Brain Tumor Pathol DOI 10.1007/s10014-014-0191-3
CASE REPORT
Histiocytic sarcoma of the cavernous sinus: case report and literature review Ching-Jen Chen • Erik A. Williams • Taylor E. McAneney • Brian J. Williams James W. Mandell • Mark E. Shaffrey
•
Received: 16 March 2014 / Accepted: 18 April 2014 Ó The Japan Society of Brain Tumor Pathology 2014
Abstract Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. We describe the 2nd case of primary histiocytic sarcoma of the cavernous sinus/Meckel’s cave, and the 8th case involving the CNS. A 61-year-old Caucasian man presented with numbness on the entire left side of his face, shooting pain in the left frontal region, and headaches. Imaging revealed an enhancing extra axial soft tissue mass located in the left cavernous sinus and left Meckel’s cave. Diagnosis was established through open biopsy, after failed attempts via CT-guided trans-foramen ovale fine-needle aspiration biopsy and keyhole biopsy. The tumor was composed of large non-cohesive epithelioid cells invading nerves and ganglion cells. Tumor cells were immunopositive for CD68, CD163, and immunonegative for the anaplastic large cell lymphoma marker ALK-1 as well as other lymphoid, myeloid, and dendritic cell markers. Histiocytic sarcoma has strong potential for systemic spread; early diagnosis and treatment are important. Our patient was initially treated with radiation therapy but subsequently developed metastases.
Keywords Histiocytic sarcoma Cavernous sinus tumor CD163 Intracranial Review
Introduction Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. The tumor cells are characterized by the expression of histiocytic markers without the expression of T cell markers, dendritic cell markers, and lack of Birbeck granules on electron microscopy [1, 2]. Most of the histiocytic sarcoma cases reported in the past are now considered to represent non-Hodgkin lymphomas, such as diffuse large B-cell lymphoma or anaplastic large cell lymphoma, based on immunohistochemical studies [3–6]. Thus far, we have found seven recent cases of histiocytic sarcoma diagnosed based on CNS biopsies in the literature [7–11]. This report describes the challenging diagnosis of the 2nd case of primary histiocytic sarcoma involving the cavernous sinus/Meckel’s cave.
Case report C.-J. Chen (&) B. J. Williams M. E. Shaffrey Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA e-mail: [email protected] E. A. Williams J. W. Mandell Department of Pathology (Neuropathology), University of Virginia Health System, Charlottesville, VA, USA T. E. McAneney School of Medicine, Medical University of South Carolina, Charleston, SC, USA
A 61-year-old Caucasian man presented to an outside institution after experiencing paresthesia localized to his tongue, which progressed to the left lower lip. Imaging revealed an enhancing extra axial soft tissue mass located in the cavernous sinus and Meckel’s cave. At the time of presentation to our institution, the patient’s symptoms had progressed to numbness on the entire left side of his face, shooting pain in the left frontal region, difficulty chewing, decreased hearing on the left side and increased frequency
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Fig. 1 a Axial T-1 weight MRI with gadolinium contrast demonstrated an enhancing mass expanding into the prepontine cistern and left anterior temporal lobe associated with marked edema; b and c)
H&E staining examined under 920 and 940 showed a predominant population of large non-cohesive epithelioid cells with bizarre pleomorphic grooved, lobulated nuclei, and abundant cytoplasm
of headaches. Physical examination revealed decreased left corneal reflex, significant decrease in pinprick and light touch sensation in CN V1, V2, V3, tongue and inside of mouth. Given the presentation and the findings on imaging, diagnoses that were considered included inflammatory and neoplastic lesions such as sarcoid, granulomatous lesions, nerve sheath tumor and lymphoma. The patient underwent a CT-guided trans-foramen ovale fine-needle aspiration biopsy at our institution and a left keyhole biopsy at another institution. Neither was diagnostic. The keyhole biopsy revealed lymphohistiocytic infiltration with some necrosis. Imaging study 3 months after the keyhole biopsy demonstrated a lobulated 15 9 11 9 18 mm heterogeneously enhancing lesion involving the left Meckel’s cave and left cavernous sinus. The mass had increased in size since the first study, and appeared to extend contiguously into the left foramen rotundum and cisternal segment of the left CN V. There was slight increased enhancement of the greater petrosal nerve and geniculate ganglion indicative of perineural spread. In the following month, the patient began to notice diplopia with left gaze and occasional left eyelid ptosis. MR imaging demonstrated interval enlargement of the mass, expanding into the prepontine cistern and left anterior temporal lobe associated with marked edema. (Fig. 1a) There was also enhancement of the left clivus indicative of bony invasion. The patient underwent a left pterional craniotomy and extradural approach to the cavernous sinus, and tumor samples were sent for pathological analysis. Post-operative PET–CT scan showed no signs of distant metastases. However, there was abnormal fludeoxyglucose (18F) (18F-FDG) uptake in the inferior left eyelid, concerning for tracking along CN V2. The patient underwent radiation therapy of 66 Gy in 33 fractions. Follow-up MRIs showed gradual decrease in size and enhancement of the tumor. Seven months following the completion of radiation
therapy, the patient developed a new onset of severe right hip pain. Biopsy demonstrated metastasis of the histiocytic sarcoma. The patient underwent another course of radiation therapy for the lesion in his right ilium. The patient started chemotherapy after 1 month of radiation, completing 1 cycle CVP (cyclophosphamide, vincristine, and prednisone) and 2 cycles CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). After diagnosis of leptomeningeal involvement in the following month, he underwent trials of intrathecal cytarabine and methotrexate but was unable to tolerate either drug. The patient and his family decided to forgo further interventions.
