34βE 12 Cytokeratin Immunodetection in the Differential Diagnosis of Small Cell Tumors of Lung

Abstract

The group of small cell tumors of the lung includes the following: (1) small cell carcinoma (SCC) of neuroendocrine (NE) origin, (2) poorly differentiated squamous carcinoma, (3) the rare basaloid (basal cell) carcinomas, and (4) malignant lymphomas, primitive neuroectodermal tumors (PNETs), and rhabdomyosarcomas. The differential diagnosis among these entities carries a heavy therapeutic impact but may be difficult in small biopsy specimens or in cytologic material, especially if necrosis or artifactual alterations are present. The use of additional techniques such as immunostaining for NE markers is not always helpful, since immunoreactive chromogranin A is detectable in only a small percentage of small cell carcinomas. It has recently been reported that in the aerodigestive tract 34βE12 cytokeratin (CK) immunostaining selectively labels non-NE carcinomas, including squamous cell carcinoma, adenocarcinoma, and the rare basaloid carcinoma. We evaluated the role of such CK immunodetection in the differential diagnosis of small cell lung tumors in cytologic and biopsy specimens. Eighty-one lung tumors diagnosed by means of endoscopic bronchial biopsy, fine needle aspirate, or bronchial washing were collected. They included 43 small cell NE carcinomas and 38 cases used as controls (comprehensive of 2 large cell neuroendocrine carcinomas, 4 carcinoid tumors, 30 cases of non-NE lung carcinomas, 2 cases of bronchial infiltration by non-Hodgkin lymphomas). 34βE12 CK immunoreactivity was found in 29/30 cases of non-NE carcinomas, but in only 3/43 SCCs. The latter showed positivity in only a few scattered cells. The 2 cases of bronchial infiltration by malignant lymphoma as well as the 4 cases of carcinoid tumors and the 2 cases of large cell neuroendocrine carcinomas were negative. These findings were confirmed in the surgical specimens of operatedon cases. We conclude that, in lung carcinoma biopsies showing a small cell pattern, presence of 34βE12 CK immunoreactivity favors a non-NE carcinoma, whereas its absence supports the diagnosis of SCC.

Keywords

small cell carcinoma neuroendocrine carcinoma lung immunohisto-chemistry 34βE12 cytokeratin biopsy

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References

1. World Health Organization . The World Health Organization histological typing of lung tumors. (2nd ed) Am J Clin Pathol 77:123-126, 1982

2. Churg A , Johnston WH , Stulbarg M . Small cell squamous and mixed small cell squamous-small cell anaplastic carcinomas of the lung. Am J Surg Pathol 4:255-263, 1980

3. Nomori H , Shimosato Y , Kodama T , Morinaga S , Nakajima T , Watanabe S . Subtypes of small cell carcinoma of the lung: Morphometric, ultrastructural, and immunohistochemical analyses. Hum Pathol 17:604-613, 1986

4. Travis WD , Gal AA , Colby TV , Klimstra DS , Falk R , Koss MN . Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 29:272-279, 1998

5. Travis WD , Rush W , Flieder DB , Falk R , Fleming MV , Gal AA , Koss MN . Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22:934-944, 1998

6. Brambilla E , Moro D , Veale D , Brichon PY , Stoebner P , Paramelle B , Brambilla C . Basal cell (basaloid) carcinoma of the lung: A new morphologic and phenotypic entity with separate prognostic significance. Hum Pathol 23:993-1003, 1992

7. Moro D , Brichon PY , Brambilla E , Veale D , Labat F , Brambilla C . Basaloid bronchial carcinoma. A histologic group with a poor prognosis. Cancer 73:2734-2739, 1994

8. Zaharopoulos P , Wong JV , Stewart GD . Cytomorphology of the variants of small-cell carcinoma of the lung. Acta Cytol 26:800-808, 1982

9. Dugan JM . Cytologic diagnosis of basal cell (basaloid) carcinoma of the lung. A report of two cases. Acta Cytol 39:539-542, 1995

10.

10. Guinee DG , Fishback NF , Koss MN , Abbondanzo SL , Travis WD . The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimen from transbronchial and open-lung biopsies. Am J Clin Pathol 102:406-414, 1994

11.

11. Guiter G , Shapiro B , Dayal Y , DeLellis RA . Neuroendocrine markers in small cell carcinoma of the lung: Effects of microwave antigen retrieval. Mod Pathol 9:171A-171A, 1996

12.

