy and demonstrates high sensitivity, with a diagnostic yield ranging from 77% to 94% in patients with sarcoidosis. Histopathological evidence of noncaseating granulomas on biopsy typically confirms the diagnosis[16,20].

Early recognition of HLH is critical, as untreated disease carries a high mortality rate. Management of secondary HLH is focused on treating both the hyperinflammatory state and the underlying trigger. In our patient, corticosteroid therapy alone led to significant clinical and biochemical improvement, thereby avoiding the need for etoposide-based therapy. This approach is supported by previous reports suggesting that sarcoidosis-associated HLH may respond favorably to corticosteroids alone, particularly in clinically stable patients, with etoposide reserved for refractory or severe disease[21-23].

This case underscores the importance of a broad and systematic diagnostic approach in adults with HLH, including careful exclusion of infectious mimics and implementation of individualized treatment strategies guided by disease severity and the underlying etiology.

CONCLUSION

This case describes an exceptionally rare presentation of systemic sarcoidosis initially manifesting as secondary HLH in an adult patient. The overlap of prolonged constitutional symptoms, cytopenia, and organomegaly created significant diagnostic complexity, emphasizing the need for a broad differential diagnosis and multidisciplinary evaluation. Early recognition of HLH using validated tools such as the HScore enabled the timely initiation of therapy. The patient demonstrated favorable clinical improvement with corticosteroid treatment alone, supporting a stepwise, individualized treatment approach in sarcoidosis-associated HLH. The coordinated medical care given to our patient has clearly led to good outcomes highlighting the importance of multidisciplinary team management approach. Clinicians should consider sarcoidosis as a potential underlying etiology in adults presenting with unexplained HLH after exclusion of infectious and malignant causes.