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* From the Departments of Laboratory Medicine and Pathology (Dr. Aubry), Pulmonary and Critical Care Medicine (Drs. Thomas and Jett), and Radiology (Dr. Swensen), Mayo Clinic, Rochester, MN; and Department of Pathology (Dr. Myers), University of Michigan, Ann Arbor, MI.
Correspondence to: Marie-Christine Aubry, MD, FCCP, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905; e-mail: aubry.mariechristine{at}mayo.edu
Abstract
Background: The clinical significance of multiple carcinoid tumorlets in surgical lung specimens has not been systematically analyzed. We reviewed our experience to determine the range of clinical circumstances associated with this finding.
Methods: We reviewed clinical records, available imaging, and pathology materials from patients evaluated at Mayo Clinic Rochester (from 1987 to 2000) with two or more carcinoid tumors or tumorlets in lung specimens.
Results: Twenty-eight of 294 patients with a diagnosis of carcinoid tumor or tumorlet had two or more lesions. Twenty-six patients (93%) were women; mean age was 65 years. Patients were categorized into three groups: multiple nodules (n = 17), solitary lung nodules on preoperative imaging (n = 7), and airflow limitation (n = 4). Approximately half of patients with multiple nodules had respiratory complaints; two patients had Cushing syndrome. Ten patients (58.8%) were suspected of having pulmonary metastases, including 7 patients with previously diagnosed malignancies. Intrathoracic lymph node metastases were present in three patients, none of whom had recurrent disease. One patient had a carcinoid tumor resected 8 years later. Extrathoracic metastases developed in another patient 3 years after presentation, and the patient was alive with disease 2 years later. Only one patient with airflow limitation had a syndrome resembling diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.
Conclusions: Our series represents the largest compilation of multiple carcinoid tumors or tumorlets. Our analysis reveals that multiple carcinoid tumors or tumorlets occur most commonly in patients with multiple nodules resembling metastatic disease. Significant airflow limitation is rare. Long-term survival is excellent, although patients have persistent disease.
Key Words: carcinoid tumor • lung neoplasm • neuroendocrine cell hyperplasia • tumorlets
Pulmonary neuroendocrine cell hyperplasia and tumorlets comprise a spectrum of neuroendocrine proliferation that occurs in a variety of clinical contexts. Tumorlets are otherwise typical carcinoid tumors that measure 
5 mm in greatest dimension. The World Health Organization classification of lung tumors applies the term diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) to the following1:
a generalized proliferation of scattered single cells, small nodules (neuroendocrine bodies), or linear proliferations of pulmonary neuroendocrine cells (PNCs) that may be confined to the bronchial and bronchiolar epithelium, include local extraluminal proliferation in the form of tumorlets, or extend to the development of carcinoid tumors... other pathology that might induce reactive PNC proliferation is absent.
Others234 have used similar terms to describe a clinicopathologic syndrome in which the histologic findings described above are associated with physiologic evidence of airflow limitation, a syndrome that overlaps both clinically and morphologically with obliterative bronchiolitis.
The nature and significance of tumorlets have been the subject of controversy. Tumorlets were initially considered hyperplastic lesions occurring in association with chronic pulmonary diseases, including bronchiectasis, fibrosis, and obliterative bronchiolitis.5678 Tumorlets were subsequently demonstrated in normal lungs or in association with carcinoid tumors, and considered neoplastic.910 Reports1112 of an association with lymph node metastases further suggested the neoplastic potential of tumorlets.
Tumorlets, even when multiple, are often asymptomatic. Pulmonary symptoms, abnormalities of pulmonary function, and radiologic abnormalities have been attributed to multiple tumorlets in occasional patients with or without associated airflow limitation.2413141516
Given these myriad of findings, it is difficult to come to any firm conclusion on the clinical significance of multiple carcinoid tumorlets. We thus reviewed our experience to further characterize the range of clinical, radiologic, and pathologic findings associated with multiple tumorlets and to delineate the natural history of this unusual lesion.
Materials and Methods
Study Group
The Mayo Clinic pathology database was searched for patients with a diagnosis of carcinoid tumor or tumorlet who underwent either surgical lung biopsy or lung resection between January 1, 1987 and December 31, 2000. Only patients with two or more carcinoid tumors and/or tumorlets were included in the final study group. The study was approved by the Mayo Foundation Institutional Review Board.
Clinical Data
Medical records were reviewed and the following data were recorded: age at surgery, gender, smoking history, previous history of COPD, interstitial lung disease, multiple endocrine neoplasia, cancer, and carcinoid tumor from sites other than lung. Pulmonary symptoms and presence of neuroendocrine syndromes were recorded.
