Between a rock and a hard place
Authors: Natalia Suvorava, Steven Richmond, Neil Patel, Brian Bell, Hector Mesa
Journal: American Journal of Hematology (2015)

A 60 year old male consulted the outpatient clinic for progressively worsening right shoulder pain over the last few months, lightheadedness, and intermittent shortness of breath. He also complained of loss of balance with multiple falls in the past few weeks. He denied fever, chills, rigors, night-sweats, hematochezia, melena, or recent illness. Significant past medical history included localized diffuse large B cell lymphoma (DLBCL) of the forehead skin 4 years prior, for which he was treated with 5 of 6 cycles of rituximab, cyclophosphamide, adriamycin, vincristine and prednisone chemotherapy, bipolar disorder, a 50 pack-year smoking history, and alcohol consumption of 12 beers 4–5 times/week. The initial presentation does not raise concern for an acute illness, and is most consistent with a smoldering, progressive process with possible neurologic manifestations. The anamnesis raises the possibility of alcohol abuse related disease and/or malignancy potentially due to relapsed hematological disease or related to tobacco abuse. Physical examination showed overall good general conditions, the patient's weight did not show change compared to previous records (BMI 27.1), there was hepatosplenomegaly, 3 and 2 cm below the respective costal margins, and limited range of motion of the right shoulder. The rest of the physical was normal. The initial neurological exam was normal. Complete blood count at presentation showed normal white cell and differential counts, severe anemia and moderate thrombocytopenia: Hg 5.9 g/dL, WBC 7.2 K/uL, PLT 70 K/uL. The presence of joint pain, severe bicytopenia, organomegaly and neurologic symptoms raises the differential of alcohol induced hepatitis and alcohol toxicity derived symptoms, malnutrition, Still's disease, coagulopathy, and malignancy, especially hematolymphoid neoplasms. All these conditions warrant a hospital admission. The patient was admitted and received blood transfusions. Additional blood chemistry showed slightly abnormal liver function tests: aspartate aminotransferase 45 U/L, alanine aminotransferase 26 U/L, Gamma- glutamyl transferase 169 U/L, total bilirubin: 1.2 mg/dL, direct bilirubin 0.4 mg/dL; nutritional studies showed a normal B12, folate and zinc; the iron panel showed severe hyperferritinemia: 1,388.7 ng/mL, hemolysis panel showed a high LDH 746 U/L, undetectable haptoglobin < 7.8 mg/dL, normal plasma free hemoglobin and negative direct antibody test. Electrolytes, creatinine, coagulation studies, thyroid function tests were normal. Imaging studies showed superior subluxation of the humeral head as the cause for the shoulder pain, but also showed a significant increase in splenic size (16 x 7cm) compared to a previous study 4 years ago. There was no evidence of masses or lymphadenopathy. Acute alcoholic hepatitis and nutritional deficiencies can be excluded. The studies are suggestive of hemolysis, however the normal plasma hemoglobin and relatively low bilirubin are neither proportional to the degree of anemia nor consistent with significant hemolytic activity, and favor alcohol related chronic liver disease as an explanation for these results. A peripheral smear was requested to assess for hemolysis and/or coagulopathy; the smear showed a leukoerythroblastic reaction, hemophagocytic activity (Fig. 1A) and very rare atypical lymphoid cells. The findings prompted a flow cytometry study that showed decreased B-cells (1%) and no evidence of clonal populations. A. Peripheral blood hemophagocytosis (wright & giemsa, 100×). B. PET/CT showing enlarged hypermetabolic spleen. C. Spleen laceration at autopsy. D. Spleen microscopy: left panels show large pleomorphic lymphoid cells (up: cytology, wright & giemsa, 100×; low: sections, hematoxylin & eosin, 100×). Upper right: CD20 immunostain demonstrates B-cell lineage (40×); lower right: Ki-67 immunostain shows a high proliferative rate (20×). