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Intra-Extracranial Primary Clear Cell Sarcoma: The First Report and Review of the Literature
Original Article
Intra-Extracranial Primary Clear Cell Sarcoma: The First Report and Review of the Literature Gong Chen1, Shifeng Sun1, Zunguo Du2, Yirui Sun1, Zhiguang Pan1, Xiaoming Che1, Rong Xie1
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BACKGROUND: Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor with poor prognosis owing to metastasis and insensitive response to chemotherapy and radiotherapy.
molecular targeted therapy of CCS are needed to improve its poor prognosis.
METHODS: We first searched PubMed and Embase using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” “head,” and “neck.” In the 15 articles selected for literature review, only 27% (4/15) of patients were diagnosed with primary CCS of the head. Pathologically, those tumors arose from either the scalp or the superficial temporal fascia, but none invaded the skull and brain. Next, the search was performed in the same database using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” and “bone,” and only 24 articles were selected.
INTRODUCTION
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RESULTS: In the case reported here, a 36-year-old woman was found to have a palpable mass located at the left temporal-occipital region, and surgical finding confirmed the invasion into the skull and the brain. The diagnosis of primary CCS was made because of the detection of t(12;22)(q13;q12) in >50% of tumor cells by fluorescence in situ hybridization, and metastasis to the lymph nodes and lungs was discovered by postoperative positron emission tomography-computed tomography.
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CONCLUSIONS: To the best of our knowledge, this is the first case of primary central nervous system CCS. Primary CCS may involve the skull and should be one of the differential diagnoses for intra-extracranial communicating tumors. Further research on biological characteristics and
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C
lear cell sarcoma (CCS), first described by Enzinger in 1965,1 is a rare malignant soft tissue sarcoma deriving from the neural crest cells. Its etiology remains unknown, but some potential risk factors have been speculated, including exposure to chemicals, chronic tissue irritation, and radiation.2 In over 90% of cases, primary CCSs arise from extremities, particularly the feet and ankles.3-6 CCS usually presents as an indolent, growing, and painless mass situated in the deep soft tissue or beneath the fascia. The mean age at the time of diagnosis is approximately 25 years old, and no sex preference was observed.7 Metastasis to the lymphatic system and/or the lungs is commonly seen in CCS, which indicates the poor prognosis.5,6 Historically, CCS has been referred to as “malignant melanoma of soft tissue” because it could not be distinguished from malignant melanoma immunohistochemically. Most cases of CCS show a strong expression of S-100, HMB-45, Melan-A, and microphthalmia-associated transcription factor.8-10 Following the discovery of a recurrent chromosomal translocation, t(12;22)(q13;q12), CCS has been considered as a distinct entity apart from malignant melanoma.11-14 To date, only 15 cases of CCS arising from the head and neck have been reported in the literature.15-26 However, none of them were located within the cranial cavity. Here, we present the case of a 36-year-old woman that is likely to be the first report of intra-extracranial primary CCS and metastasis to the lungs at the early stage. Its unique clinical manifestation raised our awareness on radiologic characteristics and treatment of this rare tumor.
Key words - Brain invasion - Clear cell sarcoma (CCS) - Ewing sarcoma breakpoint region 1(EWSR1) - Intra-extracranial region
From the Departments of 1Neurosurgery and 2Pathology, Huashan Hospital, Fudan University, Shanghai, China
Abbreviations and Acronyms CCS: Clear cell sarcoma CT: Computed tomography MRI: Magnetic resonance imaging PET: Positron emission tomography T1WI: T1-weighted imaging T2WI: T2-weighted imaging
Citation: World Neurosurg. (2019) 126:e1140-e1146. https://doi.org/10.1016/j.wneu.2019.02.216
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To whom correspondence should be addressed: Rong Xie, M.D., Ph.D. [E-mail: [email protected]] Gong Chen and Shifeng Sun contributed equally to this article.
Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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Figure 1. Computed tomography (CT), magnetic resonance imaging (MRI), and 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) feature of the case. The CT bone window showed an intra-extracranial communicating lesion on the left temporal-occipital region with bone destruction and absorption (A; arrow). MRI demonstrated the lesion with isointensity in both T1-weighted imaging (T1WI; B) and T2-weighted imaging (T2WI; C). In brain edema surrounding the lesion, postcontrast T1WI showed heterogeneous
METHODS We first searched PubMed and Embase using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” “head,” and “neck.” Next, the search was performed in the same database using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” and “bone.” Inclusion criteria involved case series or case reports that included either molecular or histological diagnosis of CCS. Exclusion criteria involved metastatic CCS occurring at those locations and cases lacking the confirmation of pathological diagnosis. Selected case series and case reports were then compared, and further analysis was performed when necessary.
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enhancement (D; arrow). After surgery, CT revealed the extended resected range (E). Three-month follow-up MRI demonstrated that the tumor was totally removed, and brain edema disappeared in T1WI (F), T2WI (G), and postcontrast T1WI (H). The 18F-FDG PET/CT scans showed that left cervical (I), supraclavicular (J) lymph nodes and multiple nodules in both lungs (K; arrow) had higher levels of glucose metabolism, which was considered tumor metastasis.