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Pathological findings Microscopic examination showed a predominant population of large non-cohesive epithelioid cells with bizarre pleomorphic grooved, lobulated nuclei, and abundant cytoplasm (Fig. 1b, c). The proliferation invaded nerves and ganglion cells. Admixed within the atypical cells were scattered small lymphocytes and occasional multinucleated cells. Numerous mitoses were readily identified within the population of pleomorphic cells. There were several foci of necrosis, and no microorganisms were identified on acid fast or silver stains. An extensive immunohistochemical panel (Table 1) was performed to characterize the atypical cells, which were strongly immunoreactive for the histiocytic markers CD68 (Fig. 2a–c), CD163 (Fig. 2d–f), and lysozyme. The tumor cells were immunonegative for the Langerhan’s cell markers CD1a and langerin, and follicular dendritic cell markers CD21 and CD35. The tumor cells were also immunonegative for CD45 and B-cell markers CD79a and PAX-5. They showed focal immunoreactivity for S-100, rare scattered reactivity for myeloperoxidase, and were
Brain Tumor Pathol Table 1 Immunohistochemistry results Antibodies
Major cell specificity
Reactivity
CD68
Histiocytes/macrophage
???
CD163
Histiocytes/macrophage
???
Lysozyme
Histiocytes/macrophage
???
CD1a
Dendritic cell
-
Langerin
Dendritic cell
-
CD21
Dendritic cell
-
CD35
Dendritic cell
-
CD45
T/B lymphocytes
-
CD79
B lymphocytes
-
PAX-5
B lymphocytes
-
CD3 CD5
Pan T lymphocytes T lymphocytes
?? ??
CD8
T lymphocytes
??
S-100
Melanocytes
? (Focal)
Myeloperoxidase
Myeloid cells
? (Scattered)
CD15
Reed-Sternberg cells, myeloid cells
-
ALK-1
Anaplastic large cell lymphoma
-
CD30
Anaplastic large cell lymphoma
-
??? Strong reactivity ?? Moderate reactivity ? Weak reactivity - No reactivity
immunonegative for CD15. Immunohistochemistry for ALK-1 (Fig. 2c) and CD30 was negative ruling out anaplastic large cell lymphoma. Infiltrating lymphocytes were immunoreactive for CD3, CD5, and CD8. Although there was not a prominent plasma cell infiltrate, a diagnosis of inflammatory pseudotumor was considered. IgG4 immunohistochemistry was negative in admixed lymphoid cells. The Ki-67 proliferation labeling index was 12.9 ± 2.4 % in the histiocytic proliferation supporting a neoplastic process. This case showed a markedly atypical histiocytic proliferation with an immunophenotypic profile consistent with histiocytic sarcoma as defined by the 2008 Hematopoietic and Lymphoid Tissues WHO classification. Given the consideration of Langerhan’s cell sarcoma, electron microscopy was performed and no Birbeck granules were identified.
