Primary splenic histiocytic sarcoma complicated with prolonged idiopathic thrombocytopenia and secondary bone marrow involvement: a unique surgical case presenting with splenomegaly but non-nodular lesions
© Yamada et al.; licensee BioMed Central Ltd. 2012
Received: 25 September 2012
Accepted: 12 October 2012
Published: 17 October 2012
A 67-year-old Japanese female was followed up due to prolonged idiopathic thrombocytopenia with non-response to steroid therapy for 4 years, but recent progressive pancytopenia, hypo-albuminemia, and hypo-γ-globulinemia were presented. An abdominal CT scan revealed heterogeneously enhanced splenomegaly without any nodular lesions. A splenectomy was performed, and gross examination showed markedly hyperemic red pulp, weighing 760 g, accompanied by multiple foci of peripheral anemic infarction. Surprisingly, microscopic findings exhibited a diffuse proliferation of medium-sized to large tumor cells having pleomorphic nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm, predominantly within the sinuses and cords of the red pulp, which occasionally displayed conspicuous hemophagocytosis and vascular permeation. In immunohistochemistry, these atypical cells were specifically positive for CD68 (KP-1), CD163, and lysozyme, which was consistent with histiocytic sarcoma (HS) of the spleen. Subsequently, section from the aspiration of bone marrow showed infiltration of the neoplastic cells associated with erythrophagocytosis 2 months after the operation, but never before it. Therefore, primary splenic HS presenting with secondary bone marrow involvement was conclusively diagnosed. Since early diagnosis and treatment are necessary for the HS patients with poor outcomes, splenic HS should be considered as a differential diagnosis in cases with chronic thrombocytopenia and splenomegaly.
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KeywordsThrombocytopenia Spleen Splenomegaly Histocytic sarcoma (HS) Hemophagocytosis
Comparison of the main clinical features among the reported cases with primary splenic HS, including ours
Imaging or Gross features
Weight of spleen
Indeed, this is not the first case reported. Despite that, we reported a very rare and unique surgical case of primary splenic HS complicated with prolonged idiopathic thrombocytopenia, progressive pancytopenia, hypo-albuminemia, hypo-γ-globulinemia, and secondary bone marrow involvement, which grossly presented as splenomegaly with multiple peripheral infarction but without any nodular foci.
Materials and methods
The patient was a 67-year-old Japanese female. The specimen after fixation in 10% neutral buffered formalin was embedded in paraffin for histological or immunohistochemical examinations. All immunohistochemical stainings were carried out using Dako Envision kit (Dako Cytomation Co., Glostrup, Denmark) according to the manufacturer’s instructions, and using commercially available prediluted monoclonal antibodies against the following antigens: CD1a (Immuno Tech. Co., Ltd., Osaka, Japan, diluted 1:2), CD3 (Dako, diluted 1:1), CD4 (Dako, diluted 1:1), CD5 (NOVOCASTRA laboratories Ltd., Newcastle, United Kingdom, diluted 1:25), CD8 (Nichirei Biosciences Inc., Tokyo, Japan, diluted 1:1), CD10 (NOVOCASTRA, diluted 1:20), CD20 (Dako, diluted 1:200), CD21 (Dako, diluted 1:10), CD23 (Nichirei, diluted 1:1), CD30 (Dako, diluted 1:40), CD45 (Dako, diluted 1:400), CD45RO (UCHL-1; Dako, diluted 1:200), CD68 (KP-1; Dako, diluted 1:100), CD79a (Dako, diluted 1:50), CD163 (Leica Microsystems, Wetzlar, Germany, diluted 1:200), lysozyme (Dako, diluted 1:600), S-100 protein (Dako, diluted 1:900), fascin (Dako, diluted 1:50), bcl-2 (Dako, diluted 1:30), myeloperoxidase (MPO; Dako, dilutede 1:500), EMA (Dako, diluted 1:100), Cam5.2 (Becton Dickinson Immunocytometry Systems, San Jose, CA, diluted 1:1), and HMB45 (Enzo Life Sciences Ltd., New York, diluted 1:100). Epstein-Barr virus (EBV) infection status was analyzed by in situ hybridization for EBV-encoded RNAs using an Epstein-Barr Early RNA Probe Reagent (EBER; Roche Applied Science, Lewes, UK). However, no chromosome studies have been performed.
Before the operation, the clinician and we pathologists had performed and examined bone marrow aspiration 5 times for 2 and half years (September in 2009, September and December in 2010, December in 2011, and January in 2012), histologically showing the tissues of normo- to hyper-cellular marrow (cellularity: 50-70%) composed of 3 series of hematopoietic cells with a mildly increasing number of bland-looking megakaryocytes (4-8/1HPF). There was no evidence of monotonous proliferation of atypical or blastoid cells in the bone marrow specimens (not shown).
