J Gastrointest Canc DOI 10.1007/s12029-014-9595-x
CASE REPORT
Esophageal small cell carcinoma without neuroendocrine features but with KITand PDGFRA expression: KITas a useful marker of this type of tumor Tadashi Terada
# Springer Science+Business Media New York 2014
Introduction KIT (CD117) is a product of an oncogene KIT mapped to 4q12 [1]. It is a transmembranous receptor tyrosine kinase oncoprotein whose ligant is stem cell factor. KIT plays an important role in cell differentiation, development, and tumorigenesis. KIT is expressed in some normal cells (interstitial cells of Cajal, malanocytes, mast cells, blood stem cells, and germ cells) and their neoplastic counterparts (GIST, melanoma, mast cell neoplasms, leukemia, and germ cell tumors, respectively) [1–4]. KIT expression is also noted in certain neoplasms such as some carcinomas and some sarcomas [1–4]. The majority of KIT-positive carcinomas are small cell carcinoma [1–4]. Platelet-derived growth factor receptoralpha (PDGFRA) is a product of an oncogene PDGFRA mapped also to 4q12, like KIT [1]. PDGFRA is a transmembranous receptor tyrosine kinase. Mutations of KIT and PDGFRA genes are recognized in gastrointestinal stromal tumor [1–4]. Small cell carcinoma is a primitive neuroendocrine malignancy and can occur in any organs though the majority develops in the lungs. Primary small cell carcinoma of the esophagus is very rare; several cases have been reported in the English literature [5]. Like small cell lung carcinoma, small cell carcinoma of the esophagus shows aggressive biological behavior and the prognosis is poor [5]. However, KIT and PDGFRA expression of esophageal small cell carcinoma has not been reported to date. We herein report a case of esophageal small cell carcinoma without neuroendocrine features but with strong KIT and T. Terada (*) Department of Pathology, Shizuoka City Shimizu Hospital, Miyakami 1231, Shimizu-Ku, Shizuoka 424-8636, Japan e-mail: [email protected]
PDGFRA expression. The KIT and PDGFRA expression was an important clue of the small cell carcinoma.
Case Report A 65-year-old man was admitted to our hospital because of headache. Brain CT showed a tumor in the brain. Resection of the tumor was performed. Pathological examination showed that it was a metastatic undifferentiated carcinoma composed of relatively small cells with hyperchromatic nuclei (Fig. 1a, b). Nucleoli are occasionally recognized. There were many mitotic and apoptotic figures. The stroma is scant. Acinar structures were recognized in a few areas (Fig. 1a, b). Mucin stains showed a little cytoplasmic mucus. Typical features of small cell carcinoma were not evident. An immunohistochemical study was performed by Dako’s Envision method as previously reported [6, 7]. The immunohistochemical study showed positive reactions for cytokeratins (AE1/3, MNF116, polyclonal, Dako, Glostrup, Demmark) and negative reactions for neuron-specific enolase (Dako), chromogranin (Dako), synaptophysin (Dako), CD56 (Dako), cytokeratin 20 (Dako), cytokeratin 7 (Dako), cytokeratin 34βE12 (Dako), AFP (Dako), PSA (Dako), surfactant-apoprotein A (Dako), TTF-1 (Dako), HMB45 (Dako), S100 protein (Dako), CEA (Dako), and CA19-9 (TFB, Tokyo, Japan). The origin of the tumor cannot be estimated. Clinical scrutiny for the primary site, using endoscopy, revealed an esophageal tumor. Pathological diagnosis was undifferentiated carcinoma composed of small cells (Fig. 2a, b). The histological and immunohistochemical features were the same as those of the brain tumor. The patient underwent radiation and chemotherapy, but he developed systemic metastasis, and the therapy effects
J Gastrointest Canc
Fig. 1 a Low power view of the brain tumor. It is metastatic carcinoma. Acinar formations are noted in a few areas. H & E, ×40. b High power view of the brain tumor. The carcinoma cells are relatively small and contain hyperchromatic nuclei and occasional nucleoli. Acinar formation is recognized in a few areas. H & E, ×200
Fig. 2 a Low power view of the esophageal tumor. It is an undifferentiated carcinoma composed of small cells. H & E, ×40. b High power view of esophageal tumor. It is compatible with small cell carcinoma in this field. H & E, ×200
gradually decreased. Reexamination of the tumors 2 years after the first diagnosis showed strong immunoreactive KIT (Dako) and moderate immunoreactive PDGFRA (Santa Cruz, CA) positivity both in the brain tumor (Fig. 3a, b) and in the esophageal tumor (Fig. 3c, d). Therefore, the patient was diagnosed as having small cell carcinoma with a little adenocarcinomatous differentiation. A new regimen of therapy was performed.