RESULTS Clinic Findings A 36-year-old woman presented with a palpable mass under the left temporal-occipital scalp for 4 months, especially in the state of fatigue. One week before admission to our hospital, she experienced dizziness once lasting for several seconds, without loss of consciousness and tic of extremities. She had neither recent weight loss, nor a family history of brain tumors. No hyperpigmented macule was found on her body surface. Computed tomography (CT) revealed an intra- and extracranial communicating lesion approximately 3 x 3 x 3 cm in size on the left temporal-occipital region with
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Figure 2. Histopathological findings of the case. The neoplasms were distributed in solid and nest-like bundles, separated by scattered fibers and vessels. A small tumor cell cluster infiltrated the base material of dura (A; hematoxylin & eosin [H&E] stain, magnification 40). In oval or fusiform cells with the cytoplasm generally clear or mildly eosinophilic, pathologic mitosis was easily seen (B; H&E stains, magnification 400).
hyperdensity, accompanied with bone destruction and absorption. Followed magnetic resonance imaging (MRI) demonstrated the lesion with both isointense in T1-weighted imaging (T1WI) and T2weighted imaging (T2WI), heterogeneous enhanced, and brain edema surrounding the lesion (Figure 1). The preoperation diagnosis was considered as meningioma. Treatment and Follow-Up Under general anesthesia, the tumor was totally removed with the assistance of neuro-navigation, including the subcutaneous tissue,
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Immunohistochemical staining showed that the tumor cells were positive for HMB45 (C), SOX10 (D), and S100 (E). In the detection of Ewing sarcoma breakpoint region 1 (EWSR1) rearrangement by fluorescence in situ hybridization analysis, the separation of red and green signals (F; arrow) correspond to the rearranged EWSR1 allele.
skull, dura, and partial edema brain. It was a grayish-white mass with light vascularity, soft, multinodular irregularly shaped and measured approximately 3 3 3 cm3, and the margin of the tumor toward the cortex was not distinct. We used a neuropatch (Integra LifeSciences Corp., Plainsboro, New Jersey, USA), titanium plate, and screws (Medtronic, Minneapolis, Minnesota, USA) to compensate for the defect following resection. Several days after the operation, a palpable nodule was found on the left side of her neck, and lymphatic metastasis was highly suspected. Next, 2-[18F]-fluoro-2-deoxy-D-glucose positron
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Table 1. Clinical Features of Previously Reported Primary Clear Cell Sarcoma of the Head and Neck Author
Age/Sex
Site
Size (cm)
Treatment
24/F
Scalp
1.5
Surgery
33/M
Scalp
1.4
SurgeryþRT
No
No
23
NA
20/M
Face
0.6
Surgery
NA
NA
NA
NA
44/M
Tongue
NA
Surgery
NA
NA
NA
NA
Fan et al., 2015
20/F
Parapharyngeal
4.4
Surgery
No
No
NA
NA
Singh et al., 201421
29/F
Tongue
NA
Surgery
NA
NA
NA
NA
Ogawa et al., 201724 23
Feasel et al., 2016
22
26
Recurrence Metastasis Follow-Up (Months) Status No
No
24
NED
Sidiroupoulos et al., 2013
13/M
Lip
NA
Surgery
No
No
3
NED
Kraft et al., 201320
82/F
Tongue
2
Surgery
No
LN met
NA
NA
17/F
Mandibular
1.5
Surgery
No
No
33
NED
Garcia de Marcos et al., 2009
36/F
Superficial temporal fascia
2
SurgeryþRT
No
No
12
NED
Poignonec et al., 199416
75/M
Preparotid zone
NA
Surgery
NA
NA
NA
NA
Lucas et al., 1992
NA
Parotid gland
NA
NA
NA
NA
NA
NA
Manoel et al., 201217
43/F
Parotid
5
SurgeryþRT
8
No
14
NED
Hocar et al., 20124
20/F
Scalp
4
Surgery
84
96
120
DOD
26/F
Larynx
3.5
SurgeryþCh
No
11
16
NA
Inoue et al., 2013
19 25
15
18
Fukada et al., 2013
F, female; M, male; NA, not available; RT, radiation therapy; Ch, chemotherapy; NED, no evidence of disease; No, no recurrence or metastasis during follow-up; LN, lymph nodes; DOD, died of disease.
emission tomography (PET) and CT showed that the left cervical and supraclavicular lymph nodes, as well as multiple nodules in both lungs (peripheral nodule in lower lobe of both sides, with the diameter <8 mm) had much higher levels of glucose metabolism considered as tumor metastasis (Figure 1). Six days after tumor resection, she complained of headache, followed by sensory aphasia for several minutes. This time, CT scan revealed brain edema surrounding the resection region, and symptoms were relieved after treating with an antiepileptic drug and a dehydrating agent. Three months after surgery, she had recovered well and went back to work. However, she refused to undergo chemotherapy or radiotherapy. The palpable neck nodule disappeared, which was confirmed by the followed ultrasonic testing at the 3-month follow-up. CT revealed that the multiple nodules in both lungs maintained their original size. MRI demonstrated that the tumor was totally removed, and brain edema had also disappeared (Figure 1). Histological Findings Macroscopically, it was a grayish-white mass, multinodular irregularly shaped, and closely related to the cerebral dura mater, and invaded the skull. Microscopically, the neoplasms were distributed in solid and nest-like, a few in bundles, separated by scattered fibers and vessels. A small tumor cell cluster infiltrated the base material of the dura and skull, accompanied with neoplasm necrosis consisting of oval or fusiform cells with most of the cytoplasm generally clear or mildly eosinophilic. Few melanic pigments were observed. The nuclei were oval or short shuttle-like and granular, and pathologic mitosis was easily seen at 6-8 per 10HPF in a high-power field. Immunohistochemical staining showed that the tumor cells were
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positive for HMB45, SOX10, S100 (Figure 2), and PNL2 and negative for GFAP, UMB1, PR, CD117, STAT6, DES, CD34, and EMA-SMA. Ki67 made up approximately 10% of cells. Gene Analysis Fluorescence in situ hybridization using a Ewing sarcoma breakpoint region 1 probe showed that translocation t (22q12) can be found in >50% of cells (Figure 2). No genetic mutation was found in BRAF or NRAS genes. Therefore, this case was finally diagnosed with CCS of the soft tissue on the left temporal-occipital intra- and extracranial communicating region. Literature Review The study was approved by the institutional review boards of our hospital. The case presented here was retrieved from the institutional archives and consultation files. Extensive review of the English language literature to identify all previously reported cases of primary CCS arising from the head and neck, as well as that involving the bone, was performed by searching PubMed and Embase database. Primary CCS originating from the head and neck is an uncommon subgroup of this orphan malignancy. Our review of 15 cases previously reported in English-language literature showed that the tumors mainly occur in the tongue, parotid region, and scalp (Table 1). Women at the age ranging from 20e40 years seem to occupy the dominance. With the exception of one case lacking information of depth, the lesions of the scalp were limited within the dermis and subcutis.4,23,24 In addition, one case of multicentric CCS dependent on the superficial temporal fascia involved the temporal muscle.25
