Typical and Atypical Pulmonary Carcinoids

Typical and Atypical Pulmonary Carcinoids* Outcome in Patients Presenting With Regional Lymph Node Involvement Charles F. Thomas, Jr., MD; Henry D. Tazelaar, MD, FCCP; and James R. Jett, MD, FCCP

Study objective: Typical pulmonary carcinoid tumors are well-differentiated neuroendocrine tumors that are associated with good patient survival rates, while atypical carcinoid tumors are more aggressive and have worse patient survival rates. Because these tumors rarely involve the thoracic lymph nodes at presentation, it is currently unknown to what extent the presence of thoracic lymph node metastases at the time of diagnosis influences patient survival. Methods: A computerized search of the medical records for pulmonary carcinoid tumor at the Mayo Clinic from 1976 to 1997 revealed 517 patients, from which we identified 36 patients with pulmonary carcinoid tumors involving regional thoracic lymph nodes but without distant disease. For each patient, we reviewed the tumor histology, stage, and outcome. In addition, because the histologic criteria for the diagnosis of carcinoid tumors had changed significantly during the time of the study, we reexamined all of the histologic specimens using the current World Health Organization (WHO) criteria for classifying pulmonary neuroendocrine tumors. Results: After reclassification with the WHO criteria for neuroendocrine tumors, 23 patients had typical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, 19 patients had no evidence of disease (NED), 2 patients had developed systemic metastases (SM) and are still alive, and 2 patients had died. Eleven patients had atypical carcinoid tumors with thoracic lymph node involvement. At the last follow-up, four patients had NED, seven patients had developed SM within a median time of 17 months, and six patients with SM died shortly thereafter (median survival time, 25.5 months), while one is still alive. Two patients had been reclassified with large cell neuroendocrine carcinoma at the time of this review; both of these patients had developed SM (at 4 months and 21 months after diagnosis) and had died (at 15 months and 21 months after diagnosis, respectively). Conclusions: These data suggest that patients with atypical pulmonary carcinoid tumors with regional lymph node metastases have a high likelihood of developing recurrent disease if treated with surgical resection alone and have significantly worse outcome (p < 0.001) compared to those patients with typical carcinoid tumors with thoracic lymph node involvement. (CHEST 2001; 119:1143–1150) Key words: atypical carcinoid; bronchial carcinoid; survival Abbreviations: NED ⫽ no evidence of disease; SM ⫽ systemic metastases; WHO ⫽ World Health Organization

carcinoid tumors are malignant neoP ulmonary plasms that show neuroendocrine differentiation.1–3 Although the distinction between typical and atypical carcinoid tumors was first described by Engelbreth-Holm4 in 1944, it was not until 1972 that *From the Department of Medicine (Dr. Thomas), the Department of Anatomic Pathology (Dr. Tazelaar), and the Department of Oncology (Dr. Jett), Division of Pulmonary, Critical Care, and Internal Medicine, Mayo Clinic and Foundation, Rochester, MN. Manuscript received July 28, 2000; revision accepted October 17, 2000. Correspondence to: Charles F. Thomas, Jr., MD, Thoracic Diseases Research Unit, Guggenheim Bldg 696, Mayo Clinic and Foundation, Rochester, MN 55905; e-mail: [email protected]

histologic criteria for separating these tumors were proposed by Arrigoni et al.5 In the intervening 25 years, numerous studies have continued to confirm that there is a spectrum of neuroendocrine-appearing 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 applied.6 – 8 The 1981 World Health Organization (WHO) classification of neuroendocrine neoplasms stated only that atypical carcinoid tumors had “inCHEST / 119 / 4 / APRIL, 2001

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creased mitotic activity, cellularity and could have necrosis.”9 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.10,11 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.10 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).5,6,12–20 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 survival

Table 1—1999 WHO Criteria for the Diagnosis of Neuroendocrine Tumors* Tumor Type

Criteria

Carcinoid morphology and ⬍2 mitoses/2 mm2 (10 HPFs), lacking necrosis and ⱖ0.5 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: ⱖ10/2 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: ⱖ11 mitoses/2 mm2 (10 HPFs), median of 80/2 mm2 (10 HPFs); and Frequent necrosis often in large zones. Typical carcinoid