Discussion Histiocytic sarcoma was first described in 1970 by Mathe et al. [12] to include all forms of malignancy of mononuclear phagocytic origin, ranging from the localized true
histiocytic neoplasms to the disseminated malignant histiocytosis. Microscopically, histiocytic sarcoma has high cellularity composed of non-cohesive diffuse proliferation of large ovoid cells with diameters between 18 and 26lm [2, 8, 13, 14]. The nuclei are pleomorphic with dispersed chromatin and can possess indented or bizarre profiles with prominent nucleoli [2, 8]. The cytoplasm often contains numerous lysosomes and is eosinophilic with H&E and gray with Giemsa stain [2, 15]. A study of 18 cases of histiocytic sarcoma by the International Lymphoma Study Group (ILSG) showed moderate cellular pleomorphism with occasional multinucleate giant cells and rare spindle cells [2]. Neoplasms such as diffuse large B-cell lymphoma and anaplastic large cell lymphoma can have overlapping histopathologic features, thus more definitive differentiations can be made using immunohistochemistry. Histiocytic sarcoma is characterized by the expression of histiocytic antigens (CD68, lysozyme, CD11c, and CD14) in addition to the lack of expression of dendritic cell markers (CD1a, CD21, and CD35), B-cell markers, myeloid markers, follicular dendritic cell markers, CD30, and Birbeck granules. Of the 18 cases reported in the ILSG study, all of them demonstrated expression of CD68, 94 % were immunoreactive for lysozyme, 33 % were immunoreactive for S-100, and none were immunoreactive for CD1a or CD21/CD35 [2]. Histiocytic sarcomas are rare neoplasms of hematopoietic origin and present more commonly in males in the second and third decade [8]. Lymph nodes, skin, and gastrointestinal tract [1, 2, 16–22] are the most common primary sites of involvement, while the spleen [2, 23–26], central nervous system [7–9], and other sites [18, 27, 28] are more rarely involved. Primary histiocytic sarcoma involving the CNS is exceptionally rare; no cases were identified by Bataille et al. [29] in a review of 220 cases of primary CNS lymphomas and other large studies [1, 2, 18, 30]. Given the rarity of primary histiocytic sarcoma involving the CNS, differential diagnosis should be broad; inflammatory, infectious and autoimmune conditions must be considered as the histology mimics inflammatory processes. Diagnoses to consider include diffuse large B-cell lymphoma, anaplastic large cell lymphoma, malignant fibrous histiocytoma, metastatic melanoma, inflammatory pseudotumor, sarcoid, cerebral abscess, glial cell tumors, and germ cell tumors. Based on the neuroimaging studies and the tumor location in our patient, we also considered schwannoma, meningioma, epidermoid tumor, and peripheral nerve sheath tumor. There have been only seven previous reported cases of histiocytic sarcoma involving the CNS (Table 2), and our report presents the 8th case of histiocytic sarcoma with CNS involvement. The largest study of histiocytic sarcoma involving the CNS thus far was presented by Cheuk et al. [7], in which 3 cases with
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Fig. 2 Immunohistochemical staining for a–c CD68 at 910, 920 and 940 and d–f CD163 at 910, 920 and 940 demonstrated strong reactivity. Staining for g–i ALK-1 was negative at 910, 920 and 940
immunochemistry were reported. Wu et al. [11] reported the most recent case in 2013, which demonstrated immunoreactivity for CD163, CD68, CD4, and fascin, with no immunoreactivity for CD1a, myeloperoxidase, CD43, CD45, CD35, CD23, CD21, GFAP, lysozyme, and S-100. This report represents the 2nd case in the literature of histiocytic sarcoma supported by immunohistochemistry arising from the cavernous sinus/Meckel’s cave, following the 1st report by Cao et al. [10].
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Histiocytic sarcoma is an aggressive neoplasm; patients usually present at an advanced stage and have poor prognosis. Despite extensive treatment, 6 of 8 patients in the report by Lauritzen et al. [19] died of disseminated disease, 5 within 14 months of diagnosis. The average survival of previously reported cases involving the CNS with known outcomes is approximately 6 months [8]. In the report by Cheuk et al. [7], one patient died at 8 months following diagnosis despite partial resection, whole brain
Brain Tumor Pathol Table 2 Recent reports of histiocytic sarcoma involving the CNS Author, Year
Case no.
Age/ Sex
Location
Survival
Torres et al. [9], 1996
1
20 mo/ M
Diffuse meningeal
5 months
Cheuk et al. [7], 2001
2
69 yo/ F
Parietal lobe
8 months
3
43 yo/ M
Intradural, extramedullary 9th thoracic level
Alive at 5 months
4
11 yo/ M
Cerebellum, occipital lobe and frontal lobe
4 months
Sun et al. [8], 2003
5
13 yo/ M
Occipital lobe and meninges
7 months
Cao et al. [10], 2007
6
53 yo/ F
Right cavernous sinus
42 months
Wu et al. [11], 2013
7
50 yo/ M
Right occipital/parietal lobe
Alive at 18 months
Present case
8
61 yo/ M
Cavernous sinus, Meckel’s cave and temporal lobe
Alive at 31 months
3.
5.
6.
