| Abstract|| |
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening condition associated with high mortality and can be classified into primary (familial) and secondary HLH. Primary HLH is an inherited, autosomal recessive disorder associated with defects in perforin function, whereas secondary HLH is associated with infections, especially Epstein–Barr virus infection, malignancies, and autoimmune disorders. Patients with malignancy-associated secondary HLH experience symptoms that overlap with those described for other HLH types, which is associated with an increased incidence of misdiagnosis and mortality. Here, we report the case of a patient with secondary HLH associated with a solid malignancy (signet-ring cell carcinoma of the stomach).
Keywords: Hemophagocytosis, malignancy, malignancy-associated hemophagocytic lymphohistiocytosis, reactive hemophagocytosis, secondary hemophagocytic lymphohistiocytosis, signet-ring cell carcinoma
|How to cite this article:|
Ramkumar S. Malignancy-induced hemophagocytic lymphohistiocytosis in a case of signet ring cell carcinoma of the stomach. Indian J Pathol Microbiol 2021;64, Suppl S1:85-8
|How to cite this URL:|
Ramkumar S. Malignancy-induced hemophagocytic lymphohistiocytosis in a case of signet ring cell carcinoma of the stomach. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Sep 21];64, Suppl S1:85-8. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/85/317931
| Introduction|| |
Hemophagocytosis is a reactive mononuclear phagocytic response that occurs in association with a constellation of conditions such as malignancies and infections. The pathogenesis involves impaired natural killer (NK) and T-cell functions, the subsequent exaggerated immune response against target cells, causing hypercytokinemia, phagocytosis of hematopoietic, and peripheral blood cells by aberrantly activated macrophage accompanied by severe systemic inflammation [Figure 1]., HLH is a rare and potentially life-threatening condition with high mortality and can be classified into primary and secondary HLH. Primary HLH is an inherited autosomal recessive disease associated with defects in perforin function, whereas secondary HLH is associated with infections, malignancies, and autoimmune disorders. The symptoms of malignancy-associated secondary HLH (M- HLH) overlap with those of other HLH types. We report a case of secondary HLH associated with signet-ring cell carcinoma of the stomach.
|Figure 1: Pathogenesis of malignancy-associated hemophagocytic lymphohistiocytosis|
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| Case History|| |
A 53-year-old man with chronic renal failure, on maintenance hemodialysis, and a history of hypertension and a cerebrovascular event, underwent endoscopic biopsy due to anorexia, persistent vomiting, and progressive mild pancytopenia. Signet-ring cell carcinoma of the stomach was diagnosed. Preoperative laboratory tests revealed initial mild leukopenia (3,500/mm3), thrombocytopenia (106,000/mm3), and mild anemia (hemoglobin, 10 mg/dL). Coagulation parameters were normal [prothrombin time (PT), 16 s; international normalized ratio (INR), 1.13;activated partial thromboplastin time (aPTT), 28.2 s]. Post-hemodialysis blood urea and serum creatinine levels were 32 mg/dL and 3.2 meq/L, respectively. Routine ultrasound/sonography (USG) of the abdomen was performed as part of the diagnostic workup and showed mild splenomegaly and mild ascites. The patient also underwent fine-needle aspiration cytology (FNAC) for supraclavicular lymphadenopathy, which showed lymph node histiocytosis and hemophagocytosis in the lymph node aspirate [Figure 2]]. Ascitic fluid tapping also revealed multiple hemophagocytosis foci [Figure 2].
|Figure 2: Ascitic fluid and lymph node aspirates from the patient showing multiple foci of haemophagocytosis (PAP stain, 40×)|
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A bone marrow aspiration biopsy for refractory cytopenia revealed mild trilineage marrow hypoplasia with occasional hemophagocytic foci. The HLH preoperative diagnostic workup [Table 1] revealed hyperferritinemia (910 ng/ml), hypertriglyceridemia (490 mg/dL), and increased serum interleukin (IL)-2 levels. The patient tested negative for Epstein–Barr virus, hepatitis A, B, C, and E viruses, Widal, malarial parasite, and dengue. He was provisionally diagnosed with HLH; a tumor-induced cytokine response was the possible etiology.
|Table 1: Criteria for hemophagocyticlymphohistiocytosis (preoperative and post operative)|
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Distal gastrectomy was well-tolerated and a relative improvement incomplete blood count (CBC) was first observed on postoperative day (POD) 3 (Total count- 3,900/mm3, Platelet count-120,000/mm3, Hb-10.5 mg/dl, and continued until POD 12.
