Hematological Oncology Hematol Oncol (2015) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hon.2275
Case Report
Retroperitoneal and mediastinal follicular dendritic cell sarcoma: report of 3 cases with review of literature Suvendu Purkait1†, Saumyaranjan Mallick1†, Prashant P. Joshi1, Supriyo Mallick3, N Vijaya Murugan2, Meher C. Sharma1, Vaishali Suri1, Biplab Mishra4 and Sandeep R. Mathur1* 1
Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India Department of Surgery, All India Institute of Medical Sciences, New Delhi, India 3 Department of Radiation, All India Institute of Medical Sciences, New Delhi, India 4 Oncology and Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India 2
*Correspondence to: Dr Sandeep R Mathur, Additional professor, Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: [email protected] † Both Suvendu and Saumyaranjan contributed equally for the Manuscript
Received 21 July 2015 Revised 5 October 2015 Accepted 27 October 2015
Abstract Follicular dendritic cell sarcoma (FDCS) is a rare malignant histiocytic proliferation of antigen presenting follicular dendritic cell. It is an uncommon primary malignancy first described by Monda et al. in 1986. Most commonly reported cases are lymph nodal. Occasional cases occur in extra nodal sites. Here, we describe the clinicopathological features, histomorphology and outcome of three patients with extranodal FDCS along with a concise review of literature on the topic. All three patients were adult females. Two patients were in third decade, and one had age of 50 years. Among the three cases, two cases are presented as retroperitoneal mass and one as mediastinal mass. CT scans revealed heterogeneously enhancing masses. All the cases showed ovoid to spindle neoplastic cells arranged predominantly in whorling, fascicular and storiform patterns with inflammatory infiltrate. Immunohistochemically, the tumor cells are positive for CD21, CD23, CD35 and Clustrin. In view of rarity and variable clinical presentation in FDCS, accurate diagnosis is necessary. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: follicular dendritic cell sarcoma; retroperitoneum; mediastinum
Introduction Follicular dendritic cell sarcoma (FDCS) is an uncommon primary malignancy of antigen presenting follicular dendritic cell first described by Monda et al. in 1986. [1] The dendritic cells are present in both nodal and extranodal location and form a stable network forming cell to cell attachment. This neoplasm is now grouped with other histiocytic and dendritic cell neoplasm in recent WHO classification [2]. Owing to the rarity of this lesion, there is paucity of large studies documenting clinical, histological and outcome parameters. Majority of the cases have been reported in the lymph nodes of the neck and axilla [3]. Extranodal cases comprises 33% [4]. FDCS in mesenteric and mediastinal location are extremely rare. In a pooled analysis of 343 cases, reported in English literature, primary mesenteric and mediastinal FDCS constituted only 3.8% and 6.1% respectively [5]. Because of spindle cell morphology the nodal cases are suspected easily compared extranodal where sarcoma and sarcomatoid carcinoma are more common. The rarity of this lesion may also partially be attributable to the lack of specific diagnostic markers in the past and leads to erroneous diagnosis of FDCS at presentation in approximately 19% cases. The natural history and Copyright © 2015 John Wiley & Sons, Ltd.
pathobiology are not well established. Few cases reported to be associated with Epstein Barr virus infection [6]. However, because of the availability of specific immunohistochemical markers which can determine the FDC lineage, there is an increase interest in this entity in recent years. In the present series, we highlighted the clinical characteristics, pathological features and immunohistochemical profile of two cases of mesenteric and one case of mediastinal FDCS.
Case reports Clinical features Case 1 A 24-year female presented with pain abdomen for the last 3 years, insidious onset and gradually progressive, dull aching diffuse pain present throughout the abdomen. Initially she visited a local hospital and was advised an Ultrasound abdomen, which confirmed the presence of a pelvic mass. She underwent surgery twice at outside hospitals 2.5 years and 2 years back respectively, but in both occasions the mass could not be removed as it was found to be extremely vascular. She came to our institution for
S Purkait et al.
further management. By now, the mass had grown to become palpable and was felt by the patient. The mass continued to grow gradually, and she began to have more frequent and more intense abdominal and left lower limb pain, which continued to worsen. The pain in her left lower limb was soon followed by gradual and progressive swelling of the same limb. Contrast enhanced computed tomography (CECT) abdomen revealed a well-defined solid enhancing mass in left pelvic region with extensive dense desmoplastic reaction. An attempt was made at curative surgery but in view of it being a densely adherent retroperitoneal mass, debulking was carried out. Patient denied chemotherapy, and the patient died after 3 months.
Case 2 A 50-year female presented with dull aching diffuse abdominal pain for 1 year and abdominal lump for last 6 months. Additionally, she developed patchy, scaly, skin lesion all over the body for 3 months which was clinically diagnosed as pemphigus. Fluorodeoxyglucose positron emission tomography (FDG PET) revealed a mesenteric soft tissue mass with involvement of multiple mesenteric lymph nodes. The patient underwent exploratory laparotomy and complete excision of the lesions. The patient was free of disease at 13 months of follow-up.