7.
yo years old, mo months old, M male, F female
radiotherapy and chemotherapy, and another patient died at 4 months of diagnosis following partial resection. There is no standard treatment for histiocytic sarcoma, and the optimal radiation dose and treatment volume are yet to be determined. With the progression to disseminated disease in our patient, several options for chemotherapy were considered to deliver systemic treatment. ICE (ifosfamide, carboplatin, and etoposide with mesna) and CHOP are treatment regimens for patients diagnosed with aggressive lymphomas; however, their efficacy in the treatment of systemic histiocytic sarcoma has not been evaluated. There are recent case reports demonstrating potential benefit of thalidomide treatment [31, 32]. Our patient is currently alive at last follow-up, 31 months following initial presentation. Conflict of interest
4.
8.
9.
10.
11.
12.
13. 14.
15.
None. 16.
References 1. Copie-Bergman C, Wotherspoon AC, Norton AJ, Diss TC, Isaacson PG (1998) True histiocytic lymphoma: a morphologic, immunohistochemical, and molecular genetic study of 13 cases. Am J Surg Pathol 22:1386–1392 2. Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK, Favera RD, Delsol G, De Wolf-Peeters C, Falini B, Gascoyne
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RD, Gaulard P, Gatter KC, Isaacson PG, Jaffe ES, Kluin P, Knowles DM, Mason DY, Mori S, Muller-Hermelink HK, Piris MA, Ralfkiaer E, Stein H, Su IJ, Warnke RA, Weiss LM (2002) Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 41:1–29 Arai E, Su WP, Roche PC, Li CY (1993) Cutaneous histiocytic malignancy. Immunohistochemical re-examination of cases previously diagnosed as cutaneous ‘‘histiocytic lymphoma’’ and ‘‘malignant histiocytosis’’. J Cutan Pathol 20:115–120 Gonzalez CL, Jaffe ES (1990) The histiocytoses: clinical presentation and differential diagnosis. Oncol Williston Park 4:47–60 (Discussion 60, 62) van der Valk P, van Oostveen JW, Stel HV, van der Kwast TH, Melief CJ, Meijer CJ (1990) Phenotypic and genotypic analysis of large-cell lymphomas, formerly classified as true histiocytic lymphoma: identification of an unusual group of tumors. Leuk Res 14:337–346 Wilson MS, Weiss LM, Gatter KC, Mason DY, Dorfman RF, Warnke RA (1990) Malignant histiocytosis. A reassessment of cases previously reported in 1975 based on paraffin section immunophenotyping studies. Cancer 66:530–536 Cheuk W, Walford N, Lou J, Lee AK, Fung CF, Au KH, Mak LS, Chan JK (2001) Primary histiocytic lymphoma of the central nervous system: a neoplasm frequently overshadowed by a prominent inflammatory component. Am J Surg Pathol 25:1372–1379 Sun W, Nordberg ML, Fowler MR (2003) Histiocytic sarcoma involving the central nervous system: clinical, immunohistochemical, and molecular genetic studies of a case with review of the literature. Am J Surg Pathol 27:258–265 Torres CF, Korones DN, Powers JM, Vadasz AG (1996) Primary leptomeningeal histiocytic lymphoma in a young child. Med Pediatr Oncol 27:547–550 Cao M, Eshoa C, Schultz C, Black J, Zu Y, Chang CC (2007) Primary central nervous system histiocytic sarcoma with relapse to mediastinum: a case report and review of the literature. Arch Pathol Lab Med 131:301–305 Wu W, Tanrivermis Sayit A, Vinters HV, Pope W, Mirsadraei L, Said J (2013) Primary central nervous system histiocytic sarcoma presenting as a postradiation sarcoma: case report and literature review. Hum Pathol 44:1177–1183 Mathe G, Gerard-Marchant R, Texier JL, Schlumberger JR, Berumen L, Paintrand M (1970) The two varieties of lymphoid tissue ‘‘reticulosarcomas’’, histiocytic and histioblastic types. Br J Cancer 24:687–695 Schmidt D (2001) Malignant histiocytosis. Curr Opin Hematol 8:1–4 Vos JA, Abbondanzo SL, Barekman CL, Andriko JW, Miettinen M, Aguilera NS (2005) Histiocytic sarcoma: a study of five cases including the histiocyte marker CD163. Mod Pathol 18:693–704 Zhang X, Kryston JJ, Michalak WA, Zhang K, Lin F, Schuerch C (2008) Histiocytic sarcoma in the small intestine: a case report with flow cytometry study and review of the literature. Pathol Res Pract 204:763–770 Alvaro T, Bosch R, Salvado MT, Piris MA (1996) True histiocytic lymphoma of the stomach associated with low-grade B-cell mucosa-associated lymphoid tissue (MALT)-type lymphoma. Am J Surg Pathol 20:1406–1411 Hornick JL, Jaffe ES, Fletcher CD (2004) Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy. Am J Surg Pathol 28:1133–1144 Kamel OW, Gocke CD, Kell DL, Cleary ML, Warnke RA (1995) True histiocytic lymphoma: a study of 12 cases based on current definition. Leuk Lymphoma 18:81–86