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Table 2. Clinical Features of Previously Reported Primary Clear Cell Sarcoma with Bone Invasion Author
Bone Invaded by the Tumor
Age/Sex
Hocar et al., 20124
Size (cm)
Treatment
Recurrence (Months)
Metastasis (Months)
Follow-Up (Months)
Status
9/M
Sacrum
7
SurgeryþRTþCh
12
12
20
DOD
15/F
Scapula
5
Surgery þCh
10
12
24
DOD
36/M
Tibia
3
Surgery þCh
16
20 LN 22 MT
28
DOD
15/F
Scapula
5
Surgery þCh
NA
NA
NA
NED
73/M
Scapula
10
Surgery þRTþCh
48
36 LN 24MT
96
DOD
20/M
Scapula
6
Surgery þRTþCh
18
18 LN 18 MT
24
DOD
18/M
Rib
5
Surgery þCh
3
No
55
NED
81/M
Pubic Bone
NA
Ch
NA
NA
NA
DOD
Liu et al., 2011
20/F
Humerus
24
NED
Zhang et al., 201132
25/M
Sacrum
11
Surgery
9
No
9
NA
Choi et al., 2003
48/F
Metatarsal
4.5
Surgery þRTþCh
No
7
20
DOD
Brekke et al., 199834
62/F
Metatarsal
2.5
NA
NA
NA
15
NED
17/F
Mandibular
1.5
Surgery
No
No
33
NED
Sharma et al., 2018
30/M
Calcaneal bone
9
Surgery
NA
NA
NA
NA
Licata et al., 201436
42/M
Metatarsal
4
Surgery
NA
NA
NA
NA
37
Omori et al., 2015
43/M
Carpal and metacarpal bone
5
Surgery þCh
No
16 LN 47 MT
47
DOD
Mootha et al., 201238
26/F
Tibia
NA
Surgery
No
No
18
NED
53/M
Sternum
10
Surgery
No
No
3
NED
Gelczer et al., 199929 Nakayama et al., 2012
30
31
33
Inoue et al., 2013
19 35
39
Rocco et al., 2009
Jakubauskas et al., 2011
42/M
Tibia
NA
Surgery þCh
5
1 LN 1 MT
8
DOD
Gollard et al., 200841
38/F
Thoracic vertebrae
5
Surgery þCh
NA
NA
NA
NA
Yokoyama 2000
33/F
Ulna
3.5
Surgery þCh
No
No
65
NED
Hersekli et al., 200543
28/F
Rib
9
Surgery þRT
No
No
33
NED
40/F
Calcaneal bone
NA
Surgery
No
No
36
NED
15/M
Tibia
6
Surgery þRTþCh
5
5 LN 14 MT
14
DOD
40
42
Bianchi et al., 2014
5 44
Morishita et al., 1987
F, female; M, male; NA, not available; RT, radiation therapy; Ch, chemotherapy; LN, lymph nodes; MT, metastasis; DOD, died of disease; NED, no evidence of disease; No, no recurrence or metastasis during follow-up.
Nevertheless, to date, there has been no reported case of primary CCS invading the skull and brain simultaneously. Although soft tissue sarcomas frequently rest in contact with bone, relatively few of them are able to penetrate cortical bone.27,28 Many surgeons considered the periosteum as a resistant barrier to the growth of sarcomas. According to the Ferguson et al.27 study, large, deep, and aggressive soft tissue sarcomas are more likely to invade the bone. We performed a literature search of the PubMed and Embase databases using the keyword combinations “clear cell sarcoma”/“malignant melanoma of soft parts” and “bone” and found 24 cases regarding bone invasion in primary CCS (Table 2).19,29-46 To the best of our knowledge, this is the first case of intraextracranial communicating primary CCS with bone destruction and adjacent brain edema, which would certainly add clinical value to the CCS diagnosis and therapy, especially in the neurosurgical area.
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DISCUSSION CCS is a rare malignant soft tissue tumor with poor prognosis owing to metastasis and insensitive response to chemotherapy and radiotherapy. Radical surgery has been deemed the best choice for this extremely rare malignancy accounting for only about 1% of all sarcomas. Imaging characteristics of CCS are varied and non-specific. Because of the existence of melanin pigment, some CCSs are identified by MRI as well-defined soft-tissue masses with T1WI hyperintensity and T2WI hypointensity.25,32,36,46-48 This is the result of paramagnetic properties of melanin shortening the T1 and T2 relaxing time.25,32,35 Conversely, those tumors not containing melanin pigment are more likely to show isointense signals on T1WI and isointense to hyperintense signal on T2WI.35,45 Prominent but heterogeneous enhancement is frequently observed after gadolinium-based agent injection. Moreover, CT scan with bone window may be used as supplements to identify bony
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erosion in cases where the tumors abut the bone closely.19,30 Differential diagnosis of intra-extracranial CCS based on clinical and radiologic findings may include malignant melanoma, meningioma, skull metastatic tumors, synovial sarcoma, and many other entities, which is always difficult. It is well documented that CCS has an aggressive course. The 5and 10-year overall survival is 50%e70% and 38%e50%, respectively in the literature.3-6 There are several factors associated with such poor outcomes, including the size of tumor, bone invasion, and metastasis to lymph nodes and distant organs. Early metastasis to lymph nodes and distant organs is an important characteristic of CCS. Although regional lymph node metastases are rarely seen in most soft tissue sarcomas, it accounts for 6%e13% in patients with CCS.35,47,49 Sentinel node biopsy has been reported in CCS to improve the accuracy of staging. Regional nodal involvement is often associated with synchronous or subsequent distant metastasis.48,50 The lung is the most common site of metastasis. Other sites include bone, liver, and brain. In the current case, highly metabolized lesions in left cervical and supraclavicular lymph nodes as well as both lungs were detected by PET-CT. Pulmonary metastasis was suspected because in most cases, primary lesions were assumed to be solitary, whereas metastatic ones were multiple, which was further supported by the only 2 cases of primary pulmonary CCS in the literature. In addition, lymph nodes in mediastinum regions were not affected, unlike most pulmonary malignant tumors. The neuro crest origin of CCS was further evidence supporting that primary CCS might arise from the central nervous system. We speculated that the aggressiveness of our case might be related to the increased mitotic activity and few melanin pigments, which was contrary to previous reports. However, because of the limitation of only 1 case so far, it is not sufficient to draw a conclusion that such pathologic findings are characteristics of primary CCS with skull and brain invasion.