Case 3 A 27-year-old female patient with second trimester pregnancy presented in the outpatient department with complaint of hemoptysis and fever for 3 months. On examination the patient was detected to have right cervical lymphadenopathy. The patient underwent a lymph node aspiration which raised the suspicion of malignancy and ruled out tuberculosis. CECT chest (Figure 1C) showed a heterogeneously enhancing mediastinal mass occupying almost the entire right hemithorax with compression of the lung parenchyma. The patient underwent excision biopsy of the cervical lymph node. The patient showed encasement of right hilar vessels so treated with 6 cycles of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP). Post therapy patient had partial response but lesion remained unresectable. After 6 months patients progressed, and hence chemotherapy with Gemcitabine and Docetaxel was started but patient expired in view of progression.
Figure 1. A, B) Computerized tomography of case 1 showing well defined solid enhancing mass in left pelvic region with extensive dense desmoplastic reaction. C) Coronal section of case 3 showing heterogeneously enhancing mass in the mediastinum
heterogeneity showing fleshy areas along with areas of fibrosis, hemorrhage and cystic changes (Figure 2A) while the other case showed homogeneous fleshy appearance (Figure 2B).
Histopathological findings Macroscpic features Two of the three cases underwent excision of the lesions. In both the cases the tumors were well circumscribed with bosselated external surface and separated from the surrounding by fibrous capsule. The cut surfaces were multinodular and fleshy. One of these cases (case-1) exhibited marked Copyright © 2015 John Wiley & Sons, Ltd.
All the three cases exhibited similar histomorphological features. The tumors were composed of ovoid to spindle neoplastic cells arranged predominantly in whorl, fascicular and storiform patterns with focal vague nodule formation (Figure 3A, 3B). Individual tumor cells showed oval nuclei with vesicular chromatin, smooth nuclear membrane Hematol Oncol (2015) DOI: 10.1002/hon
Follicular dendritic cell sarcoma
Figure 2. A) Gross photograph of case 1 showing relatively well circumscribed lesion. Cut surface showed marked heterogeneity with fleshy areas along with areas of fibrosis, hemorrhage and cystic changes. B) Gross photograph of case 2 showing well circumscribed tumor. The cut surface is multinodular and fleshy
and indistinct to prominent nucleoli. The cells had moderate amount of eosinophilic cytoplasm with ill-defined cell borders (Figure 3C). A significant proportion of tumor cells had an epithelioid appearance (Figure 3D). Focal nuclear atypia with scattered bi or multinucleated cells resembling Reed–Sternberg cells were also noted. There were sprinkling of small mature looking lymphocytes throughout the tumors in all cases. There were focal areas of hemorrhage. One case showed small areas of coagulative necrosis (case1). Mitotic activity in all cases ranged from 1 to 3/10 hpf.
Immunohistochemistry The neoplastic cells in all cases showed immunopositivity for follicular dendritic cell markers (CD21, CD23 and CD35) (Figure 3E,3F,3H). Clusterin and HLA DR expressions were also detected in all cases (Figure 3G,3I). The tumor infiltrating lymphocytes were admixture of B (CD 20 positive) and T (CD3 positive) cells. A certain population of these cells also showed immunopositivity for Tdt. MIB 1 labeling index was variable, ranging from 2% to 8%. Immunopositivity for EBV LMP was not detected in any of the cases.
Discussion FDCS is a rare malignant neoplasm; extra-nodal occurrence of this neoplasm was first reported by Chan et al. in 1994 [7]. Since then extranodal FDCS has been described in various anatomical site, including head and neck, abdominal cavity, soft tissue, skin, lung etc. [8]. Amongst the intra-abdominal extranodal FDCS, the most commonly described site is liver. Only rare cases have been reported to involve primarily mesentery and retroperitoneum (Table 1). The clinical presentation usually depends on the site of involvement. A localized mass is the primary complaint in most of the cases. In the Copyright © 2015 John Wiley & Sons, Ltd.
present series we identified para-neoplastic pemphigus in one case in addition to abdominal lump. Interestingly few of the reported cases of FDCS have been found to be associated with para-neoplastic pemphigus which often may be the first clinical manifestation [9,10]. On the other hand, cases of mediastinal FDCS were often found to be associated with myesthenic symptom [11]. However in the present case with mediastinal lesion no myesthenic symptoms were detected. This lesion is often mis-diagnosed or under-diagnosed, particularly in the preoperative small sized biopsy specimen due of its rarity. The diagnosis of FDCS is based on histomorphological findings and immunohistochemical analysis. On histopathological examination, typically this tumor exhibits ovoid to spindle cells arranged in sheets, nets and fascicles, with scattered mature lymphocytes. However a wide range of focal morphological variations have been described in the literature. Histopathological grade of the tumor depends upon following parameters: architecture, cellular morphology, necrosis, pattern of lymphocytic infiltration and mitotic activity/Ki 67 labeling index. High grade tumor usually has diffuse or sheet-like arrangement with epithelioid or pleomorphic cell morphology and having marked nuclear atypia. These tumors often show high mitotic activity, areas of necrosis and only focal lymphocytic infiltration [12]. The differential diagnosis based on histomorphology and anatomical site includes malignant gastrointestinal stromal tumor (GIST), leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), histiocytic sarcoma, non Hodgkin lymphoma and Hodgkin disease etc. On H & E stained slides storiform architecture and epithelioid appearance of the spindled tumor cells are commonly identified histological features. Lymphocytic sprinkling throughout the tumor is another important clue. However, the final diagnosis is established only by demonstration of follicular dendritic cell differentiation of the neoplastic cells; CD21, CD23, CD35 and clusterin immunopositivity. All the cases in the present series were histologically low Hematol Oncol (2015) DOI: 10.1002/hon
S Purkait et al.