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The presence of hemophagocytic activity in the peripheral blood is very unusual; the combination of hemophagocytosis, severe cytopenias, liver function abnormalities and hyperferritinemia are virtually diagnostic of hemophagocytic lymphohistiocytosis (HLH). The presence of HLH, a leukoerythroblastic reaction and rare atypical lymphoid cells are highly suggestive of bone marrow involvement by a lymphoma or a viral infection. A bone marrow biopsy performed the next day showed hemophagocytosis, histiocytic hyperplasia and very rare atypical B-cells apparent only on immunohistochemical stains, insufficient for diagnosis of lymphoma. Epstein Barr virus, cytomegalovirus and herpes virus immunostains were negative. Viral serologies were negative for Parvovirus B19, EBV, HSV, HIV. CMV IgG was positive with negative IgM. Blood, viral and fungal cultures were negative. Flow cytometry analysis was negative. Additional studies obtained in the course of a week included cerebrospinal fluid (CSF) tap, magnetic resonance imaging (MRI) of the brain, positron emission/computerized tomography scan (PET/CT), microbiology studies (bacterial, viral, fungal, mycobacterial), flow cytometry of CSF and autoimmune panel. Abnormal results included reactive lymphocytic pleocytosis of CSF, abnormal enhancement in the deep white matter of the right anterior frontal region, metabolically active lesions within the C1-C2 spinal cord and diffuse hypermetabolic activity of the enlarged spleen (Fig. 1B). The overall findings are most consistent with malignancy associated HLH. Although a lymphoma is very likely based on all the studies, a tissue diagnosis is necessary for classification and initiation of chemotherapy. The presence of lesions in the central nervous system (CNS) raises the possibility of CNS involvement by either lymphoma or HLH. The patient was started on dexamethasone 20mg daily as outlined by HLH-2004 protocol (ClinicalTrials.gov Identifier: NCT00426101), however etoposide was held awaiting specific chemotherapy for presumed lymphoma. The patient developed postural instability and loss of righting reflex, and intrathecal methotrexate with hydrocortisone were administered for presumed CNS involvement by HLH or lymphoma, without complications. Possible additional diagnostic interventions for confirmation of the presumed lymphoma were discussed; an image-guided percutaneous biopsy of the spleen was considered to be the procedure with the highest diagnostic yield. After discussing the potential risks, patient consent was obtained. An ultrasound (US) guided percutaneous biopsy using an 18 gauge needle was performed, followed by a gelfoam injection into the needle tract. Intraoperative pathology assistance confirmed the presence of diagnostic material after the first pass. Immediately after the biopsy was taken, the patient experienced severe abdominal pain and hemodynamic instability. The patient responded to initial fluid management and was transferred to the CT scanner to evaluate for splenic injury, whereupon he developed pulseless electrical activity and died despite resuscitation efforts. Consent for autopsy was obtained. Autopsy revealed a large iatrogenic splenic laceration: 5 cm on the surface, 7 cm deep (Fig. 1C), with massive intra-abdominal hemorrhage. DLBCL was present in the spleen (Fig. 1D), liver, iliac and sub-carinal lymph nodes, cervical spine, left deep gray nuclei and right frontal cortex. Extensive hemophagocytic activity was present in the liver, spleen and bone marrow. All procedures were performed in compliance with institutional guidelines (Veterans Health Administration handbook 1200.05). HLH is a syndrome caused by hypercytokinemia and hyperactivation of the macrophage system, associated with abnormal cytotoxic T-cell (cTC) and natural killer (NK) cell function, leading to hemophagocytosis induced severe cytopenias, abnormal liver function and progressive multi-organ failure 1. The syndrome was originally described as a hereditary autosomal recessive disorder affecting infants with an incidence of < 1–1.2/100,000 births (familial HLH). The mutations identified to date lead to abnormalities in the perforin cytotoxic pathway causing decreased function of NK- and/or cTC, indicating a pivotal role of this event in the pathogenesis of HLH 2. Recently, there have been increasing reports of adult onset HLH in the context of conditions associated with immune dysregulation: hematologic malignancies, infections, autoimmune diseases, organ/stem cell transplants and chemo- or immunosuppressive therapies 3-7. Some of the cases affecting young adults represent attenuated familial forms of the disease due to partial loss of function of the HLH-causing genes 8, while in older adults (>60 yr.) malignancy associated HLH is most common. The precarious balance between timely diagnosis and treatment of rapidly progressive, highly lethal diseases and diagnostic and/or therapeutic procedures with their inherent risks, sometimes puts providers “between a rock and a hard place”. HLH is almost invariably fatal without treatment, and has a high fatality rate even when adequately treated 4, 5. The highest chance of