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Extended surgical resection remains the primary treatment of CCS, but it is not enough for some aggressive cases. Adjuvant chemotherapy is recommended for patients with metastasis, whereas few studies supported the efficiency.5,6,51,52 Previous reports of objective response rate were all <10% for the use of systemic agents.53 For molecular targeted drug therapy of CCS, the expression of methionine induced by the pathognomonic Ewing sarcoma breakpoint region 1- activating transcription factor-1 fusion protein have subsequently been shown in CCS preclinical models, and the blocking of its activity significantly suppressed tumor growth both in vitro and in vivo.54 Therefore, a multi-tumor phase 2 clinical trial (EORTC 90101) has explored the use of the methionine/anaplastic lymphoma kinase inhibitor crizotinib for advanced CCS. The outcome was positive with a median progression-free survival of 131 days (49-235). Although extended resection was achieved in our case, systemic treatment was still recommended because of the metastasis behavior of the disease. However, the patient refused any adjuvant treatment. Then, a regular follow-up, including imaging examination was recommended at least every 6 months. Fortunately, metastatic lesions in both lungs remained stable at the 3-month follow-up, and lymphatic metastasis disappeared. One possible explanation for this phenomenon is the spontaneous regression following radical excision of the primary tumor, although it is an extremely rare event.55-57 CONCLUSIONS Primary CCS may involve the skull and should be one of the differential diagnoses for intra-extracranial communicating tumors. PET-CT is recommended for estimating the patients’ status because metastasis to lymph nodes and distant organs is commonly observed in this entity. Further research on biological characteristics and molecular targeted therapy of CCS are needed to improve its poor prognosis.
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36. Licata L, Fenga D, Speciale G, Rosa MA. Clear cell sarcoma of metatarsus. Folia Med. 2014;56:271-274. 37. Omori S, Hamada K, Outani H, et al. Intraoperative extracorporeal autogenous irradiated tendon grafts for functional limb salvage surgery of soft tissue sarcomas of the wrist and hand. World J Surg Oncol. 2015;13:179. 38. Mootha AK, Bali K, Kumar V, Rawall S, Saini R, Dhillon MS. Primary malignant melanoma of proximal tibia. J Knee Surg. 2012;25:75-78. 39. Rocco G, de Chiara AR, Fazioli F, et al. Primary giant clear cell sarcoma (soft tissue malignant melanoma) of the sternum. Ann Thorac Surg. 2009; 87:1927-1928. 40. Jakubauskas A, Valceckiene V, Andrekute K, Seinin D, Kanopka A, Griskevicius L. Discovery of two novel EWSR1/ATF1 transcripts in four chimerical transcripts-expressing clear cell sarcoma and their quantitative evaluation. Exp Mol Pathol. 2011;90:194-200. 41. Gollard R, Hussong J, Bledsoe J, Rosen L, Anson J. Clear cell sarcoma originating in a paraspinous tendon: case report and literature review. Acta Oncol. 2008;47:1593-1595. 42. Yokoyama R. Primary clear cell sarcoma of bone. Skelet Radiol. 2000;29:302. 43. Hersekli MA, Ozkoc G, Bircan S, et al. Primary clear cell sarcoma of rib. Skelet Radiol. 2005;34: 167-170. 44. Morishita S, Onomura T, Yamamoto S, Nakashima Y. Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts) with unusual roentgenologic findings. Case report. Clin Orthop Relat Res. 1987:276-279. 45. De Beuckeleer LH, De Schepper AM, Vandevenne JE, et al. MR imaging of clear cell sarcoma (malignant melanoma of the soft parts): a multicenter correlative MRI-pathology study of 21 cases and literature review. Skelet Radiol. 2000; 29:187-195. 46. Inaoka T, Takahashi K, Tandai S, et al. Primary clear cell sarcoma (malignant melanoma) in the right radius. Skelet Radiol. 2003;32:594-597. 47. Walker EA, Salesky JS, Fenton ME, Murphey MD. Magnetic resonance imaging of malignant soft tissue neoplasms in the adult. Radiol Clin North Am. 2011;49:1219-1234.vi.
48. Yanagawa T, Saito K, Takagishi K. Risk factors for lymphatic metastasis of malignant bone and softtissue tumors: a retrospective cohort study of 242 patients. Medicine (Baltimore). 2014;93:e225. 49. Hourani M, Khoury N, Mourany B, Shabb NS. MR appearance of clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft parts): radiologic-pathologic correlation. Skelet Radiol. 2005;34:543-546. 50. Keung EZ, Chiang YJ, Voss RK, et al. Defining the incidence and clinical significance of lymph node metastasis in soft tissue sarcoma. Eur J Surg Oncol. 2018;44:170-177. 51. Cornillie J, van Cann T, Wozniak A, Hompes D, Schoffski P. Biology and management of clear cell sarcoma: state of the art and future perspectives. Expert Rev Anticancer Ther. 2016;16:839-845. 52. Lee HL, Ho WY, Lam YL, et al. Prognostic factors associated with clear cell sarcoma in 14 Chinese patients. J Orthop Surg (Hong Kong). 2014;22: 236-239. 53. Jones RL, Constantinidou A, Thway K, et al. Chemotherapy in clear cell sarcoma. Med Oncol. 2011;28:859-863. 54. Schoffski P, Wozniak A, Stacchiotti S, et al. Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 “CREATE.”. Ann Oncol. 2017;28:3000-3008. 55. Takahashi T, Yoshimoto M, Kondoh N. Spontaneously regressed Langerhans cell histiocytosis of lymph nodes in an elderly patient. Intern Med. 2007;46:1757-1760. 56. Sadatomo A, Hozumi Y, Shiozawa M, Hirashima Y, Koinuma K, Kurihara K. Spontaneous regression of pulmonary metastases from a malignant phyllodes tumor. Jpn J Clin Oncol. 2011; 41:915-917. 57. Caces DB, Daniel S, Paredes-Tejada JM, Smith S. Spontaneous regression of follicular dendritic cell sarcoma. J Clin Oncol. 2012;30:e24-e26.
