Hemophagocytic lymphohistiocytosis (HLH) is a rare and rapidly progressing clinical syndrome with unknown incidence in adults that results from severe immune activation. Characteristic findings include fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, rash, and neurological symptoms with elevated triglycerides, ferritin, and hypofibrinogenemia.
HLH is often described as primary hemophagocytic lymphohistiocytosis (inherited), with underlying genetic abnormality, or secondary (acquired) to another underlying condition such as a viral infection, an autoimmune disease, or a malignancy.
To the best of our knowledge, this is the first case report of HLH complicating a nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) in an adult treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. The NLPHL showed the additional, unusual feature of cyclin D1 expression, which, to our knowledge, also has not been previously reported.The patient died after treatment failure following 3 regimens of therapy.
High clinical suspicion of HLH should prompt immediate immunochemotherapy to reverse the otherwise high likelihood of a fatal outcome.
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome caused by an exaggerated inflammatory response and cytokine defect resulting in organ infiltration by activated cytotoxic T lymphocytes and histiocytes.1,2
Disproportionate levels of TNF-alpha; interleukins (IL) 4, 6, 8, 10, and 12; and soluble IL-2 receptor (sCD25) have been recorded in patients with HLH in combination with impaired/absent natural killer (NK) cell activity.3
The aforementioned parameters can aid in distinguishing this syndrome from etiologies with similar manifestations. Primary HLH, which generally affects infants and young children, is attributed to defects in perforin function. The incidence of secondary HLH in adults is unknown. Secondary HLH, either as a presenting phenomenon or developing during the course of a primary disease, has a broad range of associations, including infections (eg, Epstein-Barr virus [EBV] and cytomegalovirus [CMV]), rheumatic diseases, and malignancies, such as lymphoma).
Clinical and laboratory findings are characteristic yet nonspecific, which can delay the diagnosis. Findings include prolonged fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, rash, and neurological symptoms, usually with a rapidly progressing course.1,4
Classic laboratory features include elevated triglycerides, markedly elevated ferritin levels, hypofibrinogenemia, and abnormal liver function tests. Bone marrow examination often reveals characteristic hemophagocytes— histocytes with engulfed hematopoietic elements, including nucleated erythroid precursors, white blood cell precursors, and platelets—which are best depicted in marrow aspirate smears.
HLH is a challenging diagnosis due to its rarity and it’s nonspecific presentation, and laboratory findings. Prompt recognition and diagnosis is important, given the necessity of early treatment to assure the best possible outcome. The main goal of therapy, especially when HLH is associated with malignancy, is to direct therapy toward the underlying condition while attempting to control the amplified inflammatory reaction.4Case Presentation
Our patient is a 26-year-old Caucasian man with past medical history significant for nodular lymphocyte–predominant Hodgkin lympoma (NLPHL) stage IIIBs (lymph node involvement above and below the diaphragm with splenic involvement). Lymph node biopsy findings at diagnosis were typical of NLPHL, including macronodular architecture with a predomi- nance of small lymphocytes, lesser numbers of histocytes, and a minor population of admixed lymphocyte–predominant (LP) cells (Figure). LP cells expressed CD45, CD20, CD79a, BCL6, and epithelial membrane antigen, and lacked expression of CD10, CD15, and CD30. Interestingly, cyclin D1 was also expressed by cells consistent with LP cells (large, pleomorphic cells having highly lobated nuclei). The patient completed 6 cycles of rituximab, doxorubicin, vincristine, and predni- sone (R-CHOP) with resolution of the presenting symptoms following 2 cycles. The patient achieved unconfirmed complete remission at the end of therapy due to a small residual node on the left infraclavicular region.