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Original Research: LUNG CANCER |

Significance of Multiple Carcinoid Tumors and Tumorlets in Surgical Lung Specimens*: Analysis of 28 Patients FREE TO VIEW

Marie-Christine Aubry, MD, FCCP; Charles F. Thomas, Jr, MD, FCCP; James R. Jett, MD, FCCP; Stephen J. Swensen, MD; Jeffrey L. Myers, MD, FCCP
Author and Funding Information

*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@mayo.edu



Chest. 2007;131(6):1635-1643. doi:10.1378/chest.06-2788
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Published online

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.

Figures in this Article

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.

Others24 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.58 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.2,4,1316

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.

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.

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.

Multiple Nodules

Sixteen women and 1 man (mean age, 66 years) were evaluated for multiple pulmonary nodules. Nearly half (47%) were neversmokers, and only one patient was a current smoker, with mean exposures of 19 pack-years. The majority (59%) had symptoms, most frequently cough (47%). Two patients presented with Cushing syndrome. No patients had a diagnosis of multiple endocrine neoplasia syndrome. Seven patients had a history of cancer (one patient had two cancers) and were thought to have pulmonary metastases. Previously diagnosed cancers included breast carcinoma (n = 3), endometrial adenocarcinoma (n = 2), colon adenocarcinoma (n = 1), thyroid papillary carcinoma (n = 1), and malignant melanoma (n = 1). Three additional patients were suspected of having pulmonary metastases despite having no history of malignancy. Other diagnostic considerations included sarcoidosis and granulomatous infection in three patients. Eight patients (59%) had borderline or mild airflow limitation on PFTs and included two neversmokers and six ex-smokers. Two patients had moderate airflow limitation, including a neversmoker and a current smoker.

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.

Histologic Findings

Nineteen patients had at least one carcinoid tumor (mean size, 1.5 cm). Carcinoid tumors were peripheral in nearly all patients (96%) and were associated with tumorlets in 17 patients (89%) [Table 3 ]. Twenty-five patients (89%) patients had either single (n = 3) or multiple (n = 22) tumorlets (mean, n = 3; range, 1 to 29) [Fig 1]. Neuroendocrine hyperplasia was a common finding in small airways (Fig 2 ), occurring in 12 patients (75%), 4 patients (57%), and 4 patients (100%) in groups 1, 2, and 3, respectively. Airway-centered proliferation of neuroendocrine cells was commonly accompanied by nonspecific chronic bronchiolitis with minimal associated fibrosis. Concentric peribronchiolar fibrosis typical of obliterative bronchiolitis occurred in only two patients, including one with a syndrome of otherwise unexplained progressive airflow limitation (Fig 3 ). The other affected patient had multiple nodules on imaging studies and normal pulmonary function studies. Adjacent lung parenchyma was generally unremarkable except for emphysema, which was severe in two patients who underwent transplantation for smoking-related COPD. Associated organizing pneumonia was seen in two patients and was a focal finding in one of them. Immunohistochemical stains were performed in 25 cases for which paraffin blocks were available. All carcinoid tumors and tumorlets stained diffusely and strongly positive for chromogranin and synaptophysin. Seventeen cases (68%) showed immunoreactivity for TTF-1.

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 colleagues16recently 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 report17of 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,6,13 and it was not until the 1990s that airflow limitation was attributed to what is now termed DIPNECH.2,4,1315,1923Table 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.

Approximately a third of patients with multiple tumorlets have either a dominant carcinoid tumor or an underlying nonneoplastic lung disease such as emphysema. Most of our patients had an associated carcinoid tumor, reflecting in part the biased nature of our retrospective sampling strategy. All carcinoid tumors associated with tumorlets and neuroendocrine cell hyperplasia were peripheral, a finding consistent with previous observations.14 Three of our patients with carcinoid tumors had lymph node metastases at the time of diagnosis, an unexpectedly high rate of nodal disease compared to other reviews of pulmonary carcinoid tumors that remains unexplained. Previous reports focusing on peripheral carcinoid tumors fail to demonstrate a higher risk of metastases based on peripheral location alone. The presence of nodal metastases did not predict for a poor outcome in our patients and therefore should not preclude a full surgical resection.

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.79,24 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.20,2629 Acromegaly and carcinoid syndrome are less commonly reported.23,3031

Multiple tumorlets are associated with a generally good prognosis regardless of the clinical setting.2,2021,23 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.

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.

Table Graphic Jump Location
Table 1. Findings in 28 Patients With Multiple Carcinoid Tumorlets/Tumors*
* 

N/D = not done; N/A = not assessable; Mod = moderate.

Table Graphic Jump Location
Table 2. Detailed Clinical Findings in Patients With Multiple Carcinoid Tumorlets and Tumors*
* 

Data are presented as No. (%) unless otherwise indicated.

Figure Jump LinkFigure 1. Top, A: Unenhanced CT with 5-mm sections shows multiple (> 100) bilateral well-circumscribed lung nodules. The nodules were uncalcified, and there was mild hilar adenopathy. Center, B: Macroscopic photograph of lung wedge biopsy showing multiple small nodules. Bottom, C: Low-power photomicrograph illustrating bronchiolocentric carcinoid tumorlets (hematoxylin-eosin, original × 40).Grahic Jump Location
Table Graphic Jump Location
Table 3. Detailed Pathologic Findings in Patients With Multiple Carcinoid Tumorlets and Tumors*
* 

Data are presented as No. (%) unless otherwise indicated.