Conflict of interest statement: This work was supported by the National Natural Science Foundation of China (81571111, 81870909, R.X.), and National Natural Science Foundation of China (81602177, G.C.). Received 27 December 2018; accepted 22 February 2019 Citation: World Neurosurg. (2019) 126:e1140-e1146. https://doi.org/10.1016/j.wneu.2019.02.216 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.02.216
Intra-Extracranial Primary Clear Cell Sarcoma: The First Report and Review of the Literature Gong Chen1, Shifeng Sun1, Zunguo Du2, Yirui Sun1, Zhiguang Pan1, Xiaoming Che1, Rong Xie1
-
BACKGROUND: Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor with poor prognosis owing to metastasis and insensitive response to chemotherapy and radiotherapy.
molecular targeted therapy of CCS are needed to improve its poor prognosis.
METHODS: We first searched PubMed and Embase using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” “head,” and “neck.” In the 15 articles selected for literature review, only 27% (4/15) of patients were diagnosed with primary CCS of the head. Pathologically, those tumors arose from either the scalp or the superficial temporal fascia, but none invaded the skull and brain. Next, the search was performed in the same database using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” and “bone,” and only 24 articles were selected.
INTRODUCTION
-
RESULTS: In the case reported here, a 36-year-old woman was found to have a palpable mass located at the left temporal-occipital region, and surgical finding confirmed the invasion into the skull and the brain. The diagnosis of primary CCS was made because of the detection of t(12;22)(q13;q12) in >50% of tumor cells by fluorescence in situ hybridization, and metastasis to the lymph nodes and lungs was discovered by postoperative positron emission tomography-computed tomography.
-
CONCLUSIONS: To the best of our knowledge, this is the first case of primary central nervous system CCS. Primary CCS may involve the skull and should be one of the differential diagnoses for intra-extracranial communicating tumors. Further research on biological characteristics and
-
C
lear cell sarcoma (CCS), first described by Enzinger in 1965,1 is a rare malignant soft tissue sarcoma deriving from the neural crest cells. Its etiology remains unknown, but some potential risk factors have been speculated, including exposure to chemicals, chronic tissue irritation, and radiation.2 In over 90% of cases, primary CCSs arise from extremities, particularly the feet and ankles.3-6 CCS usually presents as an indolent, growing, and painless mass situated in the deep soft tissue or beneath the fascia. The mean age at the time of diagnosis is approximately 25 years old, and no sex preference was observed.7 Metastasis to the lymphatic system and/or the lungs is commonly seen in CCS, which indicates the poor prognosis.5,6 Historically, CCS has been referred to as “malignant melanoma of soft tissue” because it could not be distinguished from malignant melanoma immunohistochemically. Most cases of CCS show a strong expression of S-100, HMB-45, Melan-A, and microphthalmia-associated transcription factor.8-10 Following the discovery of a recurrent chromosomal translocation, t(12;22)(q13;q12), CCS has been considered as a distinct entity apart from malignant melanoma.11-14 To date, only 15 cases of CCS arising from the head and neck have been reported in the literature.15-26 However, none of them were located within the cranial cavity. Here, we present the case of a 36-year-old woman that is likely to be the first report of intra-extracranial primary CCS and metastasis to the lungs at the early stage. Its unique clinical manifestation raised our awareness on radiologic characteristics and treatment of this rare tumor.
Key words - Brain invasion - Clear cell sarcoma (CCS) - Ewing sarcoma breakpoint region 1(EWSR1) - Intra-extracranial region
From the Departments of 1Neurosurgery and 2Pathology, Huashan Hospital, Fudan University, Shanghai, China
Abbreviations and Acronyms CCS: Clear cell sarcoma CT: Computed tomography MRI: Magnetic resonance imaging PET: Positron emission tomography T1WI: T1-weighted imaging T2WI: T2-weighted imaging
Citation: World Neurosurg. (2019) 126:e1140-e1146. https://doi.org/10.1016/j.wneu.2019.02.216
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To whom correspondence should be addressed: Rong Xie, M.D., Ph.D. [E-mail: [email protected]] Gong Chen and Shifeng Sun contributed equally to this article.
Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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ORIGINAL ARTICLE GONG CHEN ET AL.
Figure 1. Computed tomography (CT), magnetic resonance imaging (MRI), and 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) feature of the case. The CT bone window showed an intra-extracranial communicating lesion on the left temporal-occipital region with bone destruction and absorption (A; arrow). MRI demonstrated the lesion with isointensity in both T1-weighted imaging (T1WI; B) and T2-weighted imaging (T2WI; C). In brain edema surrounding the lesion, postcontrast T1WI showed heterogeneous
METHODS We first searched PubMed and Embase using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” “head,” and “neck.” Next, the search was performed in the same database using the terms “clear cell sarcoma,” “malignant melanoma of soft tissue,” and “bone.” Inclusion criteria involved case series or case reports that included either molecular or histological diagnosis of CCS. Exclusion criteria involved metastatic CCS occurring at those locations and cases lacking the confirmation of pathological diagnosis. Selected case series and case reports were then compared, and further analysis was performed when necessary.
