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].


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Clinical Summary

Comments: mw6825@itsa.ucsf.edu

Last revised 7/6/97

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