04.10.2024

Gray platelet syndrome mimicking atypical autoimmune lymphoproliferative syndrome: the key is in the blood smear

A 50-year-old African man with well-controlled HIV infection presented with constitutional symptoms, progressive multiorgan failure, and raised inflammatory markers. He had a history of Kaposi sarcoma. An infective etiology was excluded.

He had a rising white cell count and the blood film (panels A-B; May-Grünwald Giemsa stain; original magnification ×20 A and ×40 B) showed large cells with abundant, basophilic cytoplasm, irregular nuclei, and prominent nucleoli.

Two siblings of a consanguineous family, were referred due to thrombocytopenia (in the range of 30 × 103 to 80 × 103/µl), recurrent infections, and hepatosplenomegaly with a working diagnosis of atypical autoimmune lymphoproliferative syndrome (ALPS).

The workup revealed elevated levels of vitamin B12, soluble-FAS ligand, and interleukin-10; immunoglobulin G levels and CD4/CD8 double-negative T-cell counts were normal. Bone marrow biopsy revealed reticular fibrosis grade II-III. In the blood smear, large and pale platelets were observed, compatible with the diagnosis of gray platelet syndrome (GPS) (panels A-C; arrows, abnormal platelets; original magnification ×50 A and ×100 B-C; May-Grünwald Giemsa stain). Targeted next-generation sequencing for genes related to thrombocytopenia revealed homozygosity for a splice-site variation, c.7225-1G>C, in the NBEAL2 gene, causing GPS. Sanger sequencing confirmed this finding in both siblings; both parents were found heterozygous for the mutation.

GPS is an autosomal recessive disorder, caused by defects in the α-granules and characterized by large and pale platelets. Patients with GPS present with bleeding diathesis and a tendency to develop myelofibrosis that can also cause splenomegaly. A previous report included 6 patients initially suspected to have ALPS who were eventually diagnosed with GPS. It is unclear how the platelet granule defects cause elevated cytokine levels. We conclude that a blood smear should be examined for every patient suspected of having ALPS or ALPS atypical to rule out GPS.

Immunophenotyping of the peripheral blood confirmed these cells to be λ-restricted plasma cells. Bone marrow biopsy demonstrated the same clonal plasma cells (panels C,E; May-Grünwald Giemsa stain, original magnification ×60 C; CD138 stain, original magnification ×20 E) and the presence of hemophagocytosis (panel D; May-Grünwald Giemsa stain; original magnification ×60). The main differential diagnoses were myeloma plasma cell or plasmablastic lymphoma, with the latter favored in the context of HIV infection. A positron emission tomography computed tomography scan showed mild splenomegaly but no lymphadenopathy or effusions.

Subsequent results revealed a human herpesvirus 8 (HHV8) viremia of 70 million copies/mL, Kaposi sarcoma in the skin, and occasional HHV8+ cell in the trephine (panel F; HHV8 stain; original magnification ×40). Testing for Epstein-Barr virus was negative. The diagnosis was therefore revised to an HHV8-associated lymphoproliferative disorder, most likely multicentric Castleman disease. He was treated with 4 doses of rituximab and had a full clinical response. Castleman disease is known to involve the blood and bone marrow, but is only rarely seen without lymphadenopathy.

A previously healthy 3-year-old Syrian boy presented with fever and pancytopenia with 6% circulating lymphoblastlike cells (blastlike cell panel A as compared with a normal lymphocyte panel B; original magnification ×1000, Wright-Giemsa stain). There were no skin lesions. A younger sister died a few months earlier of unknown causes. The boy was suspected of having acute leukemia. Bone marrow examination with flow cytometry phenotyping showed no evidence of acute leukemia; however, Leishmania amastigotes were identified in the aspirate (panel C, numerous Donovan bodies in bone marrow aspirate; original magnification ×1000, Wright-Giemsa stain), and biopsy (panel D, numerous Donovan bodies in bone marrow biopsy; original magnification ×400, hematoxylin and eosin stain), diagnostic of leishmaniasis.

The amastigotes showed a relatively large nucleus and the characteristic deeply stained rodlike kinetoplast. Polymerase chain reaction confirmed the pathogen as Leishmania infantum.

Visceral leishmaniasis (VL) is an opportunistic life-threatening infection that usually occurs in regions of endemicity and in immunocompromised hosts. This young patient came from a region where cutaneous leishmaniasis is endemic. VL is not common, and the boy had no immunodeficiency. VL can be encountered in areas where it is not endemic and, as in this case, can clinically mimic other diseases, such as acute leukemia.

A 52-year-old man with untreated hepatitis C presented to the hospital with cough and shortness of breath. The examination was notable for ≥3 pitting edema, and cross-sectional imaging showed pleural effusions and ascites. Laboratory findings revealed a hemoglobin of 7.6 g/dL, creatinine 2.2 mg/dL, total protein 6.2 g/dL, albumin <1.5 g/dL and an immunoglobulin M monoclonal paraprotein of 1940 mg/dL. Hepatitis C quantitation by polymerase chain reaction was >11 million IU/mL; bone marrow biopsy identified B-cell lymphoma with plasmacytic differentiation (MYD88 mutation negative). The patient then developed a rash of dusky violaceous plaques and macules.

Out of concern for cryoglobulinemia, rheumatoid factor was checked and found to be elevated at >6000 IU/mL with an elevated cryocrit of 7% consistent with the diagnosis. A peripheral smear at room temperature was notable for distorted red cells, morphologically tagged mimicking acanthocytes and schistocytes (Wright stain; original magnification ×1000). Haptoglobin, lactate dehydrogenase, fibrinogen and routine coagulation tests were normal. At a different light refraction, smear revealed a marked background of cryoprecipitate (inset, arrows; Wright stain; original magnification ×1000), depositing on and deforming the red blood cell (RBC) membrane.

This case illustrates the bizarre RBC morphologic changes in the presence of cryoglobulinemia with smear findings that raise concern for intravascular hemolysis. The patient’s available historical data, including a normal complete blood cell count and spleen size, make structural hereditary RBC disorders is a highly unlikely cause of these findings.

A 43-year-old woman was admitted with chronic pelvic pain and unexplained fever. Her laboratory findings were notable for anemia (hemoglobin, 10.6 g/dL). No masses were detected by pelvic ultrasound. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Large atypical lymphocytes were noted within the vascular lumina of the cervix, endomyometrium, bilateral fallopian tubes, and ovaries (panels A-B; hematoxylin and eosin stain, original magnification ×40 A and ×200 B). They were positive for CD20, CD5, CD10, BCL-2 (panel C; original magnification ×40), and MYC (panel D; original magnification ×200) immunohistochemical stains. MYC was expressed in 40% to 50% of the lymphoma cells. The KI-67 (MIB-1) proliferation rate was 90%. The patient was diagnosed with intravascular large B-cell lymphoma, with the double expression of BCL-2 and MYC.

Fluorescent in situ hybridization showed gain of 1 copy of the MYC gene. BCL-2 and MYC rearrangements were not detected. She had minimal bone marrow involvement (<5%). Lactate dehydrogenase was elevated at 1652 U/L (normal, 300-600 U/L). She received 6 cycles of rituximab, etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin) (R-EPOCH) and prophylactic intrathecal methotrexate followed by an autologous stem cell transplant and has achieved complete remission.

Intravascular lymphomas are uncommon and carry a poor prognosis. Uterine involvement is rare and is manifested as vaginal bleeding and/or fever. MYC and BCL-2 protein coexpression in diffuse large B-cell lymphomas are associated with inferior survival and central nervous system relapse; however, their prognostic relevance in intravascular lymphomas is unclear.

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