Pulmonary function tests (PFTs) were reviewed and results interpreted according to the American Thoracic Society/European Respiratory Society Task Force for the Standardization of Lung Function Testing, Interpretative strategies for lung function tests; thus, all patients had a FEV1/FVC < 70% of predicted, and mild obstruction was FEV1 of 60 to 80%, moderate obstruction was FEV1 of 40 to 59%, and severe obstruction was FEV1 of < 40%. The term DIPNECH was limited to patients with neuroendocrine cell hyperplasia and otherwise unexplained airflow limitation.
When available, the presumptive clinical diagnosis or indication for surgery was abstracted. Surgeries and adjuvant treatment with chemotherapy and radiotherapy were recorded.
Radiologic Data
All available chest radiographs and CT scans obtained prior to surgery, at the time of surgery, and following surgery were reviewed. The number of nodules, size, location, edge, presence of calcification, growth, and presence of other pulmonary diseases were recorded. All patients had at least one radiologic study. Twenty-one patients underwent chest radiography, and 22 patients underwent a chest CT examination.
Pathology Data
All lung specimens were obtained from surgical resection. Hematoxylin-eosin–stained sections from all lung and, when available, lymph node specimens were reviewed by two pathologists (M.C.A. and J.L.M.). Immunohistochemical stains were performed using antibodies directed against chromogranin (LK2H10, 1:1000; Roche Diagnostics Corporation; Indianapolis, IN), synaptophysin (SY38, 1:40; ICN Biomedicals; Aurora, OH), and thyroid transcription factor (TTF)-1 (8G7G311, 1:1000; Dako; Carpenteria, CA). Stains were performed on a Dako autostainer with protease pretreatment as required and using a standard streptavidin-biotin technique. Aminoethylcarbazole and diaminobenzadine were the chromogens.
The term carcinoid tumor was applied to neuroendocrine neoplasms with a maximum dimension of > 0.5 cm; the term tumorlet was restricted to neuroendocrine neoplasms 0.5 cm; and the term neuroendocrine cell hyperplasia referred to increased numbers of neuroendocrine cells within bronchial and bronchiolar mucosa. Number and size of pulmonary nodules, and their location (peribronchiolar, perivenular, and subpleural) were recorded. The presence of chronic bronchiolitis, fibrosis, obliterative bronchiolitis, organizing pneumonia, and centriacinar emphysema was noted. Peribronchial and/or mediastinal lymph nodes were evaluated for presence or absence of metastases.
Follow-up
Follow-up information was obtained from medical records. Patients not followed up at our institution were contacted by telephone. If the patient or family member could not be reached, the date and information at the last follow-up in the medical record was used. Patients were classified at follow-up as follows: alive with no evidence of disease (AWNED), alive with stable disease, alive with progressive disease, alive status of disease unknown, dead of disease (DOD), dead of unrelated cause, or death of unknown cause. Information recorded included growth of existing nodules, recurrence, new surgery, and metastasis in other sites.
Results
Twenty-eight of 294 patients (9.5%) seen at the Mayo Clinic between 1987 and 2000 with a diagnosis of carcinoid tumor or tumorlet had two or more lesions. Twenty-six patients (93%) were women. Mean age at diagnosis was 65 years (range, 45 to 84 years). Thirteen patients (44%) were past or current smokers, with average exposures of 24 pack-years (range, 2 to 90 pack-years) [Table 1 ]. Patients were classified into three groups based on preoperative clinical and radiologic findings (Table 2 ). Distribution of patients within these groups varied over time; all patients with solitary nodules on preoperative imaging studies were seen prior to 1995.
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Nearly all patients underwent wedge biopsy (76%), with segmentectomy in two patients (12%) and lobectomy in one patient (6%). An average of one carcinoid tumor and eight tumorlets was present in resected lung tissue. Thirteen patients had at least one carcinoid tumor, while 4 patients had multiple tumorlets without an associated carcinoid tumor. Three patients (11%), all with a dominant carcinoid tumor, had lymph node metastases including one patient with N1 (stage IIA) disease and two patients with N2 (stage IIIA) disease.
Patients were followed up for an average of 66 months (range, 3 to 154 months). One patient died of unknown causes. Four patients had complete excision of all nodules and did not have any recurrence. Most patients with residual nodules (n = 9) had stable disease with no growth in residual small indeterminate nodules. None of the patients with lymph node metastases had recurrence or further metastases. A small indeterminate nodule grew to a maximum diameter just over 1 cm in one patient and proved to be a carcinoid tumor in a resection performed 8 years after the first surgery. In another patient, the lung nodules grew and a metastasis appeared in one eye 3 years after the initial diagnosis. Despite treatment with somatostatin, the eye lesion progressed and bone metastases (rib, femur, and pelvis) were diagnosed the following year. She was treated with radiation therapy, but 5 years after the initial diagnosis widespread metastases developed involving thyroid, submandibular lymph nodes, and skin.
