Primary Central Nervous System Histiocytic Sarcoma With Relapse to Mediastinum: A Case Report and Review of the Literature

By Cao, Ming; Eshoa, Camellia; Schultz, Christopher; Black, Jennifer; Et al

* Histiocytic sarcoma is a rare, malignant neoplasm of the lymphohematopoietic system that usually occurs in the skin, lymph node, and intestinal tract. Here we describe a unique case of primary central nervous system histiocytic sarcoma that initially showed an indolent clinical course following local resection and radiotherapy. However, relapse of disease within the mediastinum was noted 3 years later. Biopsies of the initial brain lesion and subsequent mediastinal recurrence each revealed an identical, diffuse proliferation of histiocytes with expression of CD45, CD68, and CD163 but not pan-cytokeratin, epithelial membrane antigen, CD3, CD15, CD20, CD30, CD43, CD79a, CD138, myeloperoxidase, ALK-1, PAX- 5, CAM 5.2, S100, CD1a, or glial fibrillary acidic protein. In the literature, central nervous system histiocytic sarcoma portends a poor prognosis with median survival of 4.5 months. To our knowledge, this case represents the first case of ”lowgrade” primary central nervous system histiocytic sarcoma with relatively indolent clinical course. A thorough discussion of the differential diagnosis of histiocytic sarcoma and a review of primary central nervous system histiocytic sarcoma are also presented.

(Arch Pathol Lab Med. 2007;131:301-305)

Histiocytic sarcoma (HS) is a rare, lymphohematopoietic malignant neoplasm composed of tumor cells showing morphologic and immunophenotypic features of mature tissue histiocytes. Histiocytic neoplasms of the lymphohematopoietic system have had various names including histiocytic lymphoma, malignant histiocytosis, histiocytic medullary reticulosis, reticulum sarcoma, and malignant histiocytosis. These tumors were initially considered histiocytic in origin based on morphology alone. Subsequently, it has been recognized that most of these tumors are actually large T-cell, B- cell, or anaplastic lymphomas by modern immunophenotypic techniques.1 In the current World Health Organization classification, the diagnosis of HS requires the verification of histiocytic lineage and exclusion of malignancies of other lymphohematopoietic lineages with extensive immunophenotypic workup including histiocytic markers such as CD68, lysozyme, MAC387, 1- antitrypsin, and 1-antichymotrypsin. However, these markers are not always specific for histiocytic differentiation. Recently, several authors have reported that CD163 (hemoglobin scavenger receptor) may be a more specific marker of the monocytic/histiocytic lineage. 2-5

Histiocytic sarcoma usually arises in lymph nodes, skin, and the intestinal tract.6,7 Primary central nervous system (CNS) HS is extremely rare and all cases reported have shown a very aggressive clinical course with a median survival of 4.5 months (Table).8-10 We describe a unique case of primary CNS HS with what appeared to be a relatively indolent clinical course following local resection and radiotherapy until extracranial relapse was identified 3 years later. A thorough discussion of the differential diagnosis of HS and a review of primary CNS HS are also presented.


A 53-year-old woman presented with a left anterior mediastinal mass and a right hilar mass (Figure 1, A through C). Her past medical history was significant for a brain tumor diagnosed 3 years prior to presentation. She presented at that time with numerous CNS abnormalities secondary to the tumor, including significant visual field impairment, a right third cranial nerve deficit with ptosis, double vision, limitations in ocular mobility, difficulty walking, headache, and generalized malaise. The lesion was a multilobulated mass located in the right retro-orbital area with an epicenter in the right cavernous sinus, measuring 3.1 = 2.9 = 2.2 cm. Magnetic resonance imaging showed extension into the sella turcica with complete occlusion of the right internal carotid artery (Figure 1, D and E). Subsequently, a right frontotemporal craniotomy with creation of a bone flap, microscope-assisted decompression, and subtotal removal of the right cavernous sinus tumor were performed. The pathologic diagnosis was reported as chronic inflammation and fibrosis. She received empiric external beam radiation with a total dose of 5400 cGy. After completing therapy, she experienced gradual improvement in symptoms with complete disappearance of tumor. Annual surveillance with magnetic resonance imaging did not show evidence of tumor recurrence in the brain (Figure 1, F).