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Brain Tumor Pathol 19. Lauritzen AF, Delsol G, Hansen NE, Horn T, Ersboll J, HouJensen K, Ralfkiaer E (1994) Histiocytic sarcomas and monoblastic leukemias. A clinical, histologic, and immunophenotypical study. Am J Clin Pathol 102:45–54 20. Milchgrub S, Kamel OW, Wiley E, Vuitch F, Cleary ML, Warnke RA (1992) Malignant histiocytic neoplasms of the small intestine. Am J Surg Pathol 16:11–20 21. Soria C, Orradre JL, Garcia-Almagro D, Martinez B, Algara P, Piris MA (1992) True histiocytic lymphoma (monocytic sarcoma). Am J Dermatopathol 14:511–517 22. Wakahashi K, Shimoyama M, Katayama Y, Minagawa K, Yoshida K, Sasaki R, Nakayama S, Yokozaki H, Yanagita E, Itoh T, Hayashi Y, Matsui T (2010) Histiocytic sarcoma with two immunohistopathologically distinct populations. Int J Hematol 92:642–646 23. Audouin J, Vercelli-Retta J, Le Tourneau A, Adida C, CamilleriBroet S, Molina T, Diebold J (2003) Primary histiocytic sarcoma of the spleen associated with erythrophagocytic histiocytosis. Pathol Res Pract 199:107–112 24. Franchino C, Reich C, Distenfeld A, Ubriaco A, Knowles DM (1988) A clinicopathologically distinctive primary splenic histiocytic neoplasm. Demonstration of its histiocyte derivation by immunophenotypic and molecular genetic analysis. Am J Surg Pathol 12:398–404 25. Kimura H, Nasu K, Sakai C, Shiga Y, Miyamoto E, Shintaku M, Wakatsuki S, Tominaga K, Abe M, Maruyama Y (1998) Histiocytic sarcoma of the spleen associated with hypoalbuminemia, hypo gamma-globulinemia and thrombocytopenia as a possibly
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unique clinical entity–report of three cases. Leuk Lymphoma 31:217–224 Kobayashi S, Kimura F, Hama Y, Ogura K, Torikai H, Kobayashi A, Ikeda T, Sato K, Aida S, Kosuda S, Motoyoshi K (2008) Histiocytic sarcoma of the spleen: case report of asymptomatic onset of thrombocytopenia and complex imaging features. Int J Hematol 87:83–87 Soslow RA, Davis RE, Warnke RA, Cleary ML, Kamel OW (1996) True histiocytic lymphoma following therapy for lymphoblastic neoplasms. Blood 87:5207–5212 Yu L, Yang SJ (2010) A case of primary histiocytic sarcoma arising from thyroid gland. Pathol Oncol Res 16:127–132 Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, Guy G, Lapierre F (2000) Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg 92:261–266 Ralfkiaer E, Delsol G, O’Connor NT, Brandtzaeg P, Brousset P, Vejlsgaard GL, Mason DY (1990) Malignant lymphomas of true histiocytic origin. A clinical, histological, immunophenotypic and genotypic study. J Pathol 160:9–17 Abidi MH, Tove I, Ibrahim RB, Maria D, Peres E (2007) Thalidomide for the treatment of histiocytic sarcoma after hematopoietic stem cell transplant. Am J Hematol 82:932–933 Gergis U, Dax H, Ritchie E, Marcus R, Wissa U, Orazi A (2011) Autologous hematopoietic stem-cell transplantation in combination with thalidomide as treatment for histiocytic sarcoma: a case report and review of the literature. J Clin Oncol 29:e251–e253
CASE REPORT
Histiocytic sarcoma of the cavernous sinus: case report and literature review Ching-Jen Chen • Erik A. Williams • Taylor E. McAneney • Brian J. Williams James W. Mandell • Mark E. Shaffrey
•
Received: 16 March 2014 / Accepted: 18 April 2014 Ó The Japan Society of Brain Tumor Pathology 2014
Abstract Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. We describe the 2nd case of primary histiocytic sarcoma of the cavernous sinus/Meckel’s cave, and the 8th case involving the CNS. A 61-year-old Caucasian man presented with numbness on the entire left side of his face, shooting pain in the left frontal region, and headaches. Imaging revealed an enhancing extra axial soft tissue mass located in the left cavernous sinus and left Meckel’s cave. Diagnosis was established through open biopsy, after failed attempts via CT-guided trans-foramen ovale fine-needle aspiration biopsy and keyhole biopsy. The tumor was composed of large non-cohesive epithelioid cells invading nerves and ganglion cells. Tumor cells were immunopositive for CD68, CD163, and immunonegative for the anaplastic large cell lymphoma marker ALK-1 as well as other lymphoid, myeloid, and dendritic cell markers. Histiocytic sarcoma has strong potential for systemic spread; early diagnosis and treatment are important. Our patient was initially treated with radiation therapy but subsequently developed metastases.