12. Sumiyoshi Y , Shirakusa T , Yamashita Y , Maekawa T , Hideshima T , Sakai T , Kawahara K , Kikuchi M . Detection of Chromogranin A mRNA in small cell lung carcinoma using a new, highly sensitive in situ hybridization method with a non-radioisotope oligonucleotide probe. Cancer 82:468-473, 1998

13.

13. Balaton AJ , Galet BA . Correspondence: Detection of Chromogranin A mRNA in small cell lung carcinoma using a new, highly sensitive in situ hybridization method with a nonradioisotope oligonucleotide probe. Cancer 83:1469-1470, 1998

14.

14. Kaufmann O , Georgi T , Dietel M . Utility of 123C3 monoclonal antibody against CD56 (NCAM) for the diagnosis of small cell carcinomas on paraffin sections. Hum Pathol 28:1373-1378, 1997

15.

15. loachim HL , Pambuccian SE , Hekimgil M , Giancotti FR , Dorsett BH . Lymphoid monoclonal antibodies reactive with lung tumors. Am J Surg Pathol 20:64-71, 1996

16.

16. Ordonez NG . Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the pleura from lung adenocarcinoma. Am J Surg Pathol 22:1215-1221, 1998

17.

17. Loy TS , Calaluce RD . Utility of cytokeratin immunostaining in separating pulmonary adenocarcinomas from colonic adenocarcinomas. Am J Clin Pathol 102:764-767, 1994

18.

18. Pendleton N , Dixon GR , Green JA , Myskow MW . Expression of markers of differentiation in normal bronchial epithelium and bronchial dysplasia. J Pathol 178:146-150, 1996

19.

19. Cohen R , Guber A , Siegal A , Bruderman I , Huszar M , Yellin A , Marom Z , Geiger B . The prognostic application of cytokeratin typing of nonsmall cell lung carcinoma. A retrospective study. Cancer 79:468-473, 1997

20.

20. Morice WG , Ferreiro JA . Distinction of basaloid squamous cell carcinoma from adenoid cystic and small cell undifferentiated carcinoma by immunohistochemistry. Hum Pathol 29:609-612, 1998

21.

21. Bussolati G , Gugliotta P , Volante M , Pace M , Papotti M . Retrieved endogenous biotin: A novel marker and a potential pitfall in diagnostic immunohistochemistry. Histopathology 31:400-407, 1997

22.

22. Miller RT , Kubier P . Blocking of endogenous avidinbinding activity in immunohistochemistry. The use of egg whites. Appl Immunohistochem 5:63-66, 1997

23.

23. Hsu S-M , Raine L , Fanger H . Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 29:577-580, 1981

24.

24. Shepherd FA , Ginsberg R , Patterson GA , Feld R , Goss PE , Pearson FG , Todd TJ , Winton T , Rubinger M , Johansen E . Is there ever a role for salvage operations in limited small-cell lung cancer? J Thorac Cardiovasc Surg 101:196-200, 1991

25.

25. Smit EF , Groen HJ , Timens W , deBoer WJ , Postmus PE . Surgical resection for small cell carcinoma of the lung: A retrospective study. Thorax 49:20-22, 1994

26.

26. Viberti L , Papotti M , Abbona G , Celano A , Filosso PL , Bussolati G . Value of Ki-67 immunostaining in preoperative biopsies of carcinomas of the lung. Hum Pathol 28:189-192, 1997

27.

27. Travis WD , Linnoila RI , Tsokos MG , Hitchcock CL , Cutler GB , Nieman L , Chrousos G , Pass H , Doppman J . Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical and flow cytometric study of 35 cases. Am J Surg Pathol 15:529-553, 1991

28.

28. Hamid Q , Corrin B , Sheppard MN , Huttner WB , Polak JM . Expression of Chromogranin A mRNA in small cell carcinoma of the lung. J Pathol 163:293-297, 1991

29.

29. Abbona G , Papotti M , Viberti L , Macri L , Stella A , Bussolati G . Chromogranin A gene expression in nonsmall cell lung carcinomas. J Pathol 186:151-156, 1998

30.

30. Shy SW , Lee WH , Chou MC , Lai YS , Tu YC . Small cell lung carcinoma: Clinicopathological, immunohistochemical, and ultrastructural study. J Surg Oncol 45:146-161, 1990