Lymphoma-Driven Hemophagocytic Lymphohistiocytosis
The second case in our series on lymphoid neoplasms
Sanam Loghavi, Kamran Mirza, Paolo Strati | | Longer Read
21-year-old man with a two-month history of worsening fatigue and fever. He was transferred to our hospital from an outside institution for acute-onset renal failure and suspected tumor lysis syndrome.
Pertinent physical exam
Temperature: 103.2°F; hepatosplenomegaly.
Complete blood count and differential (reference range)
Additional laboratory results
FDG-avid multicompartmental lymphadenopathy above and below the diaphragm. Heterogeneously increased activity within the spleen and several foci of activity within the skeleton.
Bone marrow morphology
Lymph node biopsy
Classic Hodgkin lymphoma, EBV+, with associated hemophagocytic lymphohistiocytosis.
The pathologist’s view
A young patient presenting with constitutional symptoms, hepatic and renal failure, and diffuse lymphadenopathies with no overt diagnosis presents a high-stakes situation in which time is of the essence. In this case, the initial specimens received were bone marrow (BM) aspiration and biopsy that showed hypercellularity; scattered large, atypical cells; and a striking number of hemophagocytic histiocytes.
An increase in hemophagocytic histiocytes has several possible causes – most importantly hemophagocytic lymphohistiocytosis (HLH). HLH is a severe, potentially fatal hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. HLH is divided into primary and secondary forms. The primary form typically manifests in children and is associated with genetic abnormalities affecting T and NK cell regulation. The secondary and far more common form typically occurs in adults, often in the setting of an associated condition, such as malignancy, infection, or autoimmune disorders. Though infections typically trigger the onset of HLH in pediatric patients, malignancy is the most common cause of HLH in adults (Mal-HLH) (1). Among all HLH subtypes, Mal-HLH has the worst prognosis, and its risk increases with age. Lymphoma is the most common underlying malignancy, with Mal-HLH observed in up to 3 percent of patients with lymphoma.
Timely HLH diagnosis is critical, especially because symptoms can be nonspecific. The diagnostic criteria for HLH include several clinical, laboratory, and biopsy findings; increased hemophagocytic activity is only one criterion and not required for diagnosis (2).
In this case, the most time-sensitive task was to alert the clinical team to the presence of marked hemophagocytosis and confirm their clinical impression of HLH. Of equal importance is a meticulous search to identify an associated underlying pathologic disease to guide therapeutic decisions. The first specimen we saw was the bone marrow. A number of scattered large, atypical cells were present, so we performed a battery of immunohistochemical stains that highlighted the presence of large CD30+, EBV+ neoplastic cells suggestive of classic Hodgkin lymphoma. The typical stromal reaction and inflammatory infiltrate usually associated with Hodgkin lymphoma was lacking – possibly a manifestation of an underlying immunocompromised status.
Fortunately, not long after reviewing the BM specimen, a retroperitoneal lymph node biopsy was performed. In this case, the biopsy consisted of scant, poorly preserved tissue. In the better-preserved areas, one could appreciate a proliferation of large, atypical cells associated with histiocytes and few eosinophils. Though CD30 expression was weak (possibly due to poor fixation), the expression of PAX5, lack of CD45/LCA, and positivity for EBER were consistent with EBV+ Hodgkin and Reed-Sternberg cells of classic Hodgkin lymphoma.
This case highlights the importance of a holistic approach and the need for adequate, well-fixed tissue in cases of malignancy-associated HLH. Classic Hodgkin lymphoma is a diagnosis rendered when architecture and phenotype are assessed together. Limited tissue sampling hampers accurate diagnosis and subclassification. In this case, identifying the underlying malignancy was critical to proper diagnosis and management.
The hematologist’s view
My threshold for suspecting HLH is low in patients with lymphoma, particularly those with NK/T cell lymphoma or EBV+ lymphoma, the two subtypes more likely to induce Mal-HLH.
The diagnosis of HLH is currently based on the HLH-2004 criteria (3). Five of eight criteria must be met to confirm HLH and prompt treatment initiation: fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia, tissue evidence of hemophagocytosis, low NK cell activity, and high soluble IL-2 receptor. However, in the adult population, particularly when Mal-HLH is suspected, these criteria can be quite nonspecific. Thus, I recommend also using the H-score, (4) a web-based tool developed on adult cases, when considering HLH in older patients with underlying malignancy.
