Diagnostic significance of the histopathology of bone marrow macrophages in forensic autopsies

Forensic pathologists often encounter autopsies that require an assessment of antemortem general conditions (e.g., infection, metabolic disorders). To establish evaluation clues for such cases, we quantitatively examined macrophages and the general pathology of bone marrow in samples from 180 forensic autopsy cases of decedents with various conditions. Hematoxylin-eosin staining, Berlin blue staining, and immunostainings for CD163, CD138, and CD61 were performed. We determined the numbers per field (density) of total macrophages, swollen macrophages, macrophages with hemophagocytosis, and hemosiderin-laden macrophages. Each density was standardized by identifying its ratio to the total number of macrophages. The decedents' background data (cause of death, other pathological findings, postmortem interval, antemortem symptoms, and presence of resuscitation) were extracted. No correlations were found between the postmortem interval and the other decedent data, indicating that these data are not affected by postmortem changes. In the group in which inflammatory disease was the cause of death, there were significant elevations in the ratio of the swollen macrophage density to total macrophages. Significantly higher ratios of the density of swollen and hemophagocytic macrophages were observed in the group in which conditions with a prolonged agonal period were the cause of death. The group with a return of spontaneous circulation to resuscitation showed a significantly higher ratio of macrophage density with hemophagocytosis. This study provides the first statistical analysis focused on bone marrow histopathology in forensic autopsies. The results will be useful for elucidating causes of death and agonal-period conditions.     

Fatal unexpected death due to X-linked lymphoproliferative disease

X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency disease characterized by severe immune disorder and extreme vulnerability to Epstein-Barr virus (EBV) infections. Here we report a 14-month-old Chinese boy presenting with fulminant infectious mononucleosis (FIM) following EBV infection, and died of hepatic failure within one week of disease progression. Postmortem examination revealed icterus, ascites, extensive enlarged mesenteric lymph nodes and hepatosplenomegaly. Histopathological examination showed diffuse proliferation of cytotoxic T lymphoid cells and hemophagocytosis in multiple organs. The family history revealed his brother had died under similar circumstances at 5 five years of age. The cause of death of the boy was ascribed to XLP. To the best of our knowledge, there is few autopsy-confirmed XLP case in the forensic practice. The complicated manifestations and systemic pathological changes should be well recognized by clinicians and forensic pathologists.     

Accuracy of the criteria for hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis, also known as a hemophagocytic syndrome, is a life-threatening condition that can develop in critically ill patients with malignancies, severe infections, during chemotherapy, and may be associated with currently known or unknown genetic abnormalities; however, this list of potential causes can be extensive. The purpose of this study is to draw attention to the accuracy of its diagnostic criteria, association with a variety of clinical conditions, pathophysiological mechanisms, and outcomes of the diseases. From the medical records in our hospital, we retrospectively extracted 13 cases with hemophagocytosis over a 10-year period. Subsequently, we thoroughly analyzed medical records for the criteria used, the time required for making a diagnosis, adequacy of the criteria, management, and outcomes. We found that not all criteria were used for diagnosis, and the most sensitive and specific tests (genetic study, ferritin, and soluble IL-2r levels) were sometimes bypassed. Late diagnosis delayed management of some patients. Only a few treatment options were used for patient care. The hemophagocytic syndrome is a very rare and fatal entity requiring highly sensitive and specific diagnostic criteria for prompt diagnosis, targeted management, and thorough follow-up. Every patient admitted to the hospital with life-threatening conditions should be suspected and tested for the hemophagocytic syndrome as early as possible. The criteria for hemophagocytic lymphohistiocytosis should be revised, with the most sensitive and specific ones being done in all cases. Subsequently, each patient should be tested for the presence of genetic abnormalities that correlate with the syndrome.     

Histiocytic sarcoma of the spleen: case report of asymptomatic onset of thrombocytopenia and complex imaging features

Histiocytic sarcoma of the spleen, in which the malignant cells display morphologic and immunophenotypic features similar to those of mature tissue histiocytes, is a rare but potentially lethal condition that can remain asymptomatic or only mildly symptomatic for a long period of time. We studied a case of histiocytic sarcoma of the spleen in an 82-year-old woman with prolonged chronic thrombocytopenia that was non-responsive to steroid therapy. Ultrasonography, computed tomography, and magnetic resonance imaging showed a characteristically enlarged spleen and liver. Palliative irradiation therapy was clinically effective; however, disease progression proved lethal. Autopsy revealed the proliferation of tumor cells within the splenic sinus and the liver sinusoids, which displayed extreme hemophagocytosis and strong expression of the histiocytic markers CD68 (KP1 and PG-M1) and CD163. The postmortem diagnosis showed histiocytic sarcoma of the spleen with liver infiltration. This and previous reports indicate that early detection (facilitated by imaging and clinical features) and management may improve patient prognosis and survival. Histiocytic sarcoma of the spleen should be considered as a differential diagnosis in therapeutically unresponsive patients with chronic thrombocytopenia.     

