Diagnosis: Carcinoid tumor, nodes negative. T2, N0; Stage I


Case 7--Neuroendocrine Tumors--Carcinoid Tumors & Well-differentiated Neuroendocrine Carcinomas

Several types of tumor that show neuroendocrine differentiation occur in the lung. They are defined by their growth patterns, cytologic features, immunohistochemical reaction for chromogranin A, the presence of neurosecretory granules by electron microscopy, and the presence of a number of neuropeptides that can be detected biochemically or by immunohistochemical methods. The different tumor types, although all potentially malignant, vary greatly in their clinical behavior from the low-grade, slowly-growing carcinoid tumor to the rapidly-fatal, small cell carcinoma. Classification systems attempt to predict behavior on the basis of morphology. A current scheme for classifying tumors is shown in the Table.

Table: Classification of Neuroendocrine Tumors [1]

*Proposed and tentative (see [4]).

Carcinoid tumors are low-grade malignant tumors of epithelial cells showing differentiation toward Kulchitsky cells. They comprise 2% of lung cancers. Not associated with smoking, these tumors occur at an earlier age (peak in 5th decade) than other bronchogenic cancers and occur equally in men and women. Endocrine manifestations, which are rare, include syndromes related to ADH, ACTH [5-7], and growth hormone overproduction, and the carcinoid syndrome, which probably only occurs after metastases have occurred [8].

Clinical features: Central tumors cause cough, hemoptysis, or recurrent infection due to bronchial obstruction. Peripheral tumors are usually asymptomatic.

Radiographic features: Tumors usually present with sequelae of bronchial obstruction: atelectasis, post-obstructive pneumonia, and occasionally local oligemia due to vasoconstriction [9]. Although it is said that central tumors predominate over peripheral ones (4 to 1), many of the central tumors actually arise in segmental bronchi, and are thus not strictly central: 10% main bronchi, 75% lobar or segmental bronchi, and 15% peripheral [8]. In those presenting as solitary pulmonary nodules, the borders are usually smooth and well-defined. The nodules may be round, oval, lobulated, or notched [10]. Calcification is not commonly seen on plain radiographs, but has been seen in up to 1/3 of cases by CT. If frank calcification is seen, the diagnosis of carcinoid can be suggested [11]. The tumors may occasionally show marked contrast enhancement [11].

Gross: These tumors grow as sessile polyps in bronchial and bronchiolar lumens but invade the bronchial wall and adjacent parenchyma. Thus, despite the fact that they form discrete masses, they cannot be removed endobronchially. Peripheral tumors have usually obliterated the airway in which they arose.

Light Microscopy: The basic pattern is a circumscribed tumor composed of nests, trabecular arrangements, or spindled cells separated by delicate connective tissue septa containing thin-walled vessels ("endocrine pattern" of tumor growth). Arrangement of nuclei at the edge of the nest perpendicular to the margin, i.e., palisading of nuclei, is common. Cells are uniform with a normal nuclear to cytoplasmic ratio, and have round nuclei, stippled nuclear chromatin, and small nucleoli. Mitoses and necrosis are essentially absent. Occasionally, fibrosis, amyloid, gland formation, mucin production, melanin [12], oncocytic cells (cells with abundant pink cytoplasm filled with mitochondria) [12], psammoma bodies, or bone occur. Multifocal tumors have been described [13, 14]. Spindle-celled carcinoids also occur. Minute pulmonary carcinoids are termed tumorlets. Immunohistochemical stains for chromogranin A are highly specific for neuroendocrine tumors and are almost always positive in carcinoid tumors and in well-differentiated neuroendocrine carcinomas (see below), but less frequently so in small cell carcinomas [1].

Well-differentiated neuroendocrine carcinoma (WDNC) (synonyms: atypical carcinoid; Kulchitsky cell carcinoma, type II): Because many typical carcinoid tumors have "atypical" features, e.g., spindled cells, associated bone or amyloid formation, melanin pigmentation, etc., it is confusing to have another tumor with more aggressive behavior called atypical carcinoid. Hence, another term--WDNC [2]--has been introduced for tumors that have a 30-50% rate of regional node spread and a 20-30% rate of distant metastasis at diagnosis [15]. These tumors comprise about 10% of all carcinoid tumors [8]. Radiographically, they are often rounded, peripheral masses, but thin-walled cavitary lesions and ill-defined masses also occur [16].

Cytology of typical carcinoids and WDNC: Cytologic preparations are better than small, crushed tissue biopsies for distinguishing carcinoid tumors from small cell cancers. Small aggregates of cuboidal or spindled cells with pale blue cytoplasm; smooth nuclear contours; and normal nuclear to cytoplasmic ratios characterize carcinoid tumors. Small nucleoli may be present, and mitoses and molding are absent in carcinoids. Interpretation is aided by knowledge of the age of the patient and the appearance of the tumor at bronchoscopy. In patients with carcinoid tumors, sputum, bronchial washes, and brushes are often negative because tumors are covered by intact epithelium. Well-differentiated neuroendocrine carcinomas and small cell cancers can sometimes, but not always, be separated in cytologic specimens [17].