Figure 3. A) Photomicrograph showing fascicular storiform arrangement of the tumor cell with lymphocytic sprinkling (H & E × 40). B) Photomicrograph showing 3600 whorling arrangement of tumor cells (arrow) (H & E × 100). C) Photomicrograph showing individual tumor cells with vesicular nucleus and indistinct cytoplasm admixed with a significant proportion of mature looking lymphoid cells. Few tumor cells resemble mononuclear R S cells (arrow). Occasional mitotic figure is also seen (arrow head) (H & E × 200). D) Photomicrograph showing tumor cells with epithelioid appearance (H & E × 400). E) Photomicrograph showing cytoplasmic immunopositivity for CD21 (× 200), CD23 (F, × 200), clusterin (G × 200), CD35 (H × 200), HLA-DR (I × 200). J) Intratumoral lymphocytes highlighted by LCA. (× 200)
grade and showed immunoreactivity for all the follicular dendritic cell markers. None of the cases were immunopositive for EBV-LMP. The cases were also immunonegative for SMA, CD117, DOG1, S100, Pan Cytokeratin and CD68 ruling out other mesenchymal or histiocytic neoplasm with spindle cell morphology. Hence, in a sarcomatous lesion with storiform arrangement of spindle to ovoid tumor cells along with focal epithelioid cell morphology and significant amount of intratumoral lymphocytic sprinkling, one should suspect the possibility of this rare malignancy. Copyright © 2015 John Wiley & Sons, Ltd.
FDCS usually behaved like a low-grade soft tissue sarcoma with a tendency of local recurrence, reported in 23%–28% cases [5,12]. Distance metastasis has also been described in approximately in 27% cases by Saygin et al. [5] with common site of metastasis being lung, lymph nodes, liver and bone. Li et al. [12] in their clinicopathological analysis of 106 cases of extanodal FDCS (including 97 cases reported in the literature) found that majority of the patient survived more than 5 years with a 5-year overall survival of 79% and 5-year disease-free survival rates of 32%. Another study by Saygin et al. [5] (n-343, including Hematol Oncol (2015) DOI: 10.1002/hon
Follicular dendritic cell sarcoma
Table 1. Clinicopathological characteristics, treatments and outcome of the cases of intra-abdominal (Not arising from any visceral organ) and mediastinal FDCS Age (yrs) Sex
Site
Size (cm)
Treatment
Follow-up
Status
Chan et al., 1997 [15] Chiaramonte et al., 2001[16] Jiang et al., 2006 [17] Shia et al., 2006 [18] Padilla-Rodríguez et al., 2007[19] Soriano et al., 2007 [20] Tu et al., 2007 [21] Liu et al., 2008 [22] Peng et al., 2008 [23] Li et al., 2010 [12]
42 39 46 29 35 55 63 42 60 36
M M F F M F M M M F
Mesocolon and LN Retroperitoneum Pelvic/abdominal cavity, multiple Lesser omentum Retroperitoneum Pelvis Jejunum mesentery Gastrocolic omentum Mesentry Mesentery
8 NA 21 12 21 6 15 12 12 15
Surg + CT Surg Surg Surg Surg + RT Surg Surg Surg Surg Surg
18 m 6m 6m 17 m 24 14 m — — — 27 m
DOD DOD NED NED NED NED — — — AWD
Ceresoli et al., 2003 [24] Krober et al., 2004 [25] Hartert et al., 2010 [26] Leipsic et al., 2007 [26] Present Series Case 1 Case 2 Case 3
35 76 39 43
M M M M
Mediastinum Dorsal mediastinum Anterior mediastinum Middle mediastinum
— 10 8 13
CT + RT Surg + RT Surg + RT Surg
7m 24 m — —
DOD NED — —
24 50 25
F F F
Retroperitoneum Mesentery Mediastinal and right hemithorax
8 7 17
Surg Surg CT
3m 13 m 6m
DOD NED DOD
Surg, surgery; NED, no evidence of disease; AWD, alive with disease; DOD, died of disease.