KIT expression was recognized in only three cases (breast carcinoma and teratocarcinoma) among 160 solid epithelial malignancies of various sites. In contrast, KIT expression was recognized in 10 among the 30 small cell lung carcinomas [4]. Thus, KIT shows a high specificity for small cell carcinoma. Extrapulmonary small cell carcinomas also frequently express KIT (Terada T, unpublished data). As to the sensitivity of KIT in small cell carcinoma, KIT expression in small cell lung carcinoma varies among researchers [4, 8–16]; it is reported to be from 33 to 78 %. The prognostic implications of positive KIT protein in small cell lung carcinoma are controversial, and no definite conclusions were obtained [8–16]. The esophageal tumor and its brain metastasis of the present case were at first diagnosed as undifferentiated carcinoma with a little adenocarcinomatous differentiation. The histological features were not typical for small cell carcinoma in that the tumor cells are not so small and tumor
Discussion KIT expression is recognized in several tumors [1–4]. In epithelial malignancies, KIT is expressed exclusively in small cell carcinoma, though KIT expression has been noted in a few cases of adenoid cystic carcinoma, renal chromophobe carcinoma, thymic carcinoma, ovarian carcinoma, and breast carcinoma [1]. Sihto et al. [4] reported that strong
J Gastrointest Canc Fig. 3 a Strong membranous expression of KIT is present in the brain tumor. KIT immunostaining, ×200. b Moderate membranous expression of PDGFRA is present in the brain tumor. Immunostaining, ×400. c Strong membranous expression of KIT is present in the esophageal tumor. KIT immunostaining, ×200. d Moderate membranous expression of PDGFRA is present in the esophageal tumor. Immunostaining, ×400
cells occasionally contained nucleoli. In addition, small cell carcinoma markers (neuroendocrine markers: synaptophysin, chromogranin, neuron-specific enolase, and CD67) were negative. However, the reexamination after 2 years using KIT and PDGFRA immunostainings strongly suggested small cell carcinoma. Because it is well known that small cell lung carcinoma can be associated with adenocarcinomatous and squamous cell carcinomatous elements, the presence of adenocarcinomatous differentiation in the present case does not hinder the diagnosis of small cell carcinoma. At present, the authors think that the present tumor is small cell carcinoma of the esophagus with a little adenocarcinomatous differentiation. Genetic analysis of KIT and PDGFRA was not performed in the present case. In the English literature, small cell lung carcinoma lacks KIT mutations [4]; Sihto et al. [4] showed that no mutations of KIT and PDGFRA genes were recognized in 31 small cell lung carcinoma cases. Extrapulmonary small cell carcinoma also shows no mutations of KIT and PDGFRA genes (Terada T, unpublished data). The overexpression of KIT is reported to be derived from gene amplification of KIT [4]. In summary, the present case indicates that KIT and PDGFRA are useful markers of small cell carcinoma without neuroendocrine features. Conflict of interest The authors declare that they have no conflict of interest.
References 1. Miettinen M, Lasota J. KIT (CD117): a review on expression in normal and neoplastic tissue, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 2005;13:205–20. 2. Miettinen M, Lasota J. Gastrointestinal stromal tumor: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–78. 3. Dow N, Giblen G, Sobin LH, Miettinen M. Gastrointestinal stromal tumors: differential diagnosis. Semin Diagn Pathol. 2006;23:111–9. 4. Sihto H, Sarlomo-Rikara M, Tynnienen O, Tanner M, Andersson LC, Franssila K, et al. KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol. 2005;23:49–57. 5. Koide N, Saito H, Suzuki A, Sato T, Koiwai K, Nakamura N, et al. Clinicopathologic features and histochemical analuses of proliferative activity and angiogenesis in small cell carcinoma of the esophagus. J Gastroenterol. 2007;42:932–8. 6. 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;52:740–6. 7. Terada T, Kawaguchi M. Primary clear cell adenocarcinoma of the peritoneum. Tohoku J Exp Med. 2005;271:271–5. 8. 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: 401–6. 9. Lopes-Martin A, Ballenstin C, Garcia-Carbonero R, Castano A, LopezRios F, Lopes-Encuentra A, et al. Prognostic value of KIT expression in small cell lung carcinoma. Lung Cancer. 2007;56:405–13. 10. Micke P, Basral M, Faldum A, Bittinger F, Ronnstrand L, Blaukat A, et al. Characterization of c-kit expression in small cell lung carcinoma: prognostic and therapeutic implications. Clin Cancer Res. 2003;9:188–94.