Keywords Histiocytic sarcoma Cavernous sinus tumor CD163 Intracranial Review
Introduction Histiocytic sarcoma is a rare malignant neoplasm of hematopoietic origin composed of cells showing morphologic and immunophenotypic evidence of histiocytic differentiation. The tumor cells are characterized by the expression of histiocytic markers without the expression of T cell markers, dendritic cell markers, and lack of Birbeck granules on electron microscopy [1, 2]. Most of the histiocytic sarcoma cases reported in the past are now considered to represent non-Hodgkin lymphomas, such as diffuse large B-cell lymphoma or anaplastic large cell lymphoma, based on immunohistochemical studies [3–6]. Thus far, we have found seven recent cases of histiocytic sarcoma diagnosed based on CNS biopsies in the literature [7–11]. This report describes the challenging diagnosis of the 2nd case of primary histiocytic sarcoma involving the cavernous sinus/Meckel’s cave.
Case report C.-J. Chen (&) B. J. Williams M. E. Shaffrey Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA e-mail: [email protected] E. A. Williams J. W. Mandell Department of Pathology (Neuropathology), University of Virginia Health System, Charlottesville, VA, USA T. E. McAneney School of Medicine, Medical University of South Carolina, Charleston, SC, USA
A 61-year-old Caucasian man presented to an outside institution after experiencing paresthesia localized to his tongue, which progressed to the left lower lip. Imaging revealed an enhancing extra axial soft tissue mass located in the cavernous sinus and Meckel’s cave. At the time of presentation to our institution, the patient’s symptoms had progressed to numbness on the entire left side of his face, shooting pain in the left frontal region, difficulty chewing, decreased hearing on the left side and increased frequency
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Fig. 1 a Axial T-1 weight MRI with gadolinium contrast demonstrated an enhancing mass expanding into the prepontine cistern and left anterior temporal lobe associated with marked edema; b and c)
H&E staining examined under 920 and 940 showed a predominant population of large non-cohesive epithelioid cells with bizarre pleomorphic grooved, lobulated nuclei, and abundant cytoplasm
of headaches. Physical examination revealed decreased left corneal reflex, significant decrease in pinprick and light touch sensation in CN V1, V2, V3, tongue and inside of mouth. Given the presentation and the findings on imaging, diagnoses that were considered included inflammatory and neoplastic lesions such as sarcoid, granulomatous lesions, nerve sheath tumor and lymphoma. The patient underwent a CT-guided trans-foramen ovale fine-needle aspiration biopsy at our institution and a left keyhole biopsy at another institution. Neither was diagnostic. The keyhole biopsy revealed lymphohistiocytic infiltration with some necrosis. Imaging study 3 months after the keyhole biopsy demonstrated a lobulated 15 9 11 9 18 mm heterogeneously enhancing lesion involving the left Meckel’s cave and left cavernous sinus. The mass had increased in size since the first study, and appeared to extend contiguously into the left foramen rotundum and cisternal segment of the left CN V. There was slight increased enhancement of the greater petrosal nerve and geniculate ganglion indicative of perineural spread. In the following month, the patient began to notice diplopia with left gaze and occasional left eyelid ptosis. MR imaging demonstrated interval enlargement of the mass, expanding into the prepontine cistern and left anterior temporal lobe associated with marked edema. (Fig. 1a) There was also enhancement of the left clivus indicative of bony invasion. The patient underwent a left pterional craniotomy and extradural approach to the cavernous sinus, and tumor samples were sent for pathological analysis. Post-operative PET–CT scan showed no signs of distant metastases. However, there was abnormal fludeoxyglucose (18F) (18F-FDG) uptake in the inferior left eyelid, concerning for tracking along CN V2. The patient underwent radiation therapy of 66 Gy in 33 fractions. Follow-up MRIs showed gradual decrease in size and enhancement of the tumor. Seven months following the completion of radiation
therapy, the patient developed a new onset of severe right hip pain. Biopsy demonstrated metastasis of the histiocytic sarcoma. The patient underwent another course of radiation therapy for the lesion in his right ilium. The patient started chemotherapy after 1 month of radiation, completing 1 cycle CVP (cyclophosphamide, vincristine, and prednisone) and 2 cycles CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). After diagnosis of leptomeningeal involvement in the following month, he underwent trials of intrathecal cytarabine and methotrexate but was unable to tolerate either drug. The patient and his family decided to forgo further interventions.
