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We report a case of hemophagocytic lymphohistiocytosis (HLH) in which the histologic features of “bean bag cells” found in the skin biopsy specimen facilitated the diagnosis of this rare disorder.
A 15-year-old previously healthy boy presented with fever, nausea, and right upper quadrant abdominal pain, all of 1 week’s duration. He was found to have thrombocytopenia and leukopenia.
Magnetic resonance imaging and computed tomography (CT) scans showed multiple focal enhancing lesions throughout the lungs, kidneys, and liver. Subsequent positron emission tomography–CT scans revealed abnormal foci of increased uptake in the bone marrow, mandible, scapulae, ribs, pelvis, liver, lung, and kidneys (Figure 1A). Levels of lactate dehydrogenase, alkaline phosphatase, aspartate transaminase, direct bilirubin, triglycerides, ferritin, and D-dimer were elevated. The fibrinogen level was low. Findings for hepatitis A, B, and C, Epstein-Barr virus, coccidioidomycosis, cytomegalovirus, and human immunodeficiency virus were negative. Likewise, findings of viral respiratory panel, aspergillus galactomannan enzyme immunoassay, blood cultures, and bacterial, mycobacterial, and fungal tissue cultures were all negative.
A, The initial PET-CT scan reveals abnormal foci of increased uptake in the bone marrow, mandible, scapulae, ribs, and pelvis, and diffuse uptake in the liver, lung, and kidneys. B, The PET-CT scan 3 months after admission reveals resolution of pulmonary, bone, and hepatic lesions.
Within 1 week of admission, the patient developed multiple, asymptomatic, round pink papules and plaques measuring 0.5 to 1.5 cm over the back, arm, shoulder, chest, cutaneous upper lip, and abdomen (Figure 2). Biopsy of a plaque on the chest demonstrated a superficial and deep perivascular and perineural infiltrate of histiocytes and lymphocytes extending to the subcutis and vacuolar interface alteration (Figure 3A). Histiocytes exhibiting hemophagocytosis, known as bean bag cells, were found (Figure 3B). Findings from periodic acid–Schiff–diastase, Grocott–methenamine silver, Gram, and Fite stainings were negative.
A, Right upper back with a pink plaque with overlying subtle scale. B, Left upper cutaneous lip with a pink papule and plaque without scale.
A and B, Superficial and deep perivascular and perineural infiltrate of histiocytes and lymphocytes extending to the subcutis and vacuolar interface dermatitis without substantial epidermal alteration. B, At higher magnification, the “bean bag cells” characteristic of hemophagocytosis are apparent.
In the setting of pancytopenia and fluorodeoxyglucose avidity in the bone marrow, a biopsy was performed, which demonstrated a hypocellular marrow, scattered foci of clusters of histiocytes, increased interstitial T cells, decreased iron stores, and a mild increase in reticulin fibrosis. Liver biopsy demonstrated Kupffer cells. Skin biopsy together with bone marrow and liver biopsies and clinical laboratory data led to a diagnosis of HLH.
The HLH-94 protocol was used as a treatment guideline,1 and dexamethasone and etoposide therapy were initiated. Additional blood tests revealed elevated levels of soluble interleukin (IL)-2 receptor (sIL-2r) and neopterin, supporting a diagnosis of HLH. Three months after diagnosis, a repeat PET-CT scan demonstrated resolution of pulmonary, bone, and hepatic lesions (Figure 1B).
Hemophagocytic lymphohistiocytosis is a rare, potentially life-threatening condition in which immune activation, of macrophages in particular, is unregulated and there is excess production of proinflammatory cytokines including IL-6, IL-10, and interferon (IFN)-γ.2 Elevated neopterin levels are produced by monocytes and macrophages on stimulation of IFN- γ. If left untreated, HLH carries a median estimated survival of less than 2 months.2
The 8 diagnostic criteria for HLH are as follows: (1) fever (>38.5°C); (2) elevated ferritin level (>500 ng/mL); (3) elevated fasting triglycerides level (>265 mg/dL) or low fibrinogen level (<150 mg/dL); (4) cytopenia (involving >2 of 3 lineages in peripheral blood); (5) splenomegaly; (6) absent or low natural killer cell activity; (7) hemophagocytosis in the spleen, bone marrow, or lymph nodes without malignancy; and (8) increased level of soluble CD25, also known as sIL-2R (>2500 U/mL).1 (To convert ferritin to picomoles per liter, multiply by 2.247; triglycerides to millimoles per liter, multiply by 0.0113; fibrinogen to micromoles per liter, by 0.0294.) The diagnosis is made when a patient meets 5 of the 8 characteristics or there is a molecular defect consistent with HLH.2 The present patient met 7 of the 8 criteria. Treatment, which focuses on impeding the immune response and downgrading cell proliferation, includes systemic glucocorticoids, etoposide, cyclosporine, intravenous immunoglobulin, methotrexate, and cyclophosphamide.2
Cutaneous findings are not one of the diagnostic criteria for HLH. Our case demonstrates that skin biopsy may be specifically helpful in diagnosis if hemophagocytosis is demonstrated. Cutaneous manifestations are varied and occur in 6% to 65% of cases.3 The patient presented with discrete erythematous superficial papules and plaques, which to our knowledge have not been described in previously reported cases. Histologic features reported for skin lesions in HLH are variable, but cutaneous hemophagocytosis has only been reported by Smith et al,4 and all of those cases were associated with deep lymphoid infiltrates (ie, cytophagic histiocytic panniculitis).4 To our knowledge, the current case is one of few to describe hemophagocytosis found on histopathologic analysis in the absence of primary panniculitis.4-6 Typically, bone marrow or liver biopsy demonstrates key histopathological features of HLH: phagocytosis of hematopoietic cells by activated macrophages.
In the present case, the cutaneous findings of HLH were crucial in making a prompt diagnosis. Inclusion of cutaneous findings should be considered in the diagnostic criteria because they may be helpful in the expedited diagnosis of HLH.
Corresponding Author: Victoria R. Sharon, MD, DTMH, Department of Dermatology, University of California–Davis, 3301 C St, Ste 1400, Sacramento, CA 95816 (firstname.lastname@example.org).
Published Online: May 18, 2016. doi:10.1001/jamadermatol.2016.0978.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This case was presented at the 52nd Annual Meeting of the American Society of Dermatopathology; October 8, 2015; San Francisco, California.
Additional Contributions: We thank the patient and his parents for granting permission to publish this information.
Millsop JW, Ho B, Kiuru M, Fung MA, Sharon VR. Cutaneous Hemophagocytic Lymphohistiocytosis: Bean Bags From the Bone. JAMA Dermatol. 2016;152(8):950–952. doi:10.1001/jamadermatol.2016.0978
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