J Gastrointest Canc 11. Camps C, Sirera R, Bremnes RM, Garde J, Safont MJ, Blasco A, et al. Analysis of c-kit expression in small cell lung carcinoma: prevalence and prognostic implications. Lung Cancer. 2006;52:343–7. 12. Rossi G, Cavazza A, Marchioni A, Miggaldi M, Bavierli M, Fracciolongo N, et al. KIT expression in small cell carcinoma of the lung: effects of chemotherapy. Mod Pathol. 2003;16:1041–7. 13. Naeem M, Dahiya M, Clark JI, Creech SD, Alkin S. Analysis of c-kit protein expression in small-cell lung carcinoma and its implications for prognosis. Hum Pathol. 2002;33:1182–7.
14. Mojica WD, Saxena R, Starostik P, Cheney RT. CD117+small cell lung cancer lacks the asp 816 val point mutation in exon 17. Histopathology. 2005;47:517–22. 15. Boldrini L, Ursino S, Gisfredi S, Faviana P, Donati V, Camcci T, et al. Expression and mutational status of c-kit in small-cell lung cancer: prognostic relevance. Clin Cancer Res. 2004;15:4101–8. 16. Burger H, Den Bakker MA, Stoter G, Verweij J, Nooter K. Lack of ckit exon 11 activating mutations in c-kit/CD117-positive SCLC tumor specimens. Eur J Cancer. 2003;39:793–9.
CASE REPORT
Esophageal small cell carcinoma without neuroendocrine features but with KITand PDGFRA expression: KITas a useful marker of this type of tumor Tadashi Terada
# Springer Science+Business Media New York 2014
Introduction KIT (CD117) is a product of an oncogene KIT mapped to 4q12 [1]. It is a transmembranous receptor tyrosine kinase oncoprotein whose ligant is stem cell factor. KIT plays an important role in cell differentiation, development, and tumorigenesis. KIT is expressed in some normal cells (interstitial cells of Cajal, malanocytes, mast cells, blood stem cells, and germ cells) and their neoplastic counterparts (GIST, melanoma, mast cell neoplasms, leukemia, and germ cell tumors, respectively) [1–4]. KIT expression is also noted in certain neoplasms such as some carcinomas and some sarcomas [1–4]. The majority of KIT-positive carcinomas are small cell carcinoma [1–4]. Platelet-derived growth factor receptoralpha (PDGFRA) is a product of an oncogene PDGFRA mapped also to 4q12, like KIT [1]. PDGFRA is a transmembranous receptor tyrosine kinase. Mutations of KIT and PDGFRA genes are recognized in gastrointestinal stromal tumor [1–4]. Small cell carcinoma is a primitive neuroendocrine malignancy and can occur in any organs though the majority develops in the lungs. Primary small cell carcinoma of the esophagus is very rare; several cases have been reported in the English literature [5]. Like small cell lung carcinoma, small cell carcinoma of the esophagus shows aggressive biological behavior and the prognosis is poor [5]. However, KIT and PDGFRA expression of esophageal small cell carcinoma has not been reported to date. We herein report a case of esophageal small cell carcinoma without neuroendocrine features but with strong KIT and T. Terada (*) Department of Pathology, Shizuoka City Shimizu Hospital, Miyakami 1231, Shimizu-Ku, Shizuoka 424-8636, Japan e-mail: [email protected]
PDGFRA expression. The KIT and PDGFRA expression was an important clue of the small cell carcinoma.