123
Pathological findings Microscopic examination showed a predominant population of large non-cohesive epithelioid cells with bizarre pleomorphic grooved, lobulated nuclei, and abundant cytoplasm (Fig. 1b, c). The proliferation invaded nerves and ganglion cells. Admixed within the atypical cells were scattered small lymphocytes and occasional multinucleated cells. Numerous mitoses were readily identified within the population of pleomorphic cells. There were several foci of necrosis, and no microorganisms were identified on acid fast or silver stains. An extensive immunohistochemical panel (Table 1) was performed to characterize the atypical cells, which were strongly immunoreactive for the histiocytic markers CD68 (Fig. 2a–c), CD163 (Fig. 2d–f), and lysozyme. The tumor cells were immunonegative for the Langerhan’s cell markers CD1a and langerin, and follicular dendritic cell markers CD21 and CD35. The tumor cells were also immunonegative for CD45 and B-cell markers CD79a and PAX-5. They showed focal immunoreactivity for S-100, rare scattered reactivity for myeloperoxidase, and were
Brain Tumor Pathol Table 1 Immunohistochemistry results Antibodies
Major cell specificity
Reactivity
CD68
Histiocytes/macrophage
???
CD163
Histiocytes/macrophage
???
Lysozyme
Histiocytes/macrophage
???
CD1a
Dendritic cell
-
Langerin
Dendritic cell
-
CD21
Dendritic cell
-
CD35
Dendritic cell
-
CD45
T/B lymphocytes
-
CD79
B lymphocytes
-
PAX-5
B lymphocytes
-
CD3 CD5
Pan T lymphocytes T lymphocytes
?? ??
CD8
T lymphocytes
??
S-100
Melanocytes
? (Focal)
Myeloperoxidase
Myeloid cells
? (Scattered)
CD15
Reed-Sternberg cells, myeloid cells
-
ALK-1
Anaplastic large cell lymphoma
-
CD30
Anaplastic large cell lymphoma
-
??? Strong reactivity ?? Moderate reactivity ? Weak reactivity - No reactivity
immunonegative for CD15. Immunohistochemistry for ALK-1 (Fig. 2c) and CD30 was negative ruling out anaplastic large cell lymphoma. Infiltrating lymphocytes were immunoreactive for CD3, CD5, and CD8. Although there was not a prominent plasma cell infiltrate, a diagnosis of inflammatory pseudotumor was considered. IgG4 immunohistochemistry was negative in admixed lymphoid cells. The Ki-67 proliferation labeling index was 12.9 ± 2.4 % in the histiocytic proliferation supporting a neoplastic process. This case showed a markedly atypical histiocytic proliferation with an immunophenotypic profile consistent with histiocytic sarcoma as defined by the 2008 Hematopoietic and Lymphoid Tissues WHO classification. Given the consideration of Langerhan’s cell sarcoma, electron microscopy was performed and no Birbeck granules were identified.