Clinical evaluation of the new mediastinal mass revealed 4 ovoid lesions on computed tomographic imaging with intravenous contrast scanning of the chest: 2 lesions in the right hilum and 2 lesions in the left chest. The largest tumor measured 9.0 = 7.0 = 8.0 cm. There was a small left pleural effusion. An ultrasound- guided aspiration and biopsy were performed on the left anterior mediastinal mass and the resulting specimen was submitted for pathologic examination. She received 3 cycles of cyclophosphamide, doxorubicin, and vincristine, and prednisone without noticeable improvement. At the same time, she developed bony metastasis in the right hip and thoracic vertebrae. The metastases were treated with radiation but without response. She developed severe respiratory distress, chest pain, and pleural effusion. Subsequent salvation chemotherapy with ifosfamide, carboplatin, and etoposide was administered, but she received only 1 cycle before going to hospice care. She died shortly thereafter, 7 months following the development of the mediastinal masses.


The brain and mediastinal biopsy specimens were fixed in 10% buffered formalin, embedded in paraffin, sectioned (4 m), and stained with hematoxylin-eosin. Immunohistochemical stains were performed for the following markers: CD1a, CD3, CD15, CD20, CD30, CD43, CD45, CD68, CD79a, CD138, CD163, myeloperoxidase, pan- cytokeratin, epithelial membrane antigen, ALK-1, PAX-5, CAM 5.2, S100, and glial fibrillary acidic protein. Immunoglobulin heavy- chain (IgH) and T-cell receptor = (TCR=) gene rearrangement clonality were determined by polymerase chain reaction using the IgH and TCR= gene rearrangement assays (InVivoscribe Technology, San Diego, Calif) with ABI (Applied Biosystems, Foster City, Calif) fluorescence detection. Polymerase chain reaction was performed in 20-L reaction with consensus primers for framework region 3 (FR3) and JH, 100 ng DNA from paraffin-embedded lymph node tissue, dNTP, Taq polymerase, and 4.0 mM Mg2α using Lightcycler (Roche Diagnostic). The sequences of the primers were 5


Cytologic smears of the mediastinal mass revealed a population of large neoplastic cells with eccentrically situated round to irregular, lobulated nuclei, some with distinctive nucleoli, and abundant cytoplasm (Figure 2, A). There were also many scattered small reactive lymphocytes. The biopsy showed a diffuse infiltrate of large noncohesive polygonal cells with oval to slightly irregular nuclei, distinct nucleoli, vesicular chromatin, and abundant eosinophilic cytoplasm (Figure 2, B). Some cells with more pleomorphic features and occasional giant cells with multilobated nuclei were present. There was focal necrosis, but mitotic figures were rare. Hemophagocytosis or emperipolesis was not identified. There were many scattered small reactive lymphocytes present within the infiltrate. The vast majority of these lymphocytes were of T- cell lineage (CD3α). Tumor cells invaded the adjacent pulmonary parenchyma.

Immunohistochemical staining of the mediastinal masses showed that the neoplastic cells were positive for CD45, CD68 (Figure 2, C), and CD163 (Figure 2, D), but negative for CD1a, CD3, CD15, CD20, CD30, CD43, CD79a, CD138, myeloperoxidase, pan-cytokeratin, epithelial membrane antigen, ALK-1, PAX-5, CAM 5.2, S100, and glial fibrillary acidic protein. There were scattered Ki-67 positive cells (approximately 20%). The IgH and TCR= gene rearrangement studies by polymerase chain reaction showed polyclonal B- and T-cell populations. The bone marrow evaluation revealed no evidence of acute myeloid leukemia, myeloproliferative disorders, myelodysplastic syndromes, or involvement of HS.