Solitary Nodule
Six women and one man (mean age, 65 years) underwent surgery for a solitary peripheral lung nodule. Two patients had a history of malignant neoplasm including papillary serous carcinoma of the ovary and soft-tissue leiomyosarcoma of the thigh. One patient had a history of sarcoidosis. All but two patients were neversmokers. Three patients were asymptomatic, while three patients had nonspecific respiratory complaints. Five patients underwent pulmonary function testing, and two patients showed borderline (ex-smoker) or mild (neversmoker) obstruction. All underwent lobectomy for carcinoid tumor. At surgery, incidental nodules were discovered within the lobectomy specimen in all patients, including an additional carcinoid tumor and an average of three associated tumorlets (Table 1). Additional nodules were found in different lobes of three patients and were resected with wedge biopsies. Intrathoracic lymph nodes were sampled in six patients, and all were negative. Six patients in whom follow-up was available were alive and were either free of disease (n = 4) or the status of their disease was unknown (n = 2).
Obstructive Lung Disease
Four women (mean age, 61 years) were referred for investigation and treatment of obstructive lung disease. Two patients were neversmokers. One patient had a history of right middle lobe resection for carcinoid tumor, and another patient was status post mastectomy for breast cancer. Two patients underwent lung transplantation for obstructive lung disease; FEV1 values were 12% and 19%, and FEV1/FVC values were 17% and 24%, respectively. A third patient underwent wedge biopsy after a chest CT scan showed a combination of small indeterminate nodules and a mosaic pattern of attenuation consistent with air trapping. The PFT showed an FEV1 of 50%, with an FEV1/FVC of 67%. The fourth patient had a clinical diagnosis of asthma and underwent wedge biopsy for suspected organizing pneumonia. Her FEV1 was 42% and FEV1/FVC was 43%. An average of four tumorlets was identified in each patient. Multiple tumorlets were associated with severe emphysema in both explanted lungs. Obliterative bronchiolitis with neuroendocrine cell hyperplasia was the main histologic abnormality in the patient with nodules and mosaic attenuation on CT scan. Biopsy from the patient with asthma showed only multiple tumorlets without associated neuroendocrine cell hyperplasia or constrictive bronchiolitis. Both patients who underwent transplantation died: one patient in the immediate postoperative period, and the other patient 3 years later due to chronic rejection. The other two patients were alive 46 months and 77 months after biopsy, respectively.
Radiologic Findings
One or more lung nodules were demonstrated in 26 of the 28 patients. Seventeen patients had multiple nodules, which were bilateral in 5 patients (Fig 1
). The nodules measured anywhere from 0.1 to 4.0 cm. The edges of the nodules were usually smooth and spherical (18 of 26 patients, 70%). Eight of 26 patients had nodules with irregular, poorly circumscribed edges. Only 1 of the 26 patients had a nodule that was faintly calcified. A pattern of mosaic attenuation suggestive of air trapping was described in one patient. Another patient had an obstructed segmental bronchus with distal bronchiectasis. Two patients had hilar and mediastinal adenopathy.
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Multiple nodules mimicking pulmonary metastases is the most common setting in which multiple carcinoid tumors and tumorlets are discovered in surgical lung specimens. Darvishian and colleagues16 recently described 12 women who presented with multiple lung nodules 1 month to > 13 years after diagnosis of various types of malignant breast neoplasms. Their experience augments a previous report17 of a 63-year-old woman discovered to have multiple tumorlets after surgery for presumed metastatic breast carcinoma. Akashiba et al18 described a 74-year-old, male smoker discovered to have multiple nodules thought to represent metastatic disease. Clinical investigation failed to demonstrate a primary tumor, and the patient underwent lung biopsy demonstrating multiple tumorlets. Combined with our own experience, these observations indicate that older women, often with a previously diagnosed cancer, are most commonly affected. The reason for the female predominance in our study and others16 is unclear, although driven in part by a focus on patients with breast carcinoma. About half of patients have respiratory symptoms, most frequently complaining of cough. Most patients have stable, nonprogressive lung disease following lung biopsy.