Case Report A 65-year-old man was admitted to our hospital because of headache. Brain CT showed a tumor in the brain. Resection of the tumor was performed. Pathological examination showed that it was a metastatic undifferentiated carcinoma composed of relatively small cells with hyperchromatic nuclei (Fig. 1a, b). Nucleoli are occasionally recognized. There were many mitotic and apoptotic figures. The stroma is scant. Acinar structures were recognized in a few areas (Fig. 1a, b). Mucin stains showed a little cytoplasmic mucus. Typical features of small cell carcinoma were not evident. An immunohistochemical study was performed by Dako’s Envision method as previously reported [6, 7]. The immunohistochemical study showed positive reactions for cytokeratins (AE1/3, MNF116, polyclonal, Dako, Glostrup, Demmark) and negative reactions for neuron-specific enolase (Dako), chromogranin (Dako), synaptophysin (Dako), CD56 (Dako), cytokeratin 20 (Dako), cytokeratin 7 (Dako), cytokeratin 34βE12 (Dako), AFP (Dako), PSA (Dako), surfactant-apoprotein A (Dako), TTF-1 (Dako), HMB45 (Dako), S100 protein (Dako), CEA (Dako), and CA19-9 (TFB, Tokyo, Japan). The origin of the tumor cannot be estimated. Clinical scrutiny for the primary site, using endoscopy, revealed an esophageal tumor. Pathological diagnosis was undifferentiated carcinoma composed of small cells (Fig. 2a, b). The histological and immunohistochemical features were the same as those of the brain tumor. The patient underwent radiation and chemotherapy, but he developed systemic metastasis, and the therapy effects
J Gastrointest Canc
Fig. 1 a Low power view of the brain tumor. It is metastatic carcinoma. Acinar formations are noted in a few areas. H & E, ×40. b High power view of the brain tumor. The carcinoma cells are relatively small and contain hyperchromatic nuclei and occasional nucleoli. Acinar formation is recognized in a few areas. H & E, ×200
Fig. 2 a Low power view of the esophageal tumor. It is an undifferentiated carcinoma composed of small cells. H & E, ×40. b High power view of esophageal tumor. It is compatible with small cell carcinoma in this field. H & E, ×200
gradually decreased. Reexamination of the tumors 2 years after the first diagnosis showed strong immunoreactive KIT (Dako) and moderate immunoreactive PDGFRA (Santa Cruz, CA) positivity both in the brain tumor (Fig. 3a, b) and in the esophageal tumor (Fig. 3c, d). Therefore, the patient was diagnosed as having small cell carcinoma with a little adenocarcinomatous differentiation. A new regimen of therapy was performed.
KIT expression was recognized in only three cases (breast carcinoma and teratocarcinoma) among 160 solid epithelial malignancies of various sites. In contrast, KIT expression was recognized in 10 among the 30 small cell lung carcinomas [4]. Thus, KIT shows a high specificity for small cell carcinoma. Extrapulmonary small cell carcinomas also frequently express KIT (Terada T, unpublished data). As to the sensitivity of KIT in small cell carcinoma, KIT expression in small cell lung carcinoma varies among researchers [4, 8–16]; it is reported to be from 33 to 78 %. The prognostic implications of positive KIT protein in small cell lung carcinoma are controversial, and no definite conclusions were obtained [8–16]. The esophageal tumor and its brain metastasis of the present case were at first diagnosed as undifferentiated carcinoma with a little adenocarcinomatous differentiation. The histological features were not typical for small cell carcinoma in that the tumor cells are not so small and tumor
Discussion KIT expression is recognized in several tumors [1–4]. In epithelial malignancies, KIT is expressed exclusively in small cell carcinoma, though KIT expression has been noted in a few cases of adenoid cystic carcinoma, renal chromophobe carcinoma, thymic carcinoma, ovarian carcinoma, and breast carcinoma [1]. Sihto et al. [4] reported that strong
J Gastrointest Canc Fig. 3 a Strong membranous expression of KIT is present in the brain tumor. KIT immunostaining, ×200. b Moderate membranous expression of PDGFRA is present in the brain tumor. Immunostaining, ×400. c Strong membranous expression of KIT is present in the esophageal tumor. KIT immunostaining, ×200. d Moderate membranous expression of PDGFRA is present in the esophageal tumor. Immunostaining, ×400
cells occasionally contained nucleoli. In addition, small cell carcinoma markers (neuroendocrine markers: synaptophysin, chromogranin, neuron-specific enolase, and CD67) were negative. However, the reexamination after 2 years using KIT and PDGFRA immunostainings strongly suggested small cell carcinoma. Because it is well known that small cell lung carcinoma can be associated with adenocarcinomatous and squamous cell carcinomatous elements, the presence of adenocarcinomatous differentiation in the present case does not hinder the diagnosis of small cell carcinoma. At present, the authors think that the present tumor is small cell carcinoma of the esophagus with a little adenocarcinomatous differentiation. Genetic analysis of KIT and PDGFRA was not performed in the present case. In the English literature, small cell lung carcinoma lacks KIT mutations [4]; Sihto et al. [4] showed that no mutations of KIT and PDGFRA genes were recognized in 31 small cell lung carcinoma cases. Extrapulmonary small cell carcinoma also shows no mutations of KIT and PDGFRA genes (Terada T, unpublished data). The overexpression of KIT is reported to be derived from gene amplification of KIT [4]. In summary, the present case indicates that KIT and PDGFRA are useful markers of small cell carcinoma without neuroendocrine features. Conflict of interest The authors declare that they have no conflict of interest.