Discussion Histiocytic sarcoma was first described in 1970 by Mathe et al. [12] to include all forms of malignancy of mononuclear phagocytic origin, ranging from the localized true
histiocytic neoplasms to the disseminated malignant histiocytosis. Microscopically, histiocytic sarcoma has high cellularity composed of non-cohesive diffuse proliferation of large ovoid cells with diameters between 18 and 26lm [2, 8, 13, 14]. The nuclei are pleomorphic with dispersed chromatin and can possess indented or bizarre profiles with prominent nucleoli [2, 8]. The cytoplasm often contains numerous lysosomes and is eosinophilic with H&E and gray with Giemsa stain [2, 15]. A study of 18 cases of histiocytic sarcoma by the International Lymphoma Study Group (ILSG) showed moderate cellular pleomorphism with occasional multinucleate giant cells and rare spindle cells [2]. Neoplasms such as diffuse large B-cell lymphoma and anaplastic large cell lymphoma can have overlapping histopathologic features, thus more definitive differentiations can be made using immunohistochemistry. Histiocytic sarcoma is characterized by the expression of histiocytic antigens (CD68, lysozyme, CD11c, and CD14) in addition to the lack of expression of dendritic cell markers (CD1a, CD21, and CD35), B-cell markers, myeloid markers, follicular dendritic cell markers, CD30, and Birbeck granules. Of the 18 cases reported in the ILSG study, all of them demonstrated expression of CD68, 94 % were immunoreactive for lysozyme, 33 % were immunoreactive for S-100, and none were immunoreactive for CD1a or CD21/CD35 [2]. Histiocytic sarcomas are rare neoplasms of hematopoietic origin and present more commonly in males in the second and third decade [8]. Lymph nodes, skin, and gastrointestinal tract [1, 2, 16–22] are the most common primary sites of involvement, while the spleen [2, 23–26], central nervous system [7–9], and other sites [18, 27, 28] are more rarely involved. Primary histiocytic sarcoma involving the CNS is exceptionally rare; no cases were identified by Bataille et al. [29] in a review of 220 cases of primary CNS lymphomas and other large studies [1, 2, 18, 30]. Given the rarity of primary histiocytic sarcoma involving the CNS, differential diagnosis should be broad; inflammatory, infectious and autoimmune conditions must be considered as the histology mimics inflammatory processes. Diagnoses to consider include diffuse large B-cell lymphoma, anaplastic large cell lymphoma, malignant fibrous histiocytoma, metastatic melanoma, inflammatory pseudotumor, sarcoid, cerebral abscess, glial cell tumors, and germ cell tumors. Based on the neuroimaging studies and the tumor location in our patient, we also considered schwannoma, meningioma, epidermoid tumor, and peripheral nerve sheath tumor. There have been only seven previous reported cases of histiocytic sarcoma involving the CNS (Table 2), and our report presents the 8th case of histiocytic sarcoma with CNS involvement. The largest study of histiocytic sarcoma involving the CNS thus far was presented by Cheuk et al. [7], in which 3 cases with
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Fig. 2 Immunohistochemical staining for a–c CD68 at 910, 920 and 940 and d–f CD163 at 910, 920 and 940 demonstrated strong reactivity. Staining for g–i ALK-1 was negative at 910, 920 and 940
immunochemistry were reported. Wu et al. [11] reported the most recent case in 2013, which demonstrated immunoreactivity for CD163, CD68, CD4, and fascin, with no immunoreactivity for CD1a, myeloperoxidase, CD43, CD45, CD35, CD23, CD21, GFAP, lysozyme, and S-100. This report represents the 2nd case in the literature of histiocytic sarcoma supported by immunohistochemistry arising from the cavernous sinus/Meckel’s cave, following the 1st report by Cao et al. [10].
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Histiocytic sarcoma is an aggressive neoplasm; patients usually present at an advanced stage and have poor prognosis. Despite extensive treatment, 6 of 8 patients in the report by Lauritzen et al. [19] died of disseminated disease, 5 within 14 months of diagnosis. The average survival of previously reported cases involving the CNS with known outcomes is approximately 6 months [8]. In the report by Cheuk et al. [7], one patient died at 8 months following diagnosis despite partial resection, whole brain
Brain Tumor Pathol Table 2 Recent reports of histiocytic sarcoma involving the CNS Author, Year
Case no.
Age/ Sex
Location
Survival
Torres et al. [9], 1996
1
20 mo/ M
Diffuse meningeal
5 months
Cheuk et al. [7], 2001
2
69 yo/ F
Parietal lobe
8 months
3
43 yo/ M
Intradural, extramedullary 9th thoracic level
Alive at 5 months
4
11 yo/ M
Cerebellum, occipital lobe and frontal lobe
4 months
Sun et al. [8], 2003
5
13 yo/ M
Occipital lobe and meninges
7 months
Cao et al. [10], 2007
6
53 yo/ F
Right cavernous sinus
42 months
Wu et al. [11], 2013
7
50 yo/ M
Right occipital/parietal lobe
Alive at 18 months
Present case
8
61 yo/ M
Cavernous sinus, Meckel’s cave and temporal lobe
Alive at 31 months
3.
5.
6.
7.
yo years old, mo months old, M male, F female
radiotherapy and chemotherapy, and another patient died at 4 months of diagnosis following partial resection. There is no standard treatment for histiocytic sarcoma, and the optimal radiation dose and treatment volume are yet to be determined. With the progression to disseminated disease in our patient, several options for chemotherapy were considered to deliver systemic treatment. ICE (ifosfamide, carboplatin, and etoposide with mesna) and CHOP are treatment regimens for patients diagnosed with aggressive lymphomas; however, their efficacy in the treatment of systemic histiocytic sarcoma has not been evaluated. There are recent case reports demonstrating potential benefit of thalidomide treatment [31, 32]. Our patient is currently alive at last follow-up, 31 months following initial presentation. Conflict of interest
4.
8.
9.
10.
11.
12.
13. 14.
15.
None. 16.
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