*HPF ⫽ high-power field; NSCLC ⫽ non-small cell carcinoma; N ⫽ neuroendocrine. 1144

rate 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.10 The pathologic stage of disease using the TNM classification for non-small cell lung cancer also was confirmed.21 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.22

Results Thirty-six patients with pulmonary carcinoid tumors had thoracic lymph node involvement at the time of surgical resection and staging from 1976 to 1997. These included 15 men and 21 women with a mean age of 55.9 years (age range, 17 to 77 years). The original classification was 24 typical carcinoid tumors and 12 atypical carcinoid tumors (Table 3). Using the current criteria for classifying pulmonary neuroendocrine tumors, four patients originally receiving diagnoses of typical carcinoid tumors were reclassified as having atypical carcinoid tumors. In addition, three patients originally receiving diagnoses of atypical carcinoid tumor were reclassified as having typical carcinoid tumors, and two patients originally receiving diagnoses of atypical carcinoid tumors were reclassified as having large cell neuroendocrine carcinoma. Therefore, using the current WHO criteria, there were 23 patients with typical Clinical Investigations

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

Regional LN Involvement, No.

Study/yr

TC

AC

TC

AC

TC

AC

McCaughan et al12 /1985 Attar et al14/1985 Torre et al16/1989

72 31 99

23 12 12

8 2 3

11 7 9

100 92 100

Schreurs et al17/1992 Harpole et al15/1992

93 80

0 41

9 0 See comments

100 96

69 59 See comments — 40

Akiba et al13/1992 Vadasz et al19/1993

28 109

4 11

2 2 See comments

100 25 See comments

Gould et al20/1998

64

23

Travis et al18/1998 Present study

51 23

62 11

12

11

See comments 23 11

5-yr Survival, %

10-yr Survival, % TC

AC

87 88 100

52 59 —

100 92

— 31

90.9 —

25 —

See comments

—

—

87 95

87 95

35 54

56 54

Comments

11% 2-yr survival rate for the 12 pts with AC 9 pts with N1 disease 41 pts had LN involvement but were not identified as having TC or AC 7 pts had LN involvement but were not defined as having TC or AC; 5-yr survival rate for combined tumors is ⬎90% 4-yr survival 95% for TC and 70% for AC LN involvement not discussed Survival figures based on histology and presence of LN metastases

*TC ⫽ typical carcinoid tumor; AC ⫽ atypical carcinoid tumor; LN ⫽ lymph node; pts ⫽ patients.

carcinoid tumors (10 men and 13 women; mean age, 52 years; age range, 17 to 74 years), 11 patients with atypical carcinoid tumors (4 men and 7 women; mean age, 63 years; age range, 34 to 77 years), and 2 patients with large cell neuroendocrine carcinoma (1 man, age, 68 years; 1 woman, age, 64 years; Table 3). Typical carcinoid tumors had a mean mitotic rate of 0.19/2 mm2 (10 high-power fields) and, by definition, did not have necrosis. Three tumors, however, had foci of discohesive cells with somewhat pyknotic nuclei and condensed, shrunken-appearing cytoplasms in comparison to adjacent cells (Fig 1); but, because of a lack of karyorrhexis, associated eosinophilic debris, or apoptosis, such foci were not accepted as necrosis. All three patients are currently alive and without metastatic disease at a median time of 88 months. Atypical carcinoid tumors had a mean mitotic rate of 1.78/2 mm2; 10 of 11 atypical carcinoid tumors also had foci of necrosis (Fig 2). Six tumors were classified as atypical carcinoid only on the basis of necrosis with a mitotic rate of ⬍ 2/2 mm2. Three patients from this subgroup are alive without evidence of metastases, one developed metastases 12 months after diagnosis but is still alive at 89 months, and two patients developed metastases and died. The two patients with large cell neuroendocrine carcinoma had foci of necrosis and mitotic rates of 19/2 mm2 and 32/2 mm2 (Fig 3). Among the 23 patients with typical pulmonary carcinoid tumors, 8 had stage IIA disease (T1N1M0), 6 had stage IIB disease (T2N1M0), and 9 had stage