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INTRA-EXTRACRANIAL PRIMARY CLEAR CELL SARCOMA
enhancement (D; arrow). After surgery, CT revealed the extended resected range (E). Three-month follow-up MRI demonstrated that the tumor was totally removed, and brain edema disappeared in T1WI (F), T2WI (G), and postcontrast T1WI (H). The 18F-FDG PET/CT scans showed that left cervical (I), supraclavicular (J) lymph nodes and multiple nodules in both lungs (K; arrow) had higher levels of glucose metabolism, which was considered tumor metastasis.
RESULTS Clinic Findings A 36-year-old woman presented with a palpable mass under the left temporal-occipital scalp for 4 months, especially in the state of fatigue. One week before admission to our hospital, she experienced dizziness once lasting for several seconds, without loss of consciousness and tic of extremities. She had neither recent weight loss, nor a family history of brain tumors. No hyperpigmented macule was found on her body surface. Computed tomography (CT) revealed an intra- and extracranial communicating lesion approximately 3 x 3 x 3 cm in size on the left temporal-occipital region with
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INTRA-EXTRACRANIAL PRIMARY CLEAR CELL SARCOMA
Figure 2. Histopathological findings of the case. The neoplasms were distributed in solid and nest-like bundles, separated by scattered fibers and vessels. A small tumor cell cluster infiltrated the base material of dura (A; hematoxylin & eosin [H&E] stain, magnification 40). In oval or fusiform cells with the cytoplasm generally clear or mildly eosinophilic, pathologic mitosis was easily seen (B; H&E stains, magnification 400).
hyperdensity, accompanied with bone destruction and absorption. Followed magnetic resonance imaging (MRI) demonstrated the lesion with both isointense in T1-weighted imaging (T1WI) and T2weighted imaging (T2WI), heterogeneous enhanced, and brain edema surrounding the lesion (Figure 1). The preoperation diagnosis was considered as meningioma. Treatment and Follow-Up Under general anesthesia, the tumor was totally removed with the assistance of neuro-navigation, including the subcutaneous tissue,
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Immunohistochemical staining showed that the tumor cells were positive for HMB45 (C), SOX10 (D), and S100 (E). In the detection of Ewing sarcoma breakpoint region 1 (EWSR1) rearrangement by fluorescence in situ hybridization analysis, the separation of red and green signals (F; arrow) correspond to the rearranged EWSR1 allele.
skull, dura, and partial edema brain. It was a grayish-white mass with light vascularity, soft, multinodular irregularly shaped and measured approximately 3 3 3 cm3, and the margin of the tumor toward the cortex was not distinct. We used a neuropatch (Integra LifeSciences Corp., Plainsboro, New Jersey, USA), titanium plate, and screws (Medtronic, Minneapolis, Minnesota, USA) to compensate for the defect following resection. Several days after the operation, a palpable nodule was found on the left side of her neck, and lymphatic metastasis was highly suspected. Next, 2-[18F]-fluoro-2-deoxy-D-glucose positron
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Table 1. Clinical Features of Previously Reported Primary Clear Cell Sarcoma of the Head and Neck Author
Age/Sex
Site
Size (cm)
Treatment
24/F
Scalp
1.5
Surgery
33/M
Scalp
1.4
SurgeryþRT
No
No
23
NA
20/M
Face
0.6
Surgery
NA
NA
NA
NA
44/M
Tongue
NA
Surgery
NA
NA
NA
NA
Fan et al., 2015
20/F
Parapharyngeal
4.4
Surgery
No
No
NA
NA
Singh et al., 201421
29/F
Tongue
NA
Surgery
NA
NA
NA
NA
Ogawa et al., 201724 23
Feasel et al., 2016
22
26
Recurrence Metastasis Follow-Up (Months) Status No
No
24
NED
Sidiroupoulos et al., 2013
13/M
Lip
NA
Surgery
No
No
3
NED
Kraft et al., 201320
82/F
Tongue
2
Surgery
No
LN met
NA
NA
17/F
Mandibular
1.5
Surgery
No
No
33
NED
Garcia de Marcos et al., 2009
36/F
Superficial temporal fascia
2
SurgeryþRT
No
No
12
NED
Poignonec et al., 199416
75/M
Preparotid zone
NA
Surgery
NA
NA
NA
NA
Lucas et al., 1992
NA
Parotid gland
NA
NA
NA
NA
NA
NA
Manoel et al., 201217
43/F
Parotid
5
SurgeryþRT
8
No
14
NED
Hocar et al., 20124
20/F
Scalp
4
Surgery
84
96
120
DOD
26/F
Larynx
3.5
SurgeryþCh
No
11
16
NA
Inoue et al., 2013
19 25
15
18
Fukada et al., 2013
F, female; M, male; NA, not available; RT, radiation therapy; Ch, chemotherapy; NED, no evidence of disease; No, no recurrence or metastasis during follow-up; LN, lymph nodes; DOD, died of disease.
