Mucosa-associated lymphoid tissue lymphoma-induced hemophagocytic lymphohistiocytosis: A case report

Abstract

Mucosa-associated lymphoid tissue (MALT) lymphoma-induced hemophagocytic lymphohistiocytosis (HLH) has rarely been reported. Herein, we report the diagnosis and treatment process of a patient with MALT lymphoma-induced HLH who received chemotherapy after diagnosis and finally achieved partial remission. In this case, blood cells were only reduced to grade II at the time of diagnosis, and the patient was then treated with the R-CHOP regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). HLH responded well to treatment. Laboratory data indicative of HLH and blood chemistry results were steadily normalized, and hepatosplenomegaly resolved. One month after chemotherapy, the patient achieved partial remission. The results also showed that the treatment was successful. In conclusion, treatment of lymphoma-triggered HLH needs to balance HLH-specific and lymphoma-specific treatment. Once HLH is initially controlled or the decrease in blood cells is better than grade II, it should actively transition to lymphoma treatment.

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disease. It is characterized by excessive activation of T lymphocytes and macrophages, leading to serious damage to organ function. ¹ HLH is often secondary to infection, malignancy, and autoimmune diseases, especially epstein-barr (EB) virus infection and non-Hodgkin’s lymphoma. ² However, HLH rarely secondary to aggressive B-cell tumors, although these forms of HLH always show a poor prognosis. Herein, we report the diagnosis and treatment process of a patient with MALT lymphoma-induced HLH who received chemotherapy after diagnosis and finally achieved partial remission.

Hemophagocytic syndrome (HPS) has been described in association with a variety of lymphomas, most commonly T- or NK-cell-type tumors. ¹ More rarely, HPS rarely occurs in association with aggressive B-cell tumors, including diffuse large B-cell lymphoma and intravascular large B-cell lymphoma.^2,3 Although these lymphoma-associated forms of HPS generally show a poor prognosis, ¹ appropriate therapy for the underlying lymphoma can lead to the resolution of this condition.

Case section

A 53-year-old female with a medical history of MALT lymphoma was transferred to our hospital with intermittent fever and chills. Nine months before presentation, the patient presented a painful right anterior auricular nodule. She then underwent excision of the superficial lobe and a mass in the right parotid gland. Histological analysis showed a large number of lymphoid tissues with small follicular centers and lymphocytes. Immunohistochemical analysis revealed infiltration by cells of B-lineage, κ/λ dissatisfied, CD10⁻, Bcl-2−, Bcl-6−/+, MUM1−, CD5⁻, cyclin D−, CD79a+, CD20⁺, CD43⁻, and CD3⁻, with a proliferation fraction (evaluated with Ki-67) of 20–30%, CD21⁺ and CD23⁺ in follicular dendritic cells. Based on clinical and laboratory examination data, MZBCL of parotid gland MALT diagnosis (stage IIIb, IPI score 2, low- and medium-risk) was made. She received two courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). However, the patient discontinued chemotherapy and received long-term anti-infective therapy after the second course due to severe lung and skin infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Until this hospitalization, the patient had a normal temperature for 2 months without drugs.

One day before presentation to our hospital, the patient started having shaking chills and a high-grade fever. Her vital signs were stable and physical examination on admission revealed splenomegaly.

Laboratory tests on admission indicated pancytopenia, while C-reactive protein, procalcitonin, lactate dehydrogenase, triglyceride, serum ferritin, and soluble CD25 levels were high (Table 1). The activity of NK cells and plasma fibrinogen was decreased. Infection-related examinations include blood culture, urine culture, sputum culture, G test, and GM test, Epstein−Barr virus, cytomegalovirus, respiratory syncytial virus, tuberculosis antibodies, hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, gonorrhea, and chlamydia were all negative. TORCH syndrome (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex virus) and the series of autoimmune antibody examinations were not significant. The analysis of gene mutations associated with HLH yielded negative results. Chest, abdomen, and pelvic computed tomography revealed multiple small- and medium-sized lymph nodes with partial fusion in the mediastinum, bilateral armpits, and retroperitoneum.

