Case Report Small cell carcinoma of the brain without extracranial involvement by serial CT, MRI and PET

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1 Int J Clin Exp Pathol 2010;3(3): /IJCEP Case Report Small cell carcinoma of the brain without extracranial involvement by serial CT, MRI and PET Tadashi Terada Department of Pathology, Shizuoka City Shimizu Hospital, Shizuoka, Japan. Received January 5, 2010, accepted January 25, 2010, available online January 28, Abstract: The author reports herein a case of small cell carcinoma of the brain without extracranial tumors by serial imaging modalities. A 75-year-old man presented with headache. Brain CT and MRI revealed a solitary cystic tumor (5 x 6 x 7 cm) in the left occipital lobe. Blood laboratory test revealed no significant findings. Preoperative diagnosis was a primary or metastatic brain tumor. Preoperative systemic examinations including CT, MRI and PET revealed no extracranial tumors. Tumorectomy was performed. Pathologically, the tumor was small cell carcinoma positive for four types of pancytokeratins, cytokeratin (CK) 7, CK 18, thyroid transcriptional factor-1 (TTF-1), CD56, chromogranin, synaptophysin, neuron-specific enolase, p53 protein, KIT, PDGFRA, and Ki-67 antigen (labeling = 100%). It was negative for high molecular weight CK, CK5/6, CK14, CK19, CK20, PE10, epithelial membrane antigen, vimentin, CEA, desmin, S100 protein, CA19-9, α-smooth muscle actin, CD34, p63, and CD68. The pathologic examination strongly suggested primary small cell lung carcinoma. However, repeated serial imaging modalities including systemic CT, MRI and PET revealed no extracranial tumors. The serial sputum cytology was always negative. The patient was treated with radiation and cisplatin-based chemotherapy, and no tumors were found seven months after the operation. The present case suggests that there are small cell carcinomas with a solitary brain metastasis without a radiologically detected primary site. In the present case, primary small cell brain carcinoma cannot be excluded completely, although such a case has not been reported in the literature. Keywords: Brain, small cell carcinoma, histopathology, immunohistochemistry Introduction Brain malignancies are classified into primary and metastatic brain tumors. Some primary carcinomas such as choroid plexus carcinoma and germ cell tumors occur in the brain. However, primary small cell brain carcinoma has not been reported, to the best of the author s knowledge. Small cell carcinoma can occur in any organ, but the majority of cases develop in the lung. Lung malignancies relatively frequently metastasize to the brain, and the majority of metastatic brain tumors are lung carcinoma, followed in order by gastrointestinal carcinoma and breast carcinoma [1-3]. Brain metastasis of carcinoma is common. In the majority of cases, extracranial carcinoma is first recognized, and brain metastases develop later. Carcinoma with a first manifestation of brain metastasis is relatively rare [1-3]. In addition, metastatic brain tumors without detectable primary sites are very rare [1-3]. In general, determination of the origin of metastatic malignancy is difficult pathologically. Immunohistochemistry is used to determine the origin. However, because few specific antibodies are known (such as PSA for prostatic carcinoma), a panel of antibodies is used. Nevertheless, determination of the origin and histological type is frequently difficult. The author herein reports a case of brain small cell carcinoma without detectable extracranial primary site by serial CT, MRI, PET and other examinations.

2 Case Report A 75-year-old man presented with a headache. Brain CT and MRI revealed a solitary cystic tumor (5 x 6 x 7 cm) in the left occipital lobe (Figure 1). Preoperative diagnosis was primary or metastatic brain tumor. Blood laboratory tests showed no significant findings. Preoperative systemic examinations including CT, MRI and PET revealed no extracranial tumors. Tumorectomy was performed. Pathologically, the tumor was composed of medullary small cells with scant cytoplasm, hyperchromatic nuclei, and molded nuclei, without nucleoli (Figure 2A). An immunohistochemical study was performed with the use of the Dako Envision method, as previously reported [4-7]. The antibodies and results are shown in Table 1. The tumor cells were positive for four types of pancytokeratins, cytokeratin (CK) 7 (Figure 2B), CK 18 (Figure 2C), thyroid transcriptional fator-1 (TTF-1) (Figure 2D), CD56 (Figure 2E), chromogranin, synaptophysin, neuron-specific enolase, p53 protein, KIT (Figure 2F), PDGFRA, and Ki-67 antigen (labeling = 100%). The tumor was negative for high molecular weight CK, CK5/6, CK14, CK19, CK20, PE10, epithelial membrane antigen, vimentin, CEA, desmin, S100 protein, CA19-9, α-smooth muscle actin, CD34, p63, and CD68 (Table 1). Therefore, a pathologic diagnosis of small cell carcinoma was made. The pathologic examination strongly suggested primary small cell lung carcinoma. However, repeated serial imaging modalities including systemic CT, MRI and PET revealed no extracranial tumors. The serial sputum cytology was also negative. The patient was treated with radiation and cisplatin-based chemotherapy. Extracranial tumors remain undetectable seven months after the operation. Discussion Figure 1. A solitary cystic brain tumor (5 x 6 x 7 cm) is present in the right occipital lobe. The present brain tumor showed typical histological features of small cell carcinoma. However, the author performed an immunohistochemical study to exclude primary small round cell tumors of the brain such as neuroblastoma and medulloblastoma. The immunohistochemical study revealed positive reactions for various cytokeratins and neuroendocrine antigens (CD56, chromogranin, synaptophysin, and neuron-specific enolase). Therefore, the present brain tumor is apparently small cell neuroendocrine carcinoma. In the present study, no extracranial tumors were observed in spite of repeated serial CT, MRI, PET and clinical cytology 11 months after the operation. A similar case has been recently reported by Hueser et al. [9]. The present small cell carcinoma of the brain may be a primary brain tumor. However, such a primary small cell brain tumor has not been reported in the literature. Otherwise, occult small cell carcinoma of other organs may be present in the present case. Small cell carcinoma can occur in any organ, but the majority of cases are small cell lung carcinoma. In addition, the most common primary site of brain metastasis is the lung [1-3]. Therefore, small cell lung carcinoma is most likely. The present immunohistochemical data also showed positive TTF-1 results, a relatively specific marker of lung and thyroid carcinoma [10-13]. The present CK profiling, in particular positive CK7 and negative CK20, also suggests a lung origin [11-14]. However, repeated CT, MRI, PET and cytology revealed no tumors in the lung. However, it is possible that very tiny occult small cell lung carcinoma not detectable by these techniques is present in the lung. 324 Int J Clin Exp Pathol 2010;3(3):