IIIA disease (T1N2M0 or T2N2M0). Nineteen patients (82.6%) had no evidence of disease (NED) at follow-up (median, 84 months after diagnosis; range, 12 to 242 months after diagnosis). Only two patients (8.7%) developed systemic metastases (SM) at 54 and 78 months after diagnosis. Both patients are currently alive. Two patients died (one at 29 months of unknown causes, and the other at 223 months of “natural causes” at age 93 years; Table 3). Among the 11 patients with atypical carcinoid tumors, 3 had stage IIA disease (T1N1M0), 4 had stage IIB disease (T2N1M0), and 4 had stage IIIA disease (T2N2M0 or T3N1M0). Only four patients (36.4%) showed NED at the time of follow-up, while seven patients (63.6%) developed SM at a median time of 17 months after diagnosis (range, 2 to 57 months after diagnosis). Six patients with SM died within a median time of 25.5 months after the initial diagnosis (range, 2 to 123 months after diagnosis). One patient with SM is still alive at 89 months (Table 3). Both patients with large cell neuroendocrine carcinoma (one man, age 68 years; one woman, age 64 years) had stage IIIA disease (T1N2M0 or T2N2M0) and developed SM at 4 months and 21 months after receiving their diagnoses, respectively. Both patients died shortly thereafter, 15 months and 21 months, respectively, after the initial diagnoses (Table 3). Survival curves for the patients classified according to the original pathologic diagnosis and the diagnosis based on the new classification scheme are shown in Figure 4. Although the number of patients in this study was too small to permit a meaningful CHEST / 119 / 4 / APRIL, 2001

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Table 3—Demographics of the 36 Patients With Typical Carcinoid Tumors, Atypical Carcinoid Tumors, or Large Cell Neuroendocrine Carcinoma*

Stage

Reclassification

Original Classification

Mitoses/10 HPF and Presence of Necrosis, No.

1/17/M 2/21/F 3/27/M 4/39/M

T2N2M0 T2N2M0 T2N2M0 T1N2M0

TC TC TC TC

TC TC TC TC

0 0 0 0.33

110 242 15 84

5/41/F 6/41/M 7/47/F 8/48/M 9/50/F

T2N1M0 T2N2M0 T2N2M0 T2N2M0 T1N1M0

TC TC TC TC TC

TC TC AC TC TC

0 0 0 0 1.67

158 75 96 88 87

10/52/F 11/52/F 12/53/F 13/59/F 14/61/F 15/62/F 16/63/M 17/64/M 18/66/M 19/70/F 20/71/M 21/72/F 22/73/M 23/74/F 24/34/M 25/44/F 26/48/F 27/54/F 28/59/M 29/62/F 30/67/M 31/69/F 32/70/M 33/73/F 34/77/F 35/64/F 36/68/M

T2N1M0 T1N1M0 T1N1M0 T2N1M0 T1N1M0 T1N2M0 T1N2M0 T2N1M0 T2N1M0 T2N1M0 T1N1M0 T1N1M0 T1N1M0 T1N1M0 T2N2M0 T3N1M0 T2N1M0 T2N1M0 T1N1M0 T1N1M0 T2N1M0 T2N1M0 T1N1M0 T2N2M0 T2N2M0 T1N2M0 T2N2M0

TC TC TC TC TC TC TC TC TC TC TC TC TC TC AC AC AC AC AC AC AC AC AC AC AC LCNEC LCNEC

AC TC TC TC AC TC TC TC TC TC TC TC TC TC TC AC TC AC AC TC AC TC AC AC AC AC AC

0 0 1 0 0.3 0.33 0 0 0.33 0 0 0.33 0 0 0.33/N 4.7/N 0/N 2.6/N 3.6/N 1/N 4.3/N 2 0/N 1/N 0/N 19/N 32/N

75 43 52 150 168 29 118 74 85 36 70 25 33 223 123 21 102 53 2 74 30 65 89 21 67 15 21