References 1. Miettinen M, Lasota J. KIT (CD117): a review on expression in normal and neoplastic tissue, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 2005;13:205–20. 2. Miettinen M, Lasota J. Gastrointestinal stromal tumor: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–78. 3. Dow N, Giblen G, Sobin LH, Miettinen M. Gastrointestinal stromal tumors: differential diagnosis. Semin Diagn Pathol. 2006;23:111–9. 4. Sihto H, Sarlomo-Rikara M, Tynnienen O, Tanner M, Andersson LC, Franssila K, et al. KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol. 2005;23:49–57. 5. Koide N, Saito H, Suzuki A, Sato T, Koiwai K, Nakamura N, et al. Clinicopathologic features and histochemical analuses of proliferative activity and angiogenesis in small cell carcinoma of the esophagus. J Gastroenterol. 2007;42:932–8. 6. 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;52:740–6. 7. Terada T, Kawaguchi M. Primary clear cell adenocarcinoma of the peritoneum. Tohoku J Exp Med. 2005;271:271–5. 8. 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: 401–6. 9. Lopes-Martin A, Ballenstin C, Garcia-Carbonero R, Castano A, LopezRios F, Lopes-Encuentra A, et al. Prognostic value of KIT expression in small cell lung carcinoma. Lung Cancer. 2007;56:405–13. 10. Micke P, Basral M, Faldum A, Bittinger F, Ronnstrand L, Blaukat A, et al. Characterization of c-kit expression in small cell lung carcinoma: prognostic and therapeutic implications. Clin Cancer Res. 2003;9:188–94.
J Gastrointest Canc 11. Camps C, Sirera R, Bremnes RM, Garde J, Safont MJ, Blasco A, et al. Analysis of c-kit expression in small cell lung carcinoma: prevalence and prognostic implications. Lung Cancer. 2006;52:343–7. 12. Rossi G, Cavazza A, Marchioni A, Miggaldi M, Bavierli M, Fracciolongo N, et al. KIT expression in small cell carcinoma of the lung: effects of chemotherapy. Mod Pathol. 2003;16:1041–7. 13. Naeem M, Dahiya M, Clark JI, Creech SD, Alkin S. Analysis of c-kit protein expression in small-cell lung carcinoma and its implications for prognosis. Hum Pathol. 2002;33:1182–7.
14. Mojica WD, Saxena R, Starostik P, Cheney RT. CD117+small cell lung cancer lacks the asp 816 val point mutation in exon 17. Histopathology. 2005;47:517–22. 15. Boldrini L, Ursino S, Gisfredi S, Faviana P, Donati V, Camcci T, et al. Expression and mutational status of c-kit in small-cell lung cancer: prognostic relevance. Clin Cancer Res. 2004;15:4101–8. 16. Burger H, Den Bakker MA, Stoter G, Verweij J, Nooter K. Lack of ckit exon 11 activating mutations in c-kit/CD117-positive SCLC tumor specimens. Eur J Cancer. 2003;39:793–9.