Review of the prior brain biopsy demonstrated a diffuse infiltrate composed of neoplastic cells with histomorphologic and immunophenotypic features almost identical to those seen in the mediastinal masses, although the degree of cytologic atypia was less pronounced in the brain tumor (Figure 2, E and F). The background of mixed inflammatory cells, including neutrophils, lymphocytes, and plasma cells, was more prominent in the CNS lesion, which may have been the basis for the previous pathologic impression of an inflammatory infiltrate. The diagnosis of HS in the mediastinum and CNS was then rendered based on the previously described findings.


The differential diagnoses that should be considered in cases of HS are numerous and include hematopoietic and nonhematopoietic lesions. Comprehensive immunohistochemical study excludes many of these diagnoses and confirms the diagnosis of HS. Negative staining for pan\-cytokeratin, epithelial membrane antigen, and CAM 5.2 rules out carcinoma or meningioma. Negative S100 protein staining does not support a diagnosis of melanoma. The absence of CD15, CD20, CD79a, PAX5, CD30, CD3, and ALK-1 expression as well as the lack of clonal IgH and TCR= rearrangement exclude Hodgkin lymphoma, poorly differentiated large B-cell/T-cell lymphoma, and anaplastic large cell lymphoma. Langerhans cell histiocytosis and interdigitating dendritic cell tumors are excluded with negative CD1a and S100 protein. Plasma cell neoplasms are ruled out by a negative CD138. A myeloid malignancy is unlikely in the absence of myeloperoxidase expression. Negative glial fibrillary acidic protein expression contradicts the diagnosis of glial-derived tumors.

The expression of CD45 indicates a hematopoietic neoplasm and many cases of HS are positive for this marker. 1,4,6 Positive CD68 and CD163 staining pattern confirm a tumor of histiocytic origin. In particular, CD163, a hemoglobin scavenger receptor, is a new immunohistochemical marker of monocytes and histiocytes. Its expression is limited to neoplasms of monocytic/histiocytic derivation and is more specific than other monocytic and histiocytic markers such as CD68.2-5 CD68 staining is also found in cells and tumors of other lineages, including angiosarcoma, melanoma, carcinoma, some lymphomas, schwannoma, Langerhans cell tumor, follicular dendritic cell tumor, interdigitating dendritic cell proliferation, and acute myeloid leukemia without monocytic differentiation.3,7 Many earlier reported cases of HS, including all 5 cases of CNS HS, were positive for CD68 but were not evaluated for CD163.6-10 Therefore, true histiocytic origin may be questionable in these cases.

In this case presentation, the diagnosis of the mediastinal mass is relatively straightforward but the brain lesion is comparatively more diagnostically challenging. The suboptimal morphology resulting from fragmentation of a small portion of brain tissue, the mild cytologic atypia of the neoplastic cells, and the profound inflammatory component created the initial impression of a chronic inflammatory process. Prominent inflammatory infiltrates were described in all 5 of the previously reported cases of primary CNS HS.8-10 This finding was also observed, although less frequently, in HS in locations other than CNS.6 Many conditions in the CNS may involve a significant inflammatory process. Inflammatory pseudotumor of the CNS, characterized by fibrotic stromal tissue and a polyclonal mononuclear infiltrate, as well as plasma cell granuloma, characterized by a granulomatous infiltrate composed predominantly of plasma cells, may both mimic HS.12 However, unlike our case, in which histiocytes are the major component, the infiltrates in these conditions are dominated by plasma cells. Furthermore, these lesions are not complicated by extracranial relapse. Other conditions with a prominent inflammatory background include sinus histiocytosis with massive lymphadenopathy (Rosai- Dorfman disease) in the CNS, inflammatory myofibroblastic tumor, primary CNS extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type, and lymphoplasma cell-rich meningioma. These conditions can be readily distinguished from HS with comprehensive histomorphologic and immunohistochemical evaluation.12-15 Follicular dendritic cell sarcoma is another rare neoplasm that should be considered in the differential diagnosis. The tumor cells in this entity express CD21, CD23, and/or CD35. Limited tissue availability precluded examination of these immunohistochemical markers in our study. A few reported cases have also shown absence of CD163 in follicular dendritic cell sarcoma, as compared with positive CD163 expression in HS.2,3 Although it is exceedingly unlikely, we cannot exclude the possibility that the CNS lesion in our case report could represent an unrelated, benign inflammatory process. X-chromosome inactivation pattern analysis could be applied to demonstrate tumor cell clonality in the CNS and mediastinal lesions. However, the available tissue from the brain lesion was exhausted in the course of immunohistochemical study.