Patient/Age, yr/Sex

Duration of Follow-Up, mo

Outcome at Last Follow-Up NED NED NED SM (54 mo but alive) NED NED NED NED SM (78 mo but alive) NED NED NED NED NED Died NED NED NED NED NED NED NED Died SM (57 mo/died) SM (2 mo/died) NED SM (17 mo/died) SM (2 mo/died) NED SM (24 mo/died) NED SM (12 mo) SM (21 mo/died) NED SM (4 mo/died) Died

*N ⫽ presence of necrosis; HPF ⫽ high-power field; LCNEC ⫽ large cell neuroendocrine carcinoma. See Table 2 for other abbreviations not used in the text.

statistical analysis between the two groups (old vs new classification), the new classification scheme does separate tumors that behave worse than the atypical carcinoid tumors, as previously classified. Discussion Pulmonary carcinoid tumors comprise 1 to 2% of all lung malignancies.1,15,23 Historically called bronchial adenomas, they were thought to be benign tumors. The recognition of a more aggressive variety of carcinoid tumor, the atypical carcinoid, suggested that they might all be malignant.4,5,11,18,20 Currently, typical and atypical carcinoids are considered to be 1146

part of a spectrum of malignant neoplasms with neuroendocrine differentiation along with large cell neuroendocrine carcinoma and small cell carcinoma.10,11,18 In general, patients with typical carcinoids have good prognoses, with ⬎ 87% of patients surviving for 10 years. In contrast, approximately 25 to 69% of patients with atypical carcinoid tumors survive 5 years, and many develop widespread disease.5,6,12–20 Multivariate analyses from four studies12,15,18,20 suggest that pathologic stage and atypical histology are the most important factors affecting survival; however, not all studies have confirmed this. In a study of 93 patients with typical carcinoid tumors, the presClinical Investigations

Figure 2. Atypical carcinoid tumor with focus of central necrosis (arrows; hematoxylin-eosin, original ⫻ 200).

Figure 1. Typical carcinoid tumor with central (top, A) and peripheral (bottom, B) foci (arrows) of cell discohesion, nuclear hyperchromatism, pyknosis, and condensed cytoplasm. Such foci were not accepted as tumor necrosis (hematoxylin-eosin, original ⫻ 100 [top, A], original ⫻ 200 [bottom, B]).

ence of lymph node metastases in 9 patients (all with N1 disease) did not have any prognostic significance. Eight patients survived a mean of 8 years, while one patient died of unrelated causes.17 In another report of 120 patients,19 there was insufficient information to allow any conclusions about the significance of either atypical features or lymph node metastases (only 7 patients had lymph node metastases). No prior studies specifically analyzed the subset of patients with typical or atypical pulmonary carcinoid tumors who presented with lymph nodal metastases at the time of surgical resection. As shown in Table 3, we compare the survival data for patients with typical or atypical pulmonary carcinoid tumors presenting with lymph node metastases with a historical series of patients with pulmonary carcinoid tumors. In the present study, patients with typical pulmo-

nary carcinoid tumors with thoracic lymph node metastases did well after surgical resection alone. The overall survival rate was excellent, with only two patients (8.7%) developing systemic disease at a median time of 66 months after diagnosis and two patients dying. This is in contrast to patients with atypical pulmonary carcinoid tumors with thoracic lymph node metastases. When treated with surgical resection alone, most of these patients (63.6%) developed SM at a median time of 17 months after diagnosis. The majority of patients with SM (54.5%) died shortly thereafter (median time, 25.5 months after initial diagnosis). The results of this study suggest that the accurate classification of pulmonary neuroendocrine tumors is essential to determining prognosis, but until recently

Figure 3. Large cell neuroendocrine carcinoma with numerous mitotic figures (arrows; hematoxylin-eosin, original ⫻ 100). CHEST / 119 / 4 / APRIL, 2001

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Figure 4. Kaplan-Meier survival analysis of study patients using the Arrigoni criteria (top, A) or the current WHO classification (bottom, B).