Although lymphoma-directed therapy is the preferred strategy in patients with lymphoma-triggered HLH, a definitive histological diagnosis is often not immediately available. In these cases, waiting for a final diagnosis is not recommended; mortality can be quite high during the first days and HLH-directed therapy needs to be quickly initiated.
The regimen currently used is derived from the HLH-1994 trial (5) and includes corticosteroids, cyclosporine, intrathecal chemotherapy, and parenteral etoposide to suppress NK/T cell function and cytokine production. However, its use can be limited in adult patients, for reasons including comorbid health conditions and HLH-induced organ failure. Additionally, etoposide may be needed as part of a lymphoma-directed therapy; as such, its use while awaiting a final diagnosis may hinder effective anti-lymphoma treatment, because excessive etoposide use may result in prolonged and potentially life-threatening myelosuppression. In these cases, it is acceptable to start using corticosteroids only; however, if no improvement is observed within two to three days, consider a subsequent line of therapy. I recommend corticosteroids in combination with tocilizumab (based on IL-6’s role in HLH biology), rather than etoposide, for patients with lymphoma-triggered HLH awaiting initiation of anti-lymphoma treatment.
IFN-γ also plays a crucial role in the etiology of HLH. The US Food and Drug Administration (FDA) recently approved emapalumab, an anti-IFN-γ antibody, for the treatment of patients with refractory, recurrent, or progressive disease or intolerance to conventional HLH therapy (6). Albeit a fascinating treatment option for patients in whom etoposide is contraindicated, emapalumab’s use is currently limited by extremely high costs and lack of sufficiently robust data in patients with secondary HLH.
Stem cell transplant, a curative approach to pediatric HLH, is rarely used in adult Mal-HLH; typically, anticancer treatment resolves the condition and relapses are very infrequent. However, in young adult patients with HLH induced by EBV+ lymphoma, a genetic basis should be suspected. I recommend genetic counseling and evaluation for stem cell transplant in young patients with EBV-associated lymphoma to avoid risk of future recurrences.
Hodgkin lymphoma (HL) is responsible for about 6 percent of Mal-HLH cases – but exponentially more in the presence of EBV-associated HL. Advanced HL presenting with HLH has a high internal prognostic score (IPS) by definition and, as such, may benefit from aggressive treatment. Unfortunately, these patients typically present with organ dysfunction – including renal and hepatic impairment – making use of the standard HL regimen virtually impossible. In cases with organ dysfunction, I recommend initially treating patients with hyperfractionated cyclophosphamide, which is safe in patients with multi-organ failure and may result in significant lymphoma and HLH control. Once clinical stability is achieved, typically starting with cycle 2, more appropriate regimens can be instituted.
In conclusion, we recommend a low threshold of suspicion for HLH in patients with NK/T cell or EBV-associated lymphomas. If anti-lymphoma treatment cannot be immediately initiated, chemotherapy-free approaches, including corticosteroids and tocilizumab, should be considered. Once a final lymphoma diagnosis is obtained, hyperfractionated cyclophosphamide is a reasonable frontline option, whereas more standard regimens can be initiated with subsequent cycles. A better understanding of HLH biology in the adult population will hopefully spur the development of safer and more effective treatment strategies for these patients.
Read on to discover our other lymphoid cases...
Case 1: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma – Accelerated Phase
Case 3: High-Grade B Cell Lymphoma with Leukemic Presentation
Case 4: Low-Grade Follicular Lymphoma with Increased Proliferation Index
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- K Lehmberg et al., “Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents,2 Br J Haematol, 170, 539 (2015). PMID: 25940575.
- P La Rosée et al., “Recommendations for the management of hemophagocytic lymphohistiocytosis in adults,” Blood, 133, 2465 (2019). PMID: 30992265.
- JI Henter et al., “HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis,” Pediatr Blood Cancer, 48, 124 (2007). PMID: 16937360.
- L Fardet et al., “Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome,” Arthritis Rheumatol, 66, 2613 (2014). PMID: 24782338.
- JI Henter et al., “Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation,” Blood, 100, 2367 (2002). PMID: 12239144.
- AZ Cheloff et al., “Emapalumab for the treatment of hemophagocytic lymphohistiocytosis,” Drugs Today (Barc), 56, 439 (2020). PMID: 32648854.