3 Figure 2. A. The brain tumor is a typical small cell carcinoma. HE, x100; B. The tumor is positive for cytokeratin 7. Immunostain, x100; C. The tumor is positive for cytokeratin 18. Immunostain, x100; D. The tumor is positive for TTF- 1. Immunostain, x100; E. The tumor is positive for CD56. Immunostain, x100; F. The tumor is positive for KIT. Immunostain, x100. The possibility of extrapulmonary small cell carcinoma should be taken into account. However, the imaging techniques and laboratory data did not identify any tumors in the body. It is possible that occult extrapulmonary small cell carcinoma may be present. The observation period of the present case was seven months. Strict follow-up and more serial imaging techniques are necessary to detect the primary site. It is of academic interest that the present small cell carcinoma of the brain expressed KIT and PDGFRA. In small cell lung carcinoma, several studies showed frequent expression of KIT, and 325 Int J Clin Exp Pathol 2010;3(3):

4 Table 1. Immunohistochemical reagents and results Antigens Antibodies (clone) Sources Results Pancytokeratin AE1/3 Dako Corp. Glostrup, Denmark +++ Pancytokeratin polyclonal wide Dako +++ Pancytokeratin KL-1 Immunotech, Marseille, France +++ Pancytokeratin CAM5.2 Bekton-Dicckinson, CA, USA +++ HMWCK 34βE12 Dako - CK5/6 D5/16 Dako - CK7 N1626 Dako - CK8 E42 Dako +++ CK14 LL002 Novocastra, Newcastle upon type, UK - CK 18 DC10 Dako +++ CK 19 RCK 108 Progen, Heidelberg, Germany - CK20 K20.8 Dako - TTF-1 8G7G3/1 Dako +++ Surfactant protein PE10 Dako - EMA E29 Dako - Vimentin Vim 3B4 Dako - Myoglobin polyclonal Dako - CEA polyclonal Dako - Desmin D33 Dako - S100 protein polyclonal Dako - CA19-9 NS19-9 TFB Lab, Tokyo, Japan - ASMA 1A4 Dako - CD34 NU-4A1 Nichirei, Tokyo, Japan - p53 protein DO-7 Dako +++ p63 4A4 Dako - Ki-67 MIB-I Dako 100% Chromogranin DAK-A3 Dako + Synaptophysin Polyconal Dako +++ NSE BBS/NC/VI-H14 Dako +++ CD56 UJ13A Dako +++ CD68 KP-1 Dako - KIT polyclonal Dako +++ PDGFRA polyclonal Santa Cruz, CA, USA % positive %. +, 1-33% positive. -, negative. HMWCK, high molecular weight cytokerain. CK, cytokeratin, TTF-1. thyroid transcriptional factor-1, EMA, epithelial membrane antigen. CEA, carcinoembryonic antigen. ASMA, α-smooth muscle antigen. NSE, neuron-specific enolase. PDGFRA, platelet-derived growth factor receptotα. almost no mutations of KIT gene [15-18]. Extrapulmonary small cell carcinoma also expresses KIT, but KIT mutations have not been reported [19-21]. PDGFRA expression and mutations have not been investigated in small cell carcinoma. In the present study, positive PDGFRA protein expression was found. In summary, a very rare case of small cell carcinoma of the brain without extracranial involve- 326 Int J Clin Exp Pathol 2010;3(3):