there have been no widely accepted criteria with which to make a reproducible or clinically meaningful separation between the various tumor types. The new WHO classification scheme, based on the work of Travis and Sobin,10 utilizes a combination of mitotic activity and the presence of necrosis to 1148

separate typical carcinoid tumors from atypical carcinoid tumors. This study supports the clinical utility of the WHO classification, demonstrating differences in the Kaplan-Meier survival curves comparing the patients’ original diagnoses with the WHO classification (Fig 4). Although our numbers are relaClinical Investigations

tively small, they do suggest that carcinoid tumors with mitotic counts between 2/2 mm2 and 10/2 mm2 of viable tumor or coagulative necrosis behave in a more aggressive fashion than ordinary carcinoid tumors and that patients with those tumors that have a very high mitotic rate (ⱖ 10/2 mm2) have the worst prognoses. Although much has been written about the difficulty in counting mitotic figures in several tumor systems, there are equally difficult problems with basing the classification scheme on such things as “cellularity and atypia.”6 – 8,24 –26 One problem encountered in this study was distinguishing between true coagulative necrosis and what might be called “incipient necrosis.” This latter finding consisted of foci of cells with somewhat pyknotic nuclei and shrunken-appearing cytoplasm, in comparison to immediately adjacent cells, and cell discohesion without frank karyorrhexis, eosinophilic necrotic debris, or apoptosis (Fig 1). Such foci were not counted as foci of coagulative necrosis and were not used to classify a tumor as an atypical carcinoid tumor. Because of the difficulty in evaluating small foci of necrosis and in counting mitotic figures on frozen sections, it may be very difficult in borderline cases to make a definitive diagnosis without examining the permanent sections. For intraoperative surgical management, however, a diagnosis of carcinoid tumor should be sufficient, and we reiterate the opinion of others that all such patients should be treated and staged similarly to other patients with lung cancer. Finally, this study supports the significance of recognizing the existence of a high-grade non-small cell tumor with neuroendocrine differentiation (ie, large cell neuroendocrine carcinoma). Although there is debate regarding the significance of nonsmall cell carcinomas the neuroendocrine differentiation of which is only suggested by the presence of chromogranin A or synaptophysin identification immunohistochemically, tumors that appear to be neuroendocrine by light microscopy and that have a mitotic rate ⬎ 10/2 mm2 behave significantly worse than those with mitotic rates ⬍ 10/2 mm2.27 We identified two patients whose tumors were reclassified from atypical carcinoid tumor to large cell neuroendocrine carcinoma. Both patients with large cell neuroendocrine carcinoma developed systemic disease and died shortly after diagnosis (median time, 18 months after initial diagnosis). We concur with others that all patients with any type of carcinoid tumor should be treated and staged similarly to other patients with malignant epithelial lung tumors. Because the majority of pulmonary carcinoid tumors occur centrally and involve the bronchial tree, lung preservation surgery (ie, bronchial sleeve resection) is recommended when possible.15,17,23,28,29 Tumors with greater involvement of

the airway or ones that are located peripherally need more extensive surgery, ranging from lobectomy to pneumonectomy.15,17,30 Bronchoscopic removal is suboptimal treatment, because the tumors can extend submucosally and adequate resection is not achieved by removing the intraluminal component. However, a minority of patients have bronchial carcinoid tumors presenting as polypoid structures in the airway lumen, and in these rare cases bronchoscopic resection alone has been curative.31 Bronchoscopic resection does not, however, allow for lymph node staging, which the results of this study suggest is very important for prognostic information and may be beneficial in making therapeutic decisions. Our data suggest that the subset of patients with atypical pulmonary carcinoid tumors and regional lymph node metastases have a high likelihood of developing recurrent disease if treated with surgical resection alone. Although there is a paucity of data available on the treatment of atypical pulmonary carcinoid tumors, previous studies32–35 have demonstrated a poor response to standard chemotherapy and radiation therapy. Currently, there is no standard therapy for treating atypical carcinoid tumors with any modality other than surgery. Further investigation is needed to determine the optimal treatment with chemotherapy, radiotherapy, or alternative promising new experimental agents. ACKNOWLEDGMENT: We thank Darrell R. Schroeder from the Mayo Clinic Section of Biostatistics for performing the statistical analysis in this study.

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Clinical Investigations