emission tomography (PET) and CT showed that the left cervical and supraclavicular lymph nodes, as well as multiple nodules in both lungs (peripheral nodule in lower lobe of both sides, with the diameter <8 mm) had much higher levels of glucose metabolism considered as tumor metastasis (Figure 1). Six days after tumor resection, she complained of headache, followed by sensory aphasia for several minutes. This time, CT scan revealed brain edema surrounding the resection region, and symptoms were relieved after treating with an antiepileptic drug and a dehydrating agent. Three months after surgery, she had recovered well and went back to work. However, she refused to undergo chemotherapy or radiotherapy. The palpable neck nodule disappeared, which was confirmed by the followed ultrasonic testing at the 3-month follow-up. CT revealed that the multiple nodules in both lungs maintained their original size. MRI demonstrated that the tumor was totally removed, and brain edema had also disappeared (Figure 1). Histological Findings Macroscopically, it was a grayish-white mass, multinodular irregularly shaped, and closely related to the cerebral dura mater, and invaded the skull. Microscopically, the neoplasms were distributed in solid and nest-like, a few in bundles, separated by scattered fibers and vessels. A small tumor cell cluster infiltrated the base material of the dura and skull, accompanied with neoplasm necrosis consisting of oval or fusiform cells with most of the cytoplasm generally clear or mildly eosinophilic. Few melanic pigments were observed. The nuclei were oval or short shuttle-like and granular, and pathologic mitosis was easily seen at 6-8 per 10HPF in a high-power field. Immunohistochemical staining showed that the tumor cells were
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positive for HMB45, SOX10, S100 (Figure 2), and PNL2 and negative for GFAP, UMB1, PR, CD117, STAT6, DES, CD34, and EMA-SMA. Ki67 made up approximately 10% of cells. Gene Analysis Fluorescence in situ hybridization using a Ewing sarcoma breakpoint region 1 probe showed that translocation t (22q12) can be found in >50% of cells (Figure 2). No genetic mutation was found in BRAF or NRAS genes. Therefore, this case was finally diagnosed with CCS of the soft tissue on the left temporal-occipital intra- and extracranial communicating region. Literature Review The study was approved by the institutional review boards of our hospital. The case presented here was retrieved from the institutional archives and consultation files. Extensive review of the English language literature to identify all previously reported cases of primary CCS arising from the head and neck, as well as that involving the bone, was performed by searching PubMed and Embase database. Primary CCS originating from the head and neck is an uncommon subgroup of this orphan malignancy. Our review of 15 cases previously reported in English-language literature showed that the tumors mainly occur in the tongue, parotid region, and scalp (Table 1). Women at the age ranging from 20e40 years seem to occupy the dominance. With the exception of one case lacking information of depth, the lesions of the scalp were limited within the dermis and subcutis.4,23,24 In addition, one case of multicentric CCS dependent on the superficial temporal fascia involved the temporal muscle.25
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Table 2. Clinical Features of Previously Reported Primary Clear Cell Sarcoma with Bone Invasion Author
Bone Invaded by the Tumor
Age/Sex
Hocar et al., 20124
Size (cm)
Treatment
Recurrence (Months)
Metastasis (Months)
Follow-Up (Months)
Status
9/M
Sacrum
7
SurgeryþRTþCh
12
12
20
DOD
15/F
Scapula
5
Surgery þCh
10
12
24
DOD
36/M
Tibia
3
Surgery þCh
16
20 LN 22 MT
28
DOD
15/F
Scapula
5
Surgery þCh
NA
NA
NA
NED
73/M
Scapula
10
Surgery þRTþCh
48
36 LN 24MT
96
DOD
20/M
Scapula
6
Surgery þRTþCh
18
18 LN 18 MT
24
DOD
18/M
Rib
5
Surgery þCh
3
No
55
NED
81/M
Pubic Bone
NA
Ch
NA
NA
NA
DOD
Liu et al., 2011
20/F
Humerus
24
NED
Zhang et al., 201132
25/M
Sacrum
11
Surgery
9
No
9
NA
Choi et al., 2003
48/F
Metatarsal
4.5
Surgery þRTþCh
No
7
20
DOD
Brekke et al., 199834
62/F
Metatarsal
2.5
NA
NA
NA
15
NED
17/F
Mandibular
1.5
Surgery
No
No
33
NED
Sharma et al., 2018
30/M
Calcaneal bone
9
Surgery
NA
NA
NA
NA
Licata et al., 201436
42/M
Metatarsal
4
Surgery
NA
NA
NA
NA
37
Omori et al., 2015
43/M
Carpal and metacarpal bone
5
Surgery þCh
No
16 LN 47 MT
47
DOD
Mootha et al., 201238
26/F
Tibia
NA
Surgery
No
No
18
NED
53/M
Sternum
10
Surgery
No
No
3
NED
Gelczer et al., 199929 Nakayama et al., 2012
30
31
33
Inoue et al., 2013
19 35
39
Rocco et al., 2009
Jakubauskas et al., 2011
42/M
Tibia
NA
Surgery þCh
5
1 LN 1 MT
8
DOD
Gollard et al., 200841
38/F
Thoracic vertebrae
5
Surgery þCh
NA
NA
NA
NA
Yokoyama 2000
33/F
Ulna
3.5
Surgery þCh
No
No
65
NED
Hersekli et al., 200543
28/F
Rib
9
Surgery þRT
No
No
33
NED
40/F
Calcaneal bone
NA
Surgery
No
No
36
NED
15/M
Tibia
6
Surgery þRTþCh
5
5 LN 14 MT
14
DOD
40
42
Bianchi et al., 2014
5 44
Morishita et al., 1987
F, female; M, male; NA, not available; RT, radiation therapy; Ch, chemotherapy; LN, lymph nodes; MT, metastasis; DOD, died of disease; NED, no evidence of disease; No, no recurrence or metastasis during follow-up.
Nevertheless, to date, there has been no reported case of primary CCS invading the skull and brain simultaneously. Although soft tissue sarcomas frequently rest in contact with bone, relatively few of them are able to penetrate cortical bone.27,28 Many surgeons considered the periosteum as a resistant barrier to the growth of sarcomas. According to the Ferguson et al.27 study, large, deep, and aggressive soft tissue sarcomas are more likely to invade the bone. We performed a literature search of the PubMed and Embase databases using the keyword combinations “clear cell sarcoma”/“malignant melanoma of soft parts” and “bone” and found 24 cases regarding bone invasion in primary CCS (Table 2).19,29-46 To the best of our knowledge, this is the first case of intraextracranial communicating primary CCS with bone destruction and adjacent brain edema, which would certainly add clinical value to the CCS diagnosis and therapy, especially in the neurosurgical area.