Immunohistochemical profile of the tumor cells in our splenic HS case
It is possible that the current case report might be pathologically remarkable for two reasons at least: first, neither nodular formation nor fibrous encapsulation was evident in the tissue of spleen appearing as splenomegaly. According to the several case reports of primary HS of the spleen as summarized in Table 1, all tumors have macroscopically exhibited nodular or multi-nodular lesions with or without fibrous encapsulation, composed of a diffuse proliferation of HS cells predominantly in a sinusoidal pattern within the red pulp , very similar to our case. However, this case showed that the existing splenic tissue was significantly small and compressed, inducing these characteristic imaging and gross features (Figures 1 and 2), possibly compared to the other splenic HS cases [10–14]. Although we cannot provide the direct evidence that the present splenic HS shows only splenomegaly, future studies will be further required to determine how its mechanism has a role in the tumor growth after collecting and examining a larger number of splenic HS cases. Second, multiple foci of peripheral anemic infarction coexisted. It is well known that vascular invasion is a common finding in high grade malignancies, frequently associated with thrombosis and ischemia, i.e., ischemic necrosis (infarction). In spite of that, merely one splenic HS case has demonstrated relatively large necrosis due to an infarction of the splenic artery , as likely shown in Figure 3. As described here (Table 1), splenic HS has an extensively aggressive behavior with vessel permeation and a poor prognosis, regardless of the localized site of tumor origin. Actually, another autopsy case of HS (but entitled ‘malignant histiocytosis’ in the published paper) with unknown primary site demonstrated that the mechanical pressure elicited by severe infiltration of HS cells in the spleen should lead to capsular weakening and splenic rupture .
Some confusion still exists even in the recent literature with regard to the terminology of this entity, i.e., histiocytic lymphoma, malignant histiocytosis, or HS. Despite that, the term HS includes whole spectrum of localized and disseminated forms from true histiocytic lymphoma to malignant histiocytosis by definition [1–3]. In this context, it is very challenging that we pathologists strictly make a final disgnosis as primary splenic HS, since many HS cases have exhibited extensive involvement of other organs at first decision, representing as dissemination of tumor cells, such as the above splenic rupture case . Indeed, so-called ‘malignant histiocytosis’ has considered to be apparently characterized by general symptoms including high fever, wasting, lymphadenopathy, hepatosplenomegaly, and progressive pancytopenia, resulting in a rapidly fatal clinical outcome, rather than localized form of HS [11, 15]. Moreover, it is likely that well-defined nodular lesions are very rare in most of the ‘malignant histiocytosis’ cases , as in the present splenic HS. In this context, the present case seems to be categorized into classical ‘malignant histiocytosis’, rather than so-called true ‘histiocytic lymphoma’. Nevertheless, splenic HS must be a unique clinical entity, particularly associated with hypo-albuminemia, hypo-γ-globulinemia, and thrombocytopenia [11–13]. Ezdinli EZ et al.  proposed that, as to those mechanisms, the neoplastic histiocytes could phagocytose albumin and immunoglobulin as well as blood cells, pathologically manifesting as hemophagocytic syndrome, as shown in Figure 3B. On the other hand, HS is very likely an uncertain neoplasm from the aspects of molecular pathogenesis. Although no cytogenetic studies have been performed here, some recent papers demonstrated a clonal immunoglobulin heavy chain gene rearrangement [17, 18], a clonal cytogenetic abnormality including t(14;18) , and a 57–80 hyperdiploid /46, XY  karyotype, including 3 to 4 copies of various chromosomes . Further studies are needed. It also remains to be elucidated whether splenectomy with or without following aggressive chemotherapy is beneficial for patients with splenic HS or not, since it has been reported that so-called ‘malignant histiocytosis’ has no or little response to splenectomy . In fact, based on the current Table 1, HS of the spleen must be potentially lethal condition with short survival even after the splenectomy combined with chemotherapy and irradiation.
Pathological differential diagnoses of this splenic HS case include interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, Langerhans cell sarcoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, metastatic carcinoma, and malignant melanoma. Morphologically, tumor cells in interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, and Langerhans cell sarcoma often have grooved, indented, folded, lobulated, or oval- to spindle-shaped nuclei, arranged in a nodular, fascicular, or storiform growth pattern, that should be absent in HS [1–3, 8, 9]. The conclusive diagnosis of HS is based on not only histological but immunohistochemical examination of histiocytic differentiation and exclusion of other immunophenotypes including lymphoid, epithelial, or melanocytic differentiation, as also described here (Table 2). The tumor cells in the present case apparently revealed positive expression of specific histiocytic markers, such as CD68 (KP-1), and lysozyme (Figure 4). But these HS cells also diffusely expressed the hemoglobin scavenger marker, CD163, regarded as a peculiar marker for HS as well .
We herein reported a unique surgical case of primary splenic HS strongly associated with pathological findings of aggressive infiltration of tumor cells in the red pulp and splenic artery, in the background of splenomegaly with multiple foci of anemic infarction, but without any nodular lesions. Although splenic HS is very uncommon, not only clinicians but we pathologists should be aware that its patients undergo a fatal condition with poor prognosis, and must consider it as a differential diagnosis in cases with prolonged thrombocytopenia with splenomegaly that is non-responsive to therapy.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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