Survival: Survival after resection of typical carcinoid tumors is 95-100% at 5 years and over 87% at 10 years [18-20]. About 5% of these tumors metastasize [8]. Low pathologic stage and asymptomatic presentation are good prognostic features. On the other hand, survival with WDNC at 10 years is 50-60% [21,22].

References

1. Travis W, Linnoila I, Tsokos M, Hitchcock C, Cutler G Jr, Nieman L, Chrousos G, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendrocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991; 15:529-553.

2. Warren W, Memoli V, Jordan A, Gould V. Reevaluation of pulmonary neoplasms resected as small cell carcinomas. Significance of distinguishing between well-differentiated and small cell neuroendocrine carcinomas. Cancer 1990; 65:1003-1010.

3. Yesner R. Classification of lung cancer histology. N Engl J Med 1985; 312:652-653.

4. Sheppard M. Neuroendocrine differentiation in lung tumours. Thorax 1991; 46:843-850.

5. Cederna P, Eckhauser F, Kealey G. Cushing's syndrome secondary to bronchial carcinoid secretion of ACTH: a review. Am Surgeon 1993; 59:438-442.

6. Limper A, Carpenter P, Scheithauer B, Staats B. The Cushing syndrome induced by bronchial carcinoid tumors. Ann Intern Med 1992; 117:209-214.

7. Pass H, Doppman J, Nieman L, Stovroff M, Vetto J, Norton J, Travis W, et al. Management of the ectopic ACTH syndrome due to thoracic carcinoids. Ann Thorac Surg 1990; 50:52-57.

8. Davila D, Dunn W, Tazelaar H, Pairolero P. Bronchial carcinoid tumors. Mayo Clin Proc 1993; 68:795-803.

9. Fraser R, Pare J, Fraser R, Pare P. Synopsis of Diseases of the Chest, 2nd ed, Philadelphia, WB Saunders Co, 1994, p 484-485.

10. Nessi R, Ricci P, Ricci S, et al. Bronchial carcinoid tumors: radiologic observations in 49 cases. J Thorac Imag 1991; 6:47-53.

11. Armstrong P. Neoplasms of the lungs, airways and pleura. In: Armstrong P, Wilson A, Dee P, Hansell D, eds. Imaging of Diseases of the Chest, 2nd ed. St. Louis, Mosby-Year Book, 1996, p 304-310.

12. Grazer R, Cohen S, Jacobs J, Lucas P. Melanin-containing peripheral carcinoid of the lung. Am J Surg Pathol 1982; 6:73-78.

13. Suzuki K, Kimula Y, Ogata T, Nakagawa H. Bronchial carcinoid with multiple aerogenous implanted foci. J Surg Oncol 1987; 34:211-215.

14. Skinner C, Ewen S. Carcinoid lung: diffuse pulmonary infiltration by a multifocal bronchial carcinoid. Thorax 1976; 31:212-219.

15. Yousem S. Pulmonary carcinoid tumors and well-differentiated neuroendocrine carcinomas. Is there room for an atypical carcinoid? Am J Clin Pathol 1991; 95:763-764.

16. Choplin R, Kawamoto E, Dyer R, Geisinger K, Mills S, Pope T. Atypical carcinoid of the lung: radiographic features. AJR 1986; 146:665-668.

17. Frierson H Jr, Covell J, Mills S. Fine needle aspiration cytology of atypical carcinoid of the lung. Acta Cytol 1987; 31:471-475.

18. Harpole D Jr, Feldman J, Buchanan S, Young W, Wolfe W. Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg 1992; 54:50-55.

19. McCaughan B, Martini N, Bains M. Bronchial carcinoids. Review of 124 cases. J Thorac Cardiovasc Surg 1985; 89:8-17.

20. Schreurs A, Westermann C, van den Bosch J, Vanderschueren R, de la Rivière A, Knaepen P. A twenty-five-year follow-up of ninety-three resected typical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1992; 104:1470-1475.

21. Lequaglie C, Patriarca C, Cataldo I, Muscolino G, Preda F, Ravasi G. Prognosis of resected well-differentiated neuroendocrine carcinoma of the lung. Chest 1991; 100:1053-1056.

22. Marty-Ané C-H, Costes V, Pujol J-L, Alauzen M, Baldet P, Mary H. Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg 1995; 59:78-83.

Clinical Summary

Comments: mw6825@itsa.ucsf.edu

Last revised 7/6/97

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