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Typical and Atypical Pulmonary Carcinoids

Typical and Atypical Pulmonary CarcinoidsPulmonary carcinoid tumors are malignant neoplasms that show neuroendocrine differentiation. Although the distinction between typical and atypical carcinoid tumors was first described by Engelbreth-Holm in 1944, it was not until 1972 that histologic criteria for separating these tumors were proposed by Arrigoni et al. In the intervening 25 years, numerous studies have continued to confirm that there is a spectrum of neuroendocrine-appear-ing tumors from the carcinoid tumorlet to small cell undifferentiated carcinoma. However, the distinction between typical carcinoids and more aggressive neuroendocrine neoplasms has been problematic, and several classification schemes have been proposed but none have been widely accepted or ap-plied. The 1981 World Health Organization (WHO) classification of neuroendocrine neoplasms stated only that atypical carcinoid tumors had “increased mitotic activity, cellularity and could have necrosis.” While this statement is true in general, strict criteria were not suggested. The most recent WHO classification has proposed more strict criteria for separating these two tumors, based on work by Travis et al. The new WHO classification (Table 1) also lays out criteria for large cell neuroendocrine carcinoma, a tumor that undoubtedly has, in the past, been included in at least some series of atypical carcinoid tumors.
Typical pulmonary carcinoid tumors rarely metastasize and, in general, patients with these tumors have a good prognosis, with 5-year survival rates ranging from 87 to 100%. This is in contrast to patients with atypical carcinoid tumors, who have a greater tendency to have metastases and a 25 to 69% 5-year survival rate (Table 2). Although previous studies have reported the outcome of patients with typical and atypical carcinoid tumors, none have specifically investigated the subset of patients who have thoracic lymph node metastases at the time of surgical staging. It is uncertain whether the survivalrate is significantly worse in this subset of patients and whether consideration of more aggressive management and follow-up is indicated for them. In this study, we retrospectively analyzed the clinical characteristics and survival rates of surgically treated patients with typical and atypical pulmonary carcinoid tumors who had thoracic lymph node metastases.
Materials and Methods
A computerized search of the medical records at the Mayo Clinic from 1976 to 1997 revealed 517 patients with pulmonary carcinoid tumors, from which we identified 36 patients with pulmonary carcinoid tumors involving regional thoracic lymph nodes but without distant disease. The medical records of these 36 patients were reviewed, and the study population included only patients with pulmonary carcinoid tumors presenting with thoracic lymph node metastases at the time of surgical resection. This group was selected because we were specifically interested in the outcomes of patients with completely resected carcinoid tumors having regional lymph node metastases. Carcinoid tumor patients presenting with distant metastases or concurrent cancers were excluded from the study.
The histologic diagnosis of pulmonary carcinoid tumor was confirmed by review of all histologic sections by a single pathologist with special expertise in neuroendocrine tumors who was blinded to the initial diagnosis (ie, typical or atypical carcinoid tumor). Histologic sections were available for all 36 patients. Because the histologic criteria for the diagnosis of pulmonary carcinoid tumors changed significantly during the dates of this study, all tumors were classified on the basis of the newly proposed WHO classification scheme and were compared to the original diagnoses. The pathologic stage of disease using the TNM classification for non-small cell lung cancer also was confirmed. Two sets of survival curves were generated using the Kaplan-Meier method, one based on the original pathologic diagnosis and the second based on tumor classification according to the new WHO criteria.
Table 1—1999 WHO Criteria for the Diagnosis of Neuroendocrine Tumors

Tumor Type Criteria
Typical carcinoid Carcinoid morphology and <2 mitoses/2 mm2 (10 HPFs), lacking necrosis and>0.5 cm
Atypical carcinoid Carcinoid morphology with 2-10 mitoses/2 mm2 (10 HPFs) or necrosis (often punctate)
Large cell Neuroendocrine morphology (organoid
neuroendocrine nesting, palisading, rosettes, trabeculae);
carcinoma High mitotic rate: >10/2 mm2 (10 HPFs), median of 70/2 mm2 (10 HPFs);Necrosis (often large zones);Cytologic features of a NSCLC: large cell size, low nuclear to cytoplasmic ratio, vesicular or fine chromatin, and/or frequent nucleoli; some tumors have fine nuclear chromatin and lack nucleoli, but qualify as NSCLC because of large cell size and abundant cytoplasm; and Positive immunohistochemical staining for one or more NE markers (other than neuron-specific enolase) and/or NE granules by electron microscopy
Small cell carcinoma Small size (generally less than the diameter of three resting lymphocytes);Scant cytoplasm;Nuclei: finely granular nuclear chromatin, absent or faint nucleoli;

High mitotic rate: >11 mitoses/2 mm2 (10 HPFs), median of 80/2 mm2 (10 HPFs); and

Frequent necrosis often in large zones.

*HPF = high-power N = neuroendocrine field; NSCLC = non-small cell carcinoma;

Table 2—Comparison of 5-Year and 10-Year Survival Rates for Pulmonary Carcinoid Tumors

Study/yr TumorHistologyTC AC Regional LN Involvement,I No.TC AC 5-yr Survival, %ITC AC 10-yr Survival, %TC AC Comments
McCaughan et al /1985 72 23 811 100 69 87 52
Attar et al/1985 31 12 27 92 59 88 59
Torre et al/1989 99 12 39 100 Seecomments 100 11% 2-yr survival rate for the 12 ptswith AC
Schreurs et al/1992 93 0 90 100 100 9 pts with N1 disease
Harpole et al/1992 80 41 See comments 96 40 92 31 41 pts had LN involvement but were not identified as having TC or AC
Akiba et al/1992 28 4 22 100 25 90.9 25
Vadasz et al/1993 109 11 See comments See comments 7 pts had LN involvement but were not defined as having TC or AC; 5-yr survival rate for combined tumors is >90%
Gould et al/1998 64 23 1211 See comments 4-yr survival 95% for TC and 70% for AC
Travis et al/1998 51 62 See comments 87 56 87 35 LN involvement not discussed
Present study 23 11 23 11 95 54 95 54 Survival figures based on histology and presence of LN metastases