337 cases reported in the literature) demonstrated 2-year survival rates for early, locally advanced and distant metastatic diseases of 82.4%, 80% and 42.8%, respectively. Interestingly, Perkins et al. [13] reported a significantly better overall survival in patients with FDCS as compared to cases of interdigitating dendritic cell sarcoma. The pathological parameters which appeared to have significant prognostic impact includes: tumor size (< 5 cm vs ≥ 5 cm), mitotic activity (< 5 mitosis/10 hpf vs ≥ 5 mitosis/10 hpf) and histological grade (low grade vs high grade). FDCS primarily involving the retro peritoneum/mesentery were found to have similar histological features and clinical outcomes as compared to their counterparts in other extranodal sites [12]. In addition to larger size (> 6 cm) and high mitotic activity (≥ 5 mitosis/10 hpf), study by Saygin et al. [5] revealed young age at diagnosis (≤ 40 years) and absence of lymphoplasmacytic are also indicators of poor prognosis. However, on multivariate analysis, only the lymphoplasmacytic infiltration and tumor size emerged as independent prognostic parameters. Interestingly disease stage did not show any significant correlation with overall survival [5]. Although there is no consensus regarding the treatment protocol of FDCS, majority of the cases described in the literature have been treated with surgery (Table 1) [5,13,14]. Saygin et al. [5] demonstrated that patients treated with surgery alone had significantly longer overall survival as compared to cases who received other treatment modalities. The role of adjuvant chemo/radiation therapy in patients with limited stage disease or respectable lesion remains controversial. Both the study by Saygin et al. [5] and Perkins et al. [13] reported no additional benefits of Copyright © 2015 John Wiley & Sons, Ltd.
adjuvant radiotherapy in localized disease. However, in patients with advanced disease combined chemoradiotherapy appeared to be an important treatment modality. Chemotherapeutic regimens designed to manage aggressive lymphomas including CHOP, ICE and ABVD (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine) remains the mainstay of treatment for disseminated FDCS and have been used with variable success. Hence, patients with localized disease may be treated similar to a soft tissue sarcoma as suggested by Perkins et al. [13], and adjuvant therapy should be reserved for patient with locally advanced or disseminated diseases. In the present series all the tumor were large sized (>5 cm). However, complete resection was achieved in only one case (cases 2). Interestingly, patient who underwent complete resection was alive without any evidence of disease at 13-month follow-up, while the other patient had progressive disease and died. Hence it can be commented that in addition to histopathological features, the anatomical site and surgical resectibility are major prognostic parameters in deciding outcome.
Conflict of interest There is no conflict of interest.
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differentiation: a report of 4 cases. Am J Pathol 1986; 122: 562–572. Jaffe ES, Harris NL, Stein H, Vardiman JW. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC, 2001. De Pas T, Spitaleri G, Pruneri G, et al Dendritic cell sarcoma: an analytic overview of the literature and presentation of original five cases. Crit Rev Oncol Hematol 2008; 65: 1–7. Fonseca R, Yamakawa M, Nakamura S, et al. Follicular dendritic cell sarcoma and interdigitating reticulum cell sarcoma: a review. Am J Hematol 1998; 59(2): 161–7. Saygin C, Uzunaslan D, Ozguroglu M, Senocak M, Tuzuner N. Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series. Crit Rev Oncol Hematol 2013; 88(2): 253–71. Biddle DA, Ro JY, Yoon GS, Yong YW, Ayala AG, Ordonez NG, Ro J. Extranodal follicular dendritic cell sarcoma of the head and neck region: three new cases, with a review of the literature. Mod Pathol. 2002; 15(1): 50–8. Review. Erratum in: Mod Pathol 2002; 15(4): 475. Chan JK, Tsang WY, Ng CS, Tang SK, Yu HC. Follicular dendritic cell tumors of the oral cavity. Am J Surg Pathol 1994; 18: 148–157. Youens KE, Waugh MS. Extranodal follicular dendritic cell sarcoma. Arch Pathol Lab Med 2008; 132: 1683–1687. Baghmar S, Kumar S, Gupta SD, Raina V. Follicular dendritic cell sarcoma with paraneoplatic pemphigus: rare case and a brief review of literature. Indian J Med Paediatr Oncol 2013; 34: 317–9. Liu KL, Shen JL, Yang CS, Chen YJ. Paraneoplastic pemphigus as the first manifestation of follicular dendritic cell sarcoma. J Dtsch Dermatol Ges 2014; 12: 68–71. Hartert M, Ströbel P, Dahm M, et al. A follicular dendritic cell sarcoma of the mediastinum with immature T cells and association with myasthenia gravis. Am J Surg Pathol 2010; 34: 742–5. Li L, Shi YH, Guo ZJ, et al. Clinicopathological features and prognosis assessment of extranodal follicular dendritic cell sarcoma. World J Gastroenterol 2010; 16: 2504–19. Perkins SM, Shinohara ET. Interdigitating and follicular dendritic cell sarcomas: a SEER analysis. Am J Clin Oncol 2013; 36: 395–8. Dalia S, Shao H, Sagatys E, Cualing H, Sokol L. Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment. Cancer Control 2014; 21: 290–300.