Table 1.

Laboratory test results of the patient during hospitalization.

Laboratory test index	Admission	Rapid progression	Recovery	Normal range
White blood cell (×109/L)	2.56	2.01	7.32	4–10
Neutrophils (×109/L)	1.99	1.20	5.61	2–7
Hemoglobin (g/L)	114	89	81	110–150
Platelet (×109/L)	68	65	99	100–300
C-reactive protein (mg/L)	32.1	69.3	1.68	<10
Lactate dehydrogenase (U/L)	435	358	456	100–280
Procalcitonin (ng/ml)	0.13	0.22	0.066	<0.05
Plasma fibrinogen (g/L)	3.98	1.07	1.88	1.7–4.0
Alanine aminotransferase (U/L)	32	64	39	10–40
Aspartate aminotransferase (U/L)	25	20	36	10–40
Triglyceride (mmol/L)	3.22	3.50	1.93	0.56–1.74
Serum ferritin (ng/ml)	2015	2228	550	15−200 ug/L
The activity of NK cells		3.8%		>15.11%
Soluble CD25 (U/ml)		>7500	2850

The patient was diagnosed with HLH according to HLH-2004 diagnostic criteria. Because there was no evidence of infection, other tumors, autoimmune diseases, or genetic defects, the patient was finally diagnosed with MALT lymphoma-associated HLH.

The patient was treated with the R-CHOP regimen. HLH responded well to treatment. Laboratory data indicative of HLH and blood chemistry results were steadily normalized, and hepatosplenomegaly resolved. One month after chemotherapy, the patient achieved partial remission.

Before the patient developed MALT lymphoma-associated HLH, she only received two courses of R-CHOP chemotherapy due to severe lung and skin infections caused by CRE in 9 months. This also resulted in the primary disease of the patients not being controlled. Immunodeficiency generated by the underlying malignancy and loss of immune homeostasis due to chemotherapy may be the main cause of HLH. ³

Discussion

HLH has a wide range of causes, symptoms, and outcomes that inevitably lead to hyperinflammatory responses and multiple organ damage. The primary pathophysiology includes two components: (1) excessive proliferation and activation of T lymphocytes and macrophages and (2) substantial upregulation of cytokines, including tumor necrosis factor-alpha, interferon alpha, interleukin (IL)-1, IL-6, IL-10, IL-12, and IL-18. ² HLH cases have varied clinical features and laboratory findings, including, but not limited to, high fever, hepatosplenomegaly, cytopenia, coagulation abnormalities, and pathological evidence of hemophagocytosis.

A timely diagnosis and identification of early risk factors are essential for the development of effective therapies for HLH. HLH should be suspected in patients with unexplained fever and pancytopenia in the treatment of lymphoma, and the examination should be improved as soon as possible to win time for treatment. Treatment of lymphoma-triggered HLH needs to balance HLH-specific and lymphoma-specific treatments.

Currently, the HLH-94 or HLH-04 regimen remains the standard treatment strategy for HLH. ⁴ However, the prognosis for patients with malignancy-associated HLH treated with this regimen is generally poor. Otrock et al. reported that patients with malignancy-associated HLH had markedly worse survival (median overall survival(OS), 1.13 months) than patients with non-malignancy-associated HLH (median OS, 46.53 months). ⁵ For patients with lymphoma-triggered HLH, it is recommended to control HLH using HLH-94 or DEP regimens before starting tumor-specific treatment.^6-7 Once HLH is initially controlled, it should actively transition to lymphoma treatment.

Corticosteroids are the main drugs in the HLH-04 regimen. However, lymphoma-triggered HLH is insufficient for the treatment of lymphoma. In this case, considering that blood cell count was only reduced to grade II at the time of diagnosis, we used the R-CHOP regimen for both HLH and lymphoma. The results also showed that the treatment was successful.

Conclusion

In conclusion, treatment of lymphoma-triggered HLH needs to balance HLH-specific- and lymphoma-specific treatment. Once HLH is initially controlled or the decrease in blood cells is better than grade II, it should actively transition to lymphoma treatment.