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DISCUSSION CCS is a rare malignant soft tissue tumor with poor prognosis owing to metastasis and insensitive response to chemotherapy and radiotherapy. Radical surgery has been deemed the best choice for this extremely rare malignancy accounting for only about 1% of all sarcomas. Imaging characteristics of CCS are varied and non-specific. Because of the existence of melanin pigment, some CCSs are identified by MRI as well-defined soft-tissue masses with T1WI hyperintensity and T2WI hypointensity.25,32,36,46-48 This is the result of paramagnetic properties of melanin shortening the T1 and T2 relaxing time.25,32,35 Conversely, those tumors not containing melanin pigment are more likely to show isointense signals on T1WI and isointense to hyperintense signal on T2WI.35,45 Prominent but heterogeneous enhancement is frequently observed after gadolinium-based agent injection. Moreover, CT scan with bone window may be used as supplements to identify bony
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erosion in cases where the tumors abut the bone closely.19,30 Differential diagnosis of intra-extracranial CCS based on clinical and radiologic findings may include malignant melanoma, meningioma, skull metastatic tumors, synovial sarcoma, and many other entities, which is always difficult. It is well documented that CCS has an aggressive course. The 5and 10-year overall survival is 50%e70% and 38%e50%, respectively in the literature.3-6 There are several factors associated with such poor outcomes, including the size of tumor, bone invasion, and metastasis to lymph nodes and distant organs. Early metastasis to lymph nodes and distant organs is an important characteristic of CCS. Although regional lymph node metastases are rarely seen in most soft tissue sarcomas, it accounts for 6%e13% in patients with CCS.35,47,49 Sentinel node biopsy has been reported in CCS to improve the accuracy of staging. Regional nodal involvement is often associated with synchronous or subsequent distant metastasis.48,50 The lung is the most common site of metastasis. Other sites include bone, liver, and brain. In the current case, highly metabolized lesions in left cervical and supraclavicular lymph nodes as well as both lungs were detected by PET-CT. Pulmonary metastasis was suspected because in most cases, primary lesions were assumed to be solitary, whereas metastatic ones were multiple, which was further supported by the only 2 cases of primary pulmonary CCS in the literature. In addition, lymph nodes in mediastinum regions were not affected, unlike most pulmonary malignant tumors. The neuro crest origin of CCS was further evidence supporting that primary CCS might arise from the central nervous system. We speculated that the aggressiveness of our case might be related to the increased mitotic activity and few melanin pigments, which was contrary to previous reports. However, because of the limitation of only 1 case so far, it is not sufficient to draw a conclusion that such pathologic findings are characteristics of primary CCS with skull and brain invasion.
REFERENCES 1. Enzinger FM. Clear-cell sarcoma of tendons and aponeuroses. An analysis of 21 cases. Cancer. 1965; 18:1163-1174. 2. Shmookler B, Bickels J, Jelinek J, Sugarbaker PH, Malawer MM. Bone and soft-tissue sarcomas: epidemiology, radiology, pathology and fundamentals of surgical treatment. In: Malawer MM, Sugarbaker PH, eds. Musculoskeletal Cancer Surgery: Treatment of Sarcomas and Allied Diseases. New York, NY: Springer; 2001:3-35. 3. Yu SJ, Zhao ZG, Zang L, Lu HZ, Zhang HT, Xu L. [Clinical treatment and prognosis for clear cell sarcoma: analysis of 19 cases]. Zhonghua Yi Xue Za Zhi. 2008;88:1458-1461.
Extended surgical resection remains the primary treatment of CCS, but it is not enough for some aggressive cases. Adjuvant chemotherapy is recommended for patients with metastasis, whereas few studies supported the efficiency.5,6,51,52 Previous reports of objective response rate were all <10% for the use of systemic agents.53 For molecular targeted drug therapy of CCS, the expression of methionine induced by the pathognomonic Ewing sarcoma breakpoint region 1- activating transcription factor-1 fusion protein have subsequently been shown in CCS preclinical models, and the blocking of its activity significantly suppressed tumor growth both in vitro and in vivo.54 Therefore, a multi-tumor phase 2 clinical trial (EORTC 90101) has explored the use of the methionine/anaplastic lymphoma kinase inhibitor crizotinib for advanced CCS. The outcome was positive with a median progression-free survival of 131 days (49-235). Although extended resection was achieved in our case, systemic treatment was still recommended because of the metastasis behavior of the disease. However, the patient refused any adjuvant treatment. Then, a regular follow-up, including imaging examination was recommended at least every 6 months. Fortunately, metastatic lesions in both lungs remained stable at the 3-month follow-up, and lymphatic metastasis disappeared. One possible explanation for this phenomenon is the spontaneous regression following radical excision of the primary tumor, although it is an extremely rare event.55-57 CONCLUSIONS Primary CCS may involve the skull and should be one of the differential diagnoses for intra-extracranial communicating tumors. PET-CT is recommended for estimating the patients’ status because metastasis to lymph nodes and distant organs is commonly observed in this entity. Further research on biological characteristics and molecular targeted therapy of CCS are needed to improve its poor prognosis.
6. Gonzaga MI, Grant L, Curtin C, Gootee J, Silberstein P, Voth E. The epidemiology and survivorship of clear cell sarcoma: a National Cancer Database (NCDB) review. J Cancer Res Clin Oncol. 2018;144:1711-1716. 7. Ibrahim RM, Steenstrup Jensen S, Juel J. Clear cell sarcoma: a review. J Orthop. 2018;15:963-966. 8. Davis IJ, Kim JJ, Ozsolak F, et al. Oncogenic MITF dysregulation in clear cell sarcoma: defining the MiT family of human cancers. Cancer Cell. 2006;9: 473-484. 9. Hisaoka M, Ishida T, Kuo TT, et al. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008;32:452-460.
4. Hocar O, Le Cesne A, Berissi S, et al. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 52 cases. Dermatol Res Pr. 2012;2012:984096.
10. Wang WL, Mayordomo E, Zhang W, et al. Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts). Mod Pathol. 2009;22:1201-1209.
5. Bianchi G, Charoenlap C, Cocchi S, et al. Clear cell sarcoma of soft tissue: a retrospective review and analysis of 31 cases treated at Istituto Ortopedico Rizzoli. Eur J Surg Oncol. 2014;40:505-510.
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Conflict of interest statement: This work was supported by the National Natural Science Foundation of China (81571111, 81870909, R.X.), and National Natural Science Foundation of China (81602177, G.C.). Received 27 December 2018; accepted 22 February 2019 Citation: World Neurosurg. (2019) 126:e1140-e1146. https://doi.org/10.1016/j.wneu.2019.02.216 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.02.216