Central nervous system histiocytic sarcoma portends a poor prognosis with median survival of 4.5 months in previously reported cases (Table). In contrast, the current case is unique in showing an initial indolent clinical course with response to local resection and radiation treatment, and subsequent relapse to the mediastinum 3 years later. Cases of HS with a favorable long-term outcome were reported in other locations.4,6 In those cases, tumor stage and size were believed to be important factors in the prognosis. In CNS HS, reported tumors vary in size from 0.7 to 1.7 cm, and the tumor in our case measures 3.1 cm.8-10 Therefore, it is still unclear at this point if tumor size and stage are prognostic features in CNS HS, as has been observed in other extranodal sites. In our case, the cytologic atypia is somewhat mild and the mitotic figures are rare in the brain lesion. The mild cytologic atypia may correlate with less aggressive biologic behavior because a much more aggressive course is noted following the mediastinal relapse, which exhibited a higher degree of cytologic atypia. The difference in mitotic activity may not completely explain the variability in the clinical course because mitotic figures were highly variable, ranging from 0 to 16 per high-power field in cases reported thus far.8-10 The degree of cytologic atypia in each case is not specified in these reports. It is necessary to examine a larger subset of CNS HS to make observations about tumor characteristics that correlate with clinical outcome.

In summary, we present a case of CNS HS that demonstrates a less aggressive initial clinical course but with subsequent relapse in an extracranial location, with more aggressive behavior. We used a comprehensive immunophenotyping panel including CD163 as well as molecular studies to establish the true histiocytic nature of these lesions. Additionally, in our case, the brain lesion shows mild cytologic atypia as well as low mitotic activity. Although we cannot make accurate conclusions about the relationship of these findings with clinical behavior in our case, future studies are warranted to determine the prognosis of these lesions.


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13. Andriko JA, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai-Dorfman disease isolated to the central nervous system: a report of 11 cases. Mod Pathol. 2001;14:172-178.

14. Itoh T, Shimizu M, Kitami K, et al. Primary extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in the CNS. Neuropathology. 2001;21:174-180.

15. Bruno MC, Ginguene C, Santangelo M, et al. Lymphoplasmacyte rich meningioma. A case report and review of the literature. J Neurosurg Sci. 2004;48: 117-124.

Ming Cao, MD; Camellia Eshoa, MD; Christopher Schultz, MD; Jennifer Black, MD; Youli Zu, MD, PhD; Chung-Che Chang, MD, PhD

Accepted for publication October 11, 2006.

From the Department of Pathology, The Methodist Hospital, Weill Medical College of Cornell University, Houston, Tex (Drs Cao, Black, Zu, and Chang); the Department of Pathology, St. Mary’s Hospital of Ozaukee, Mequon, Wis (Dr Eshoa); and the Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee (Dr Schultz).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Ch\ung-Che Chang, MD, PhD, The Methodist Hospital, Pathology, 6565 Fannin St, MS205, Houston, TX 77030 (e-mail: [email protected]).

Copyright College of American Pathologists Feb 2007

(c) 2007 Archives of Pathology & Laboratory Medicine. Provided by ProQuest Information and Learning. All rights Reserved.

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