Patients in whom multiple tumorlets are discovered usually lack evidence of severely restrictive or obstructive lung disease. Descriptions of small airway obliteration associated with tumorlets did not surface until the 1970s,613 and it was not until the 1990s that airflow limitation was attributed to what is now termed DIPNECH.241314151920212223 Table 4 summarizes 20 patients reported in the English language with multiple tumorlets and diffuse lung disease. Most (85%) were women, with a mean age of 53.0 years. The majority were neversmokers who presented with otherwise unexplained obstructive lung disease, for which one patient underwent pulmonary transplantation. All but one patient in whom follow-up was available were reported as alive, the single death occurring 7 years after onset of symptoms. Most of our patients had either normal or only mildly abnormal PFT results. A syndrome similar to that described by Aguayo and colleagues,2 in which moderate-to-severe obstruction is accompanied by a combination of obliterative bronchiolitis and neuroendocrine cell hyperplasia in lung biopsy (ie, DIPNECH), was seen in only one of our patients (3.6%). Another patient with multiple nodules had identical histopathologic findings but without physiologic evidence of airflow limitation, emphasizing that histology alone cannot predict for functionally significant airways disease as previously highlighted by Miller and Muller.14 Interestingly, an additional patient with a syndrome of obstructive lung disease previously attributed to asthma had multiple tumorlets but without associated histologic evidence of either neuroendocrine cell hyperplasia or obliterative bronchiolitis. Coupled with the observations of Miller and Muller,14 our findings suggest that multiple tumorlets and/or neuroendocrine cell hyperplasia may be associated with mild airflow limitation, but moderate-to-severe disease is uncommon. The difference in the clinical profile that emerges from previous reports compared to our own patient population almost certainly relates to differences in patient selection. Our search was intended to capture any patients with at least two tumorlets/tumors in surgical lung specimens regardless of the clinical setting and may more accurately represent the full range of clinical settings in which these unusual pathologic findings occur.
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Multiple tumorlets have been recognized as an incidental discovery of little biological or clinical significance in patients with various forms of chronic pulmonary disease since the early part of the 20th century.78924 In his review of the literature published in 1955, Whitwell8 concluded that tumorlets were multiple in over half of cases and nearly always associated with diseased lung tissue, most commonly bronchiectasis. This association reflected, in part, reliance on autopsies as the most common tool for histopathologic examination. In our own experience, clinically significant underlying chronic lung disease was uncommon and was limited to two patients who underwent transplantation for smoking-related COPD.
The risk of clinically significant neuroendocrine lung neoplasms developing is low for patients with neuroendocrine cell hyperplasia. Neuroendocrine cell hyperplasia is frequently associated with tumorlets and/or peripheral carcinoid tumors, raising the possibility that neuroendocrine cell hyperplasia is a preneoplastic lesion.25 A minority of our patients with multiple tumorlets and peripheral carcinoid tumors lacked underlying neuroendocrine cell hyperplasia, indicating that it is not an obligate precursor lesion. In addition, most patients with neuroendocrine cell hyperplasia had stable disease without growth or metastases of tumor nodules. While our findings do not preclude the possibility that neuroendocrine cell hyperplasia is preneoplastic, the risk of clinically significant disease developing appears to be low.
Multiple tumorlets, usually in association with a dominant carcinoid tumor, are rarely associated with endocrine syndromes resulting from ectopic hormone secretion. Most, as in our study, acquire Cushing syndrome due to ectopic Cushing syndrome due to adrenocorticotropic hormone secretion.2026272829 Acromegaly and carcinoid syndrome are less commonly reported.233031
Multiple tumorlets are associated with a generally good prognosis regardless of the clinical setting.2202123 No death attributable to lung disease occurred in our patients. Most patients have persistent but stable disease without specific adjuvant therapy. Progressive disease, although uncommon, takes the form of growth, metastases in patients with a dominant carcinoid tumor, or progressive diffuse disease associated with airflow limitation.
In summary, multiple tumorlets discovered in surgical lung specimens occur in various clinical settings, most commonly in patients with multiple lung nodules suspected of representing pulmonary metastases. Most patients have associated peripheral carcinoid tumors. Physiologically significant diffuse lung disease is uncommon, and most patients can be managed with observation or treatment appropriate to the underlying condition.
Footnotes
Abbreviations: AWNED = alive with no evidence of disease; DIPNECH = diffuse idiopathic neuroendocrine cell hyperplasia; DOD = dead of disease; PFT = pulmonary function test; TTF = thyroid transcription factor
This work performed at the Mayo Clinic, Rochester, MN.
The authors have no personal or financial conflicts of interest relative to the content of this article.
Received for publication December 9, 2006. Accepted for publication March 1, 2007.
References
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