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15. Chan JK, Fletcher CD, Nayler SJ, Cooper K. Follicular dendritic cell sarcoma. Clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized. Cancer 1997; 79: 294–313. 16. Chiaramonte MF, Lee D, Abruzzo LV, Heyman M, Bass BL. Retroperitoneal follicular dendritic cell sarcoma presenting as secondary amyloidosis. Surgery 2001; 130: 109–111. 17. Jiang Y, Yao M, Liu Q. Follicular dendritic cell sarcoma occurring in the pelvic and abdominal cavity, a case report. Shanghai Yixue Yingxiang 2006; 15: 174–175. 18. Shia J, Chen W, Tang LH, et al. Extranodal follicular dendritic cell sarcoma: clinical, pathologic, and histogenetic characteristics of an underrecognized disease entity. Virchows Arch 2006; 449: 148–158. 19. Padilla-Rodríguez AL, Bembassat M, Lazaro M, OrtizHidalgo C. Intra-abdominal follicular dendritic cell sarcoma with marked pleomorphic features and aberrant expression of neuroendocrine markers: report of a case with immunohistochemical analysis. Appl Immunohistochem Mol Morphol 2007; 15: 346–352. 20. Soriano AO, Thompson MA, Admirand JH, et al. Follicular dendritic cell sarcoma: a report of 14 cases and a review of the literature. Am J Hematol 2007; 82: 725–728. 21. Tu XY, Sheng WQ, Lu HF, Wang J. Clinicopathologic study of intraabdominal extranodal follicular dendritic cell sarcoma. Zhonghua Binglixue Zazhi 2007; 36: 660–665. 22. Liu YH, Wang XH, Lu LM. Pathological features of follicular cell sarcoma of gastrocolic omentum: a case report and review of the literatures. Wannan Yixueyuan Xuebao 2008; 27: 118–120. 23. Peng WJ, Yao LQ. Small mesenteric follicular dendritic cell sarcoma: a case report and literature review. Zhongguo Wu zhenxue Zazhi 2008; 8: 3040–3042. 24. Ceresoli GL, Zucchinelli P, Ponzoni M, et al. Mediastinal follicular dendritic cell sarcoma. Haematologica 2003; 88: ECR04. 25. Kröber SM, Marx A, Aebert H, Dohmen BM, Kaiserling E. Sarcoma of follicular dendritic cells in the dorsal mediastinum. Hum Pathol 2004; 35: 259–63. 26. Leipsic JA, McAdams HP, Sporn TA. Follicular dendritic cell sarcoma of the mediastinum. AJR Am J Roentgenol 2007; 188: W554–6.
Hematol Oncol (2015) DOI: 10.1002/hon
Case Report
Retroperitoneal and mediastinal follicular dendritic cell sarcoma: report of 3 cases with review of literature Suvendu Purkait1†, Saumyaranjan Mallick1†, Prashant P. Joshi1, Supriyo Mallick3, N Vijaya Murugan2, Meher C. Sharma1, Vaishali Suri1, Biplab Mishra4 and Sandeep R. Mathur1* 1
Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India Department of Surgery, All India Institute of Medical Sciences, New Delhi, India 3 Department of Radiation, All India Institute of Medical Sciences, New Delhi, India 4 Oncology and Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India 2
*Correspondence to: Dr Sandeep R Mathur, Additional professor, Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. E-mail: [email protected] † Both Suvendu and Saumyaranjan contributed equally for the Manuscript
Received 21 July 2015 Revised 5 October 2015 Accepted 27 October 2015
Abstract Follicular dendritic cell sarcoma (FDCS) is a rare malignant histiocytic proliferation of antigen presenting follicular dendritic cell. It is an uncommon primary malignancy first described by Monda et al. in 1986. Most commonly reported cases are lymph nodal. Occasional cases occur in extra nodal sites. Here, we describe the clinicopathological features, histomorphology and outcome of three patients with extranodal FDCS along with a concise review of literature on the topic. All three patients were adult females. Two patients were in third decade, and one had age of 50 years. Among the three cases, two cases are presented as retroperitoneal mass and one as mediastinal mass. CT scans revealed heterogeneously enhancing masses. All the cases showed ovoid to spindle neoplastic cells arranged predominantly in whorling, fascicular and storiform patterns with inflammatory infiltrate. Immunohistochemically, the tumor cells are positive for CD21, CD23, CD35 and Clustrin. In view of rarity and variable clinical presentation in FDCS, accurate diagnosis is necessary. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: follicular dendritic cell sarcoma; retroperitoneum; mediastinum
Introduction Follicular dendritic cell sarcoma (FDCS) is an uncommon primary malignancy of antigen presenting follicular dendritic cell first described by Monda et al. in 1986. [1] The dendritic cells are present in both nodal and extranodal location and form a stable network forming cell to cell attachment. This neoplasm is now grouped with other histiocytic and dendritic cell neoplasm in recent WHO classification [2]. Owing to the rarity of this lesion, there is paucity of large studies documenting clinical, histological and outcome parameters. Majority of the cases have been reported in the lymph nodes of the neck and axilla [3]. Extranodal cases comprises 33% [4]. FDCS in mesenteric and mediastinal location are extremely rare. In a pooled analysis of 343 cases, reported in English literature, primary mesenteric and mediastinal FDCS constituted only 3.8% and 6.1% respectively [5]. Because of spindle cell morphology the nodal cases are suspected easily compared extranodal where sarcoma and sarcomatoid carcinoma are more common. The rarity of this lesion may also partially be attributable to the lack of specific diagnostic markers in the past and leads to erroneous diagnosis of FDCS at presentation in approximately 19% cases. The natural history and Copyright © 2015 John Wiley & Sons, Ltd.