Macrophage activation syndrome complicating adult onset Still’s disease: A single center case series and comparison with literature

ObjectivesMacrophage activation syndrome (MAS) is a life-threatening condition that can complicate adult onset Still’s disease (AOSD). Due to its rarity, there is no clear consensus concerning treatment recommendations and outcomes. We studied the clinical manifestations and outcomes of a relatively large cohort of patients with MAS and AOSD, and compared the data with the literature reports.MethodsWe performed a retrospective review of 7 adult patients with MAS complicating AOSD at the Cleveland Clinic (CCF) over 7 years. All patients underwent bone marrow biopsies. Through MEDLINE and PubMed literature searches, we identified 48 cases of MAS/AOSD. We compared the data of the CCF and literature cohorts.ResultsWe identified 7 patients with MAS complicating AOSD (6 females and 1 males) for our CCF cohort, with 4 cases simultaneously presenting with MAS and AOSD. The mean age at diagnosis of MAS was 41.9 ± 20.2 years and mean follow-up time was 18.6 ± 16.0 months. All patients had fever, arthralgias, and typical rash; 6 had leukocytosis, 4 had sore throat, and 3 had lymphadenopathy. These patients with AOSD also had MAS, with renal insufficiency and disseminated intravascular coagulation in 4, lung involvement in 3, and serositis and shock in 2. There was significant hepatic dysfunction in all patients and 6 had bi-cytopenias. At onset of MAS, all 7 patients had active AOSD. In addition to systemic glucocorticoids, 5 patients received anakinra, with 3 patients receiving combination therapy with cyclosporine. We also identified 48 cases (35 females and 13 males) for the literature cohort with the mean age at diagnosis of MAS of 40.2 ± 16.0 years and mean follow-up time of 17.5 ± 32.3 months. While the 2 cohorts were similar clinically, in the CCF cohort, more patients had renal insufficiency (p < 0.001), higher soluble IL-2 receptor level (p = 0.01), and lower ESR (p = 0.02) as compared with the literature cohort. All of our patients survived with a better outcome than the literature cohort.ConclusionMAS can be a serious complication of active AOSD. Our study of a relatively large cohort in conjunction with literature suggests that prompt recognition and treatment with early addition of anakinra, systemic glucocorticoids, and cyclosporine as a triple regimen may improve clinical outcomes.     

噬血细胞综合征患儿的临床诊断与骨髓细胞学特点分析

目的探讨儿童噬血细胞综合征的临床诊断标准及其骨髓细胞学检查结果对于临床诊断的意义。方法回顾分析2008年5月-2011年5月于我院确诊为噬血细胞综合征的22例患儿的病历资料及骨髓细胞学特点。结果 22例患儿均符合国际组织细胞协会HLH-2004方案诊断标准。均有发热、脾大及血清铁蛋白增高,18/22例(82%)伴外周血至少两系减低,15/19例(79%)伴低纤维蛋白原血症,14/20例(70%)伴高三酰甘油血症,14/22例(64%)患儿在初诊时骨髓中找到噬血细胞。结论骨髓涂片见到噬血细胞不是儿童噬血细胞综合征临床诊断的必备条件,初诊时进行骨髓细胞学检查有助于噬血细胞综合征的诊断与鉴别诊断,在治疗过程中复查骨髓有助于指导治疗。     

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH VISCERAL LEISHMANIASIS

A 2-year-old child presented with fever and hepatosplenomegaly. Laboratory findings showed pancytopenia, hypertriglyceridemia, hyperferritinemia, and high levels of soluble-IL2 receptors. Initial bone marrow aspiration and biopsy revealed mild hemophagocytosis. A diagnosis of hemophagocytic lymphohistiocytosis was made and appropriate treatment was begun. Repeated marrow aspiration performed because of lack of clinical response revealed Leishmania amastigotes in macrophages in addition to active hemophagocytosis. Treatment with liposomal amphotericin resulted with rapid recovery. Visceral leishmaniasis should be considered in the differential diagnosis of hemophagocytic syndrome.     

Familial hemophagocytic lymphohistiocytosis associated with disseminated T-cell lymphoma: A report of two siblings

Summary Two siblings with evidence of disseminated T-cell lymphoma at the time of diagnosis of familial hemophagocytic lymphohistiocytosis (FHL) are reported, an association which has not been described previously. The first child with typical clinical and laboratory features of FHL died shortly after admission, before diagnosis could be established. Retrospective analysis of autoptic tissue revealed marked hemophagocytosis as well as morphological and immunohistochemical features suggestive of disseminated T-cell lymphoma. In the second child, FHL was diagnosed in time. Subsequent histologic investigation of bone marrow biopsies displayed a focal infiltration by T-cell lymphoma. DNA hybridization studies provided evidence of a monoclonal T-cell receptor beta chain gene rearrangement. Following conventional chemotherapeutic induction for FHL, the patient received an allogeneic bone marrow transplant (BMT) from a related healthy donor. Currently, 17 months after BMT, the boy is in unmaintained remission from FHL and T-cell lymphoma. The current pathogenetic concepts for FHL and a possible relationship between T-cell lymphoma and FHL are discussed.