On POD 13, a perihepatic hematoma developed accompanied with bleeding from the Ryle's tube and melena. An upper gastrointestinal endoscopy showed multiple gastric and peristomal ulcers. aPTT, PT, and INR were within normal limits, with normal fibrinogen levels and factor XIII activity; however, thrombocytopenia worsened. Direct and indirect Coombs tests and nuclear, cytoplasmic, and perinuclear anti-neutrophil antibodies yielded negative results. Urine, blood, and drain catheter culture results were negative. Despite clipping and Hemaseel® application, his bleeding tendencies worsened with a continuous decline in platelet counts.
Repeat endoscopy showed exacerbated-existing ulceration and new gastric ulcers. He developed a fever and progressive pancytopenia. HLH confirmation tests were performed [Table 1]. A repeat abdominal USG confirmed moderate splenomegaly and moderate ascites. Repeat bone marrow aspiration demonstrated markedly increased bone marrow histiocyte numbers and multiple hemophagocytic foci. Predominant platelet phagocytosis [Figure 3] was observed with many foci exhibiting erythroid [Figure 3] and myeloid [Figure 3] precursors.
|Figure 3: Bone marrow aspirate smearswithlarge clusters of histiocytesthat are predominantly phagocytosing platelets and erythroblasts (Leishman's stain, 100 × under oil immersion)|
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Based on the lab test results and clinical presentation, preoperative HLH, secondary to the malignancy was considered. Despite an initial response, following distal gastrectomy, several postoperative factors caused clinical HLH recurrence. Despite bolus steroid doses, the patient developed hospital-acquired pneumonia with sepsis and died on POD 20.
| Discussion|| |
The annual incidence of M-HLH is approximately 1 per 2,80,000, which most commonly presents as the primary type caused by genetic defects, followed by secondary M-HLH, accounting for approximately 50–75% of adult HLH cases. Hematolymphoid neoplasms with T- or NK cell lymphomas or leukemias (93.7%), followed by B-cell lymphomas (32%), have a genetic etiology. M-HLH associated with solid tumors accounts for approximately 3% of all HLH cases. Proinflammatory cytokines that are secreted by neoplastic cells induce immune dysregulation, leading to M-HLH.,
The clinical diagnosis of M-HLH remains challenging due to its rare incidence, limited literature evidence, and the non-specific and complex clinical presentations of the associated malignancies. M-HLH can also present with symptoms that significantly overlap with other secondary HLH causes, such as sepsis, systemic inflammatory response syndrome, and multiorgan failure. HLH can occur not only during the development, recurrence, or relapse of malignancy but also during the initiation, maintenance, or consolidation of chemotherapy., Although the 2004 HLH criteria were used to diagnose M-HLH, additional specific diagnostic criteria, such as increased lactic acid dehydrogenase and D-dimer levels should still be emphasized and remain controversial. The patient presented increased serum IL-2 levels in the preoperative state. Increased serum IL-2 levels can play a major role in amplifying and perpetuating tumor antigen-related lymphocyte and NK cell stimulation. Therefore, pre-existing and progressive cytopenia caused by the tumor-induced cytokine response, resulting in the phagocytosis of bone marrow components, indicated the initial M-HLH diagnosis. After distal gastrectomy, the patient's CBC improved significantly, and IL-2 levels normalized.
Postoperative hyperferritinemia and hypertriglyceridemia were not as severe as the preoperative levels. Thus, tumor-induced cytokine response was considered to be the cause of M-HLH. However, several postoperative factors caused HLH recurrence, resulting in death.
Increased awareness and multidisciplinary studies should be emphasized and conducted, respectively, to update the standard HLH diagnostic criteria.
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Conflicts of interest
There are no conflicts of interest.
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Consultant in Oncopathology, Woodland Hospitals, Dhankheti, Shillong - 793 003, Meghalaya
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]