5 ment based on repeated serial CT, MRI, PET, cytology and laboratory tests is reported. The small cell carcinoma of the brain may be the primary tumor. However, it is possible that the brain small cell carcinoma is a metastatic lesion of occult small cell lung carcinoma or extrapulmonary small cell carcinoma. In addition, protein expression of KIT and PDGFRA were examined. Please address correspondence to: Tadashi Terada, MD, PhD, Department of Pathology, Shizuoka City Shimizu Hospital, Miyakami 1231 Shimizu-Ku, Shizuoka , Japan, Tel: , Fax: , piyo0111jp@yahoo.co.jp References [1] Hu C, Chang EL, Hassenbursch SJ 3 rd, Allen PK, Woo SY, Mahajan A, Momaki R, Liao Z. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006; 106: [2] Mavrakis AN, Halpern EF, Baker FG, Conzalez RG, Hensen JW. Diagnostic evaluation of patients with a brain mass as the presenting manifestation of cancer. Neurology 2005; 65: [3] Le Chevalier T, Smith FP, Caille P, Constans JP, Rouesse JG. Sites of primary malignancies in patients presenting with cerebral metastases: a review of 120 cases. Cancer 1985; 56: [4] Terada T, Kawaguchi M. Primary clear cell adenocarcinoma of the peritoneum. Tohoku J Exp Med 2005; 206: [5] Terada T, Kawaguchi M, Furukawa K, Sekido Y, Osamura Y. Minute mixed ductal-endocrine carcinoma of the pancreas with predominant intraductal growth. Pathol Int 2002; 52: [6] Terada T. Primary multiple extragastrointestinal stromal tumors of the omentum with different mutations of c-kit gene. Would J Gastroenterol 2008; 14: [7] Terada T. Gastrointestinal stromal tumor of the uterus: A case report with genetic analyses of c- kit and PDGFRA genes. Int J Gynecol Pathol 2009; 28: [8] Terada T. Large endocervical polyp with cartilaginous and osseous metaplasia: a hitherto unreported entity. Int J Gynecol Pathol; 2009; 28: [9] Hueser CN, Nyguyen NC, Osman M, Havlioglu N, Patel AJ. Extrapulmonary small cell carcinoma: involvement of the brain without evidence of extracranial malignancy by serial PET/CT scans. World J Surg Oncol 2008; 25: 102. [10] Kargi A, Gurel D, Tuna B. The diagnostic value of TTF-1, CK5/6, and p63 immunostaining in classification of lung carcinoma. Appl Immunohistochem Mol Morphol 2007; 15: [11] Chhieng DC, Cangarella JF, Zakowski MF, Goswami S, Cohen JM, Yee HT. Use of thyroid transcriptional factor-1, PE-10, and cytokeratin 7 and 20 in discriminating between primary lung carcinoma and metastatic lesions in fine-needle aspiration biopsy specimens. Cancer 2001; 93: [12] Johansson L. Histopathological classification of lung cancer: relevance of cytokeratin and TTF-1 immunostaining. Ann Diag Pathol 2004; 8: [13] Scarpatetti M, Tsybrovskyy O, Popper HH. Cytokeratin typing as an aid in the differential diagnosis of primary versus metastatic lung carcinoma, and comparison with normal lung. Virchows Arch 2002; 440: [14] Tot T, Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma. Eur J Cancer 2002; 38: [15] LaPoint RJ, Bourne PA, Wang HL, Xu H. Coexpression of c-kit and bcl-2 in small cell carcinoma and large cell neuroendocrine carcinoma of the lung. Appl Immunohistochem Mol Morphol 2007; 15: [16] Boldrini L, Ursino S, Gisfredi S, Faviana P, Donati V, Camcci T, Lucchi M, Mussi A, Basolo F, Pingitore R. Fontanini G. Expression and mutational status of c-kit in small-cell lung cancer: prognostic relevance. Clin Cancer Res 2004; 15: [17] Burger H, Den Bakker MA, Stoter G, Verweij J, Nooter K. Lack of c-kit exon 11 activating mutations in c-kit/cd117-positive SCLC tumor specimens. Eur J Cancer 2003; 39: [18] Sihto H, Sarlomo-Rikara M, Tynnienen O, Tanner M, Andersson LC, Franssila K, Nupponen NN, Joensuu H. KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol 2005; 23: [19] Terada T. Primary small cell carcinoma of the mediastinum: A case report with immunohistochemical and molecular genetic analyses of KIT and PDGFRA genes. Medical Oncology 2009; 26: [20] Terada T. Primary small cell carcinoma of the ureter: A case report involving immunohistochemical and molecular genetic analyses of KIT and PDGFRA genes. Pathology 2010; 42: [21] Terada T. Autopsy case of primary small cell carcinoma of the urinary bladder: KIT and PDGFRA expression and mutations. Pathol Int 2009; 59: Int J Clin Exp Pathol 2010;3(3):