pathobiology are not well established. Few cases reported to be associated with Epstein Barr virus infection [6]. However, because of the availability of specific immunohistochemical markers which can determine the FDC lineage, there is an increase interest in this entity in recent years. In the present series, we highlighted the clinical characteristics, pathological features and immunohistochemical profile of two cases of mesenteric and one case of mediastinal FDCS.
Case reports Clinical features Case 1 A 24-year female presented with pain abdomen for the last 3 years, insidious onset and gradually progressive, dull aching diffuse pain present throughout the abdomen. Initially she visited a local hospital and was advised an Ultrasound abdomen, which confirmed the presence of a pelvic mass. She underwent surgery twice at outside hospitals 2.5 years and 2 years back respectively, but in both occasions the mass could not be removed as it was found to be extremely vascular. She came to our institution for
S Purkait et al.
further management. By now, the mass had grown to become palpable and was felt by the patient. The mass continued to grow gradually, and she began to have more frequent and more intense abdominal and left lower limb pain, which continued to worsen. The pain in her left lower limb was soon followed by gradual and progressive swelling of the same limb. Contrast enhanced computed tomography (CECT) abdomen revealed a well-defined solid enhancing mass in left pelvic region with extensive dense desmoplastic reaction. An attempt was made at curative surgery but in view of it being a densely adherent retroperitoneal mass, debulking was carried out. Patient denied chemotherapy, and the patient died after 3 months.
Case 2 A 50-year female presented with dull aching diffuse abdominal pain for 1 year and abdominal lump for last 6 months. Additionally, she developed patchy, scaly, skin lesion all over the body for 3 months which was clinically diagnosed as pemphigus. Fluorodeoxyglucose positron emission tomography (FDG PET) revealed a mesenteric soft tissue mass with involvement of multiple mesenteric lymph nodes. The patient underwent exploratory laparotomy and complete excision of the lesions. The patient was free of disease at 13 months of follow-up.
Case 3 A 27-year-old female patient with second trimester pregnancy presented in the outpatient department with complaint of hemoptysis and fever for 3 months. On examination the patient was detected to have right cervical lymphadenopathy. The patient underwent a lymph node aspiration which raised the suspicion of malignancy and ruled out tuberculosis. CECT chest (Figure 1C) showed a heterogeneously enhancing mediastinal mass occupying almost the entire right hemithorax with compression of the lung parenchyma. The patient underwent excision biopsy of the cervical lymph node. The patient showed encasement of right hilar vessels so treated with 6 cycles of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP). Post therapy patient had partial response but lesion remained unresectable. After 6 months patients progressed, and hence chemotherapy with Gemcitabine and Docetaxel was started but patient expired in view of progression.
Figure 1. A, B) Computerized tomography of case 1 showing well defined solid enhancing mass in left pelvic region with extensive dense desmoplastic reaction. C) Coronal section of case 3 showing heterogeneously enhancing mass in the mediastinum
heterogeneity showing fleshy areas along with areas of fibrosis, hemorrhage and cystic changes (Figure 2A) while the other case showed homogeneous fleshy appearance (Figure 2B).
Histopathological findings Macroscpic features Two of the three cases underwent excision of the lesions. In both the cases the tumors were well circumscribed with bosselated external surface and separated from the surrounding by fibrous capsule. The cut surfaces were multinodular and fleshy. One of these cases (case-1) exhibited marked Copyright © 2015 John Wiley & Sons, Ltd.
All the three cases exhibited similar histomorphological features. The tumors were composed of ovoid to spindle neoplastic cells arranged predominantly in whorl, fascicular and storiform patterns with focal vague nodule formation (Figure 3A, 3B). Individual tumor cells showed oval nuclei with vesicular chromatin, smooth nuclear membrane Hematol Oncol (2015) DOI: 10.1002/hon
Follicular dendritic cell sarcoma
Figure 2. A) Gross photograph of case 1 showing relatively well circumscribed lesion. Cut surface showed marked heterogeneity with fleshy areas along with areas of fibrosis, hemorrhage and cystic changes. B) Gross photograph of case 2 showing well circumscribed tumor. The cut surface is multinodular and fleshy
and indistinct to prominent nucleoli. The cells had moderate amount of eosinophilic cytoplasm with ill-defined cell borders (Figure 3C). A significant proportion of tumor cells had an epithelioid appearance (Figure 3D). Focal nuclear atypia with scattered bi or multinucleated cells resembling Reed–Sternberg cells were also noted. There were sprinkling of small mature looking lymphocytes throughout the tumors in all cases. There were focal areas of hemorrhage. One case showed small areas of coagulative necrosis (case1). Mitotic activity in all cases ranged from 1 to 3/10 hpf.