therapeutic success is early diagnosis and identification of a treatable trigger condition. HLH diagnosis is difficult and requires a high level of clinical suspicion 3. Consensus guidelines have helped increase the recognition of this rare entity 3-5. Peripheral blood hemophagocytosis is very rare, having been described only in a handful of case reports 9-13, always associated with HLH. Its presence allows an early recognition of this syndrome. A broad diagnostic work-up directed towards the most common triggers of HLH in adults (malignancy, infection, autoimmune) was done. The history of lymphoma, age of the patient, rare atypical cells in the bone marrow biopsy and hypermetabolic enlarged spleen on PET-CT were highly suggestive of either a de novo or relapsed splenic lymphoma, however a definitive tissue diagnosis, which is required for initiation and selection of the chemotherapy regimen was lacking. The progression of the neurologic symptoms has been reported to portend a poor prognosis 14, and prompted the initiation of systemic and intrathecal therapy for HLH. CNS involvement by HLH is common (∼50%) and the manifestations are varied, so that any neurologic, radiologic or CSF abnormalities are considered evidence of involvement until proven otherwise. In our case, autopsy showed that the CNS abnormalities were in fact secondary to DLBCL. There is currently no standard treatment for adult HLH. Current guidelines are based on the pediatric protocol HLH-1994 15 that uses a combination of etoposide and steroids, plus specific therapy for the underlying trigger. Confronted with this grim clinical scenario, numerous failed diagnostic studies and radiologic evidence of splenic and CNS lesions, it was decided to proceed with an US guided percutaneous spleen biopsy. Percutaneous spleen biopsy has historically been regarded as a high risk procedure due to the soft consistence, highly vascularized & stroma-poor composition of this organ. However, recent use of smaller gauge needles (18–20) and the possibility of performing ancillary studies on cytology and small biopsies has enabled performing either fine needle aspiration (FNA) or core needle biopsies (CNB) with high diagnostic yield, and complication rates comparable to other solid organs: spleen: <1-3% vs. liver <1–3% vs. kidney <1–6.3% 16, 17; this procedure is now considered preferable to diagnostic splenectomy and performed routinely in several institutions including ours. The most common indication for biopsy is suspected lymphoma, sensitivity and specificity are 87% and 96%, respectively, and the most common major complication is hemorrhage 16-19. At autopsy we found that despite using a small gauge needle and a single pass, the spleen showed a large laceration (5 cm on the surface × 7 cm deep). Pathologic examination of the spleen showed near complete effacement of the spleen by a non-germinal center, EBV-negative, c-MYC and BCL2 rearrangement negative diffuse large B-cell lymphoma with a Ki-67 proliferation rate of ∼100%. PET-CT showed markedly increased splenic captation with a standard uptake value of 4.9. We think that the high proliferative rate of the lesion led to a rapid enlargement of the spleen and rapid stretching of the capsule, resulting in high surface tension that caused the spleen to burst like a fluid-filled balloon upon penetration with the needle. Literature available on splenic US-FNA/US-CNB does not address differences in focal vs. diffuse splenic lesions, or slow vs. rapid enlargement of the spleen, or low vs. high metabolic activity on PET-CT. Intuitively, focal lesions and chronic, slowly progressing causes of diffuse splenomegaly should be associated with lower surface capsular tension, and thus result in lower risk of rupture. Lesions leading to rapid enlargement of the spleen are probably associated with higher surface capsular tension and at higher risk of iatrogenic rupture, as illustrated by our case; in these cases diagnostic splenectomy may be a safer option. Studies on this specific subject are however lacking. HLH in adults is most commonly associated with malignancy; treatment of the malignancy has the highest probability of resolution of HLH. Peripheral blood hemophagocytosis is an unusual but reliable indicator of HLH that allows early diagnosis. Percutaneous biopsy of the spleen is an established diagnostic modality with high diagnostic accuracy and complication rates similar to other solid organs. Splenic biopsy in the context of rapidly progressing splenomegaly may be associated with higher risk of major complications than focal lesions or conditions leading to chronic splenomegaly.