Immunohistochemistry The neoplastic cells in all cases showed immunopositivity for follicular dendritic cell markers (CD21, CD23 and CD35) (Figure 3E,3F,3H). Clusterin and HLA DR expressions were also detected in all cases (Figure 3G,3I). The tumor infiltrating lymphocytes were admixture of B (CD 20 positive) and T (CD3 positive) cells. A certain population of these cells also showed immunopositivity for Tdt. MIB 1 labeling index was variable, ranging from 2% to 8%. Immunopositivity for EBV LMP was not detected in any of the cases.
Discussion FDCS is a rare malignant neoplasm; extra-nodal occurrence of this neoplasm was first reported by Chan et al. in 1994 [7]. Since then extranodal FDCS has been described in various anatomical site, including head and neck, abdominal cavity, soft tissue, skin, lung etc. [8]. Amongst the intra-abdominal extranodal FDCS, the most commonly described site is liver. Only rare cases have been reported to involve primarily mesentery and retroperitoneum (Table 1). The clinical presentation usually depends on the site of involvement. A localized mass is the primary complaint in most of the cases. In the Copyright © 2015 John Wiley & Sons, Ltd.
present series we identified para-neoplastic pemphigus in one case in addition to abdominal lump. Interestingly few of the reported cases of FDCS have been found to be associated with para-neoplastic pemphigus which often may be the first clinical manifestation [9,10]. On the other hand, cases of mediastinal FDCS were often found to be associated with myesthenic symptom [11]. However in the present case with mediastinal lesion no myesthenic symptoms were detected. This lesion is often mis-diagnosed or under-diagnosed, particularly in the preoperative small sized biopsy specimen due of its rarity. The diagnosis of FDCS is based on histomorphological findings and immunohistochemical analysis. On histopathological examination, typically this tumor exhibits ovoid to spindle cells arranged in sheets, nets and fascicles, with scattered mature lymphocytes. However a wide range of focal morphological variations have been described in the literature. Histopathological grade of the tumor depends upon following parameters: architecture, cellular morphology, necrosis, pattern of lymphocytic infiltration and mitotic activity/Ki 67 labeling index. High grade tumor usually has diffuse or sheet-like arrangement with epithelioid or pleomorphic cell morphology and having marked nuclear atypia. These tumors often show high mitotic activity, areas of necrosis and only focal lymphocytic infiltration [12]. The differential diagnosis based on histomorphology and anatomical site includes malignant gastrointestinal stromal tumor (GIST), leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), histiocytic sarcoma, non Hodgkin lymphoma and Hodgkin disease etc. On H & E stained slides storiform architecture and epithelioid appearance of the spindled tumor cells are commonly identified histological features. Lymphocytic sprinkling throughout the tumor is another important clue. However, the final diagnosis is established only by demonstration of follicular dendritic cell differentiation of the neoplastic cells; CD21, CD23, CD35 and clusterin immunopositivity. All the cases in the present series were histologically low Hematol Oncol (2015) DOI: 10.1002/hon
S Purkait et al.
Figure 3. A) Photomicrograph showing fascicular storiform arrangement of the tumor cell with lymphocytic sprinkling (H & E × 40). B) Photomicrograph showing 3600 whorling arrangement of tumor cells (arrow) (H & E × 100). C) Photomicrograph showing individual tumor cells with vesicular nucleus and indistinct cytoplasm admixed with a significant proportion of mature looking lymphoid cells. Few tumor cells resemble mononuclear R S cells (arrow). Occasional mitotic figure is also seen (arrow head) (H & E × 200). D) Photomicrograph showing tumor cells with epithelioid appearance (H & E × 400). E) Photomicrograph showing cytoplasmic immunopositivity for CD21 (× 200), CD23 (F, × 200), clusterin (G × 200), CD35 (H × 200), HLA-DR (I × 200). J) Intratumoral lymphocytes highlighted by LCA. (× 200)
grade and showed immunoreactivity for all the follicular dendritic cell markers. None of the cases were immunopositive for EBV-LMP. The cases were also immunonegative for SMA, CD117, DOG1, S100, Pan Cytokeratin and CD68 ruling out other mesenchymal or histiocytic neoplasm with spindle cell morphology. Hence, in a sarcomatous lesion with storiform arrangement of spindle to ovoid tumor cells along with focal epithelioid cell morphology and significant amount of intratumoral lymphocytic sprinkling, one should suspect the possibility of this rare malignancy. Copyright © 2015 John Wiley & Sons, Ltd.
FDCS usually behaved like a low-grade soft tissue sarcoma with a tendency of local recurrence, reported in 23%–28% cases [5,12]. Distance metastasis has also been described in approximately in 27% cases by Saygin et al. [5] with common site of metastasis being lung, lymph nodes, liver and bone. Li et al. [12] in their clinicopathological analysis of 106 cases of extanodal FDCS (including 97 cases reported in the literature) found that majority of the patient survived more than 5 years with a 5-year overall survival of 79% and 5-year disease-free survival rates of 32%. Another study by Saygin et al. [5] (n-343, including Hematol Oncol (2015) DOI: 10.1002/hon
Follicular dendritic cell sarcoma
Table 1. Clinicopathological characteristics, treatments and outcome of the cases of intra-abdominal (Not arising from any visceral organ) and mediastinal FDCS Age (yrs) Sex
Site
Size (cm)
Treatment
Follow-up
Status
Chan et al., 1997 [15] Chiaramonte et al., 2001[16] Jiang et al., 2006 [17] Shia et al., 2006 [18] Padilla-Rodríguez et al., 2007[19] Soriano et al., 2007 [20] Tu et al., 2007 [21] Liu et al., 2008 [22] Peng et al., 2008 [23] Li et al., 2010 [12]
42 39 46 29 35 55 63 42 60 36
M M F F M F M M M F
Mesocolon and LN Retroperitoneum Pelvic/abdominal cavity, multiple Lesser omentum Retroperitoneum Pelvis Jejunum mesentery Gastrocolic omentum Mesentry Mesentery
8 NA 21 12 21 6 15 12 12 15
Surg + CT Surg Surg Surg Surg + RT Surg Surg Surg Surg Surg
18 m 6m 6m 17 m 24 14 m — — — 27 m
DOD DOD NED NED NED NED — — — AWD
Ceresoli et al., 2003 [24] Krober et al., 2004 [25] Hartert et al., 2010 [26] Leipsic et al., 2007 [26] Present Series Case 1 Case 2 Case 3
35 76 39 43
M M M M
Mediastinum Dorsal mediastinum Anterior mediastinum Middle mediastinum
— 10 8 13
CT + RT Surg + RT Surg + RT Surg
7m 24 m — —
DOD NED — —
24 50 25
F F F
Retroperitoneum Mesentery Mediastinal and right hemithorax
8 7 17
Surg Surg CT
3m 13 m 6m
DOD NED DOD
Surg, surgery; NED, no evidence of disease; AWD, alive with disease; DOD, died of disease.
337 cases reported in the literature) demonstrated 2-year survival rates for early, locally advanced and distant metastatic diseases of 82.4%, 80% and 42.8%, respectively. Interestingly, Perkins et al. [13] reported a significantly better overall survival in patients with FDCS as compared to cases of interdigitating dendritic cell sarcoma. The pathological parameters which appeared to have significant prognostic impact includes: tumor size (< 5 cm vs ≥ 5 cm), mitotic activity (< 5 mitosis/10 hpf vs ≥ 5 mitosis/10 hpf) and histological grade (low grade vs high grade). FDCS primarily involving the retro peritoneum/mesentery were found to have similar histological features and clinical outcomes as compared to their counterparts in other extranodal sites [12]. In addition to larger size (> 6 cm) and high mitotic activity (≥ 5 mitosis/10 hpf), study by Saygin et al. [5] revealed young age at diagnosis (≤ 40 years) and absence of lymphoplasmacytic are also indicators of poor prognosis. However, on multivariate analysis, only the lymphoplasmacytic infiltration and tumor size emerged as independent prognostic parameters. Interestingly disease stage did not show any significant correlation with overall survival [5]. Although there is no consensus regarding the treatment protocol of FDCS, majority of the cases described in the literature have been treated with surgery (Table 1) [5,13,14]. Saygin et al. [5] demonstrated that patients treated with surgery alone had significantly longer overall survival as compared to cases who received other treatment modalities. The role of adjuvant chemo/radiation therapy in patients with limited stage disease or respectable lesion remains controversial. Both the study by Saygin et al. [5] and Perkins et al. [13] reported no additional benefits of Copyright © 2015 John Wiley & Sons, Ltd.
adjuvant radiotherapy in localized disease. However, in patients with advanced disease combined chemoradiotherapy appeared to be an important treatment modality. Chemotherapeutic regimens designed to manage aggressive lymphomas including CHOP, ICE and ABVD (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine) remains the mainstay of treatment for disseminated FDCS and have been used with variable success. Hence, patients with localized disease may be treated similar to a soft tissue sarcoma as suggested by Perkins et al. [13], and adjuvant therapy should be reserved for patient with locally advanced or disseminated diseases. In the present series all the tumor were large sized (>5 cm). However, complete resection was achieved in only one case (cases 2). Interestingly, patient who underwent complete resection was alive without any evidence of disease at 13-month follow-up, while the other patient had progressive disease and died. Hence it can be commented that in addition to histopathological features, the anatomical site and surgical resectibility are major prognostic parameters in deciding outcome.
Conflict of interest There is no conflict of interest.
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Hematol Oncol (2015) DOI: 10.1002/hon