Figure Jump LinkFigure 2. Low-power photomicrograph illustrating range of hyperplasia with carcinoid tumorlet (chromogranin, original × 40).Grahic Jump Location
Figure Jump LinkFigure 3. Intermediate-power photomicrograph illustrating peribronchiolar fibrosis resulting in luminal narrowing in obliterative bronchiolitis (hematoxylin-eosin, original × 200). Similar findings were seen in a patient who lacked evidence of significant airflow limitation.Grahic Jump Location
Table Graphic Jump Location
Table 4. Summary of Reported Cases of Diffuse Neuroendocrine Cell Hyperplasia/Multiple Tumorlets*
* 

NA = not available; AWD = alive without disease.

Gosney, J, Travis, WD (2004) Pathology and genetics: tumors of the lung, pleura, thymus and heart. Travis, W Brambilla, E Muller-Hermelink, Het al eds.World Health Organization classification of tumors,76-77 IARC. Lyon, France:
 
Aguayo, SM, Miller, YE, Waldron, JA, Jr, et al Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease.N Engl J Med1992;327,1285-1288. [PubMed] [CrossRef]
 
Ryu, JH, Myers, JL, Swensen, S Bronchiolar disorders.Am J Respir Crit Care Med2003;168,1277-1292. [PubMed]
 
Brown, MJ, English, J, Muller, NL Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT: pathologic correlation.AJR Am J Roentgenol1997;168,1561-1562. [PubMed]
 
Canessa, PA, Santini, D, Zanelli, M, et al Pulmonary tumourlets and microcarcinoids in bronchiectasis.Monaldi Arch Chest Dis1997;52,138-139. [PubMed]
 
Churg, A, Warnock, ML Pulmonary tumorlet: a form of peripheral carcinoid.Cancer1976;37,1469-1477. [PubMed]
 
Heimburger, IL, Kilman, JW, Battersby, JS Peripheral bronchial adenomas.J Thorac Cardiovasc Surg1966;52,542-549. [PubMed]
 
Whitwell, F Tumorlets of the lung.J Pathol Bacteriol1955;70,529-541. [PubMed]
 
Felton, W, Liebow, A, Lindskog, G Peripheral and multiple bronchial adenomas.Cancer1953;6,555-567. [PubMed]
 
Bonikos, DS, Archibald, R, Bensch, KG On the origin of the so-called tumorlets of the lung.Hum Pathol1976;7,461-469. [PubMed]
 
D’Agati, VD, Perzin, KH Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature.Cancer1985;55,2472-2476. [PubMed]
 
Hausman, DH, Weimann, RB Pulmonary tumorlet with hilar lymph node metastasis: report of a case.Cancer1967;20,1515-1519. [PubMed]
 
Miller, MA, Mark, GJ, Kanarek, D Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease.Am J Med1978;65,373-378. [PubMed]
 
Miller, RR, Muller, NL Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors.Am J Surg Pathol1995;19,653-658. [PubMed]
 
Sheerin, N, Harrison, NK, Sheppard, MN, et al Obliterative bronchiolitis caused by multiple tumourlets and microcarcinoids successfully treated by single lung transplantation.Thorax1995;50,207-209. [PubMed]
 
Darvishian, F, Ginsberg, M, Klimstra, D, et al Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer.Hum Pathol2006;37,839-844. [PubMed]
 
Fabbri, N, Rocca, T, Navarra, G, et al “Carcinoid tumorlets”: case report and review of the literature.Ann Ital Chir1998;69,509-511. [PubMed]
 
Akashiba, T, Matsumoto, K, Kosaka, N, et al Multifocal peripheral bronchial carcinoid tumour.Respirology1999;4,199-201. [PubMed]
 
Lee, JS, Brown, KK, Cool, C, et al Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features.J Comput Assist Tomogr2002;26,180-184. [PubMed]
 
Arioglu, E, Doppman, J, Gomes, M, et al Cushing’s syndrome caused by corticotropin secretion by pulmonary tumorlets.N Engl J Med1998;339,883-886. [PubMed]
 
Armas, OA, White, DA, Erlandson, RA, et al Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease.Am J Surg Pathol1995;19,963-970. [PubMed]
 
Cohen, AJ, King, TE, Jr, Gilman, LB, et al High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells.Am J Respir Crit Care Med1998;158,1593-1599. [PubMed]
 
Skinner, C, Ewen, SW Carcinoid lung: diffuse pulmonary infiltration by a multifocal bronchial carcinoid.Thorax1976;31,212-219. [PubMed]
 
Kay, S Histologic and histogenetic observation on the peripheral adenoma of the lung.Arch Pathol1958;65,395-402
 
Gosney, JR Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors.Chest2004;125(5 suppl),108S
 
Sobota, J, Reed, R Multiple bronchial adenomas, Cushing’s syndrome and hypokalemic alkalosis: report of a case.Dis Chest1964;46,367-371. [PubMed]
 
Pirie, FJ, Motala, AA, Amod, A, et al Cushing’s syndrome caused by ectopic ACTH secretion from pulmonary tumourlets.S Afr Med J2001;91,952-954. [PubMed]
 
Ozbey, N, Bozbora, A, Kalayci, G, et al Cushing’s syndrome caused by ectopic corticotropin secretion by multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type.J Endocrinol Invest2000;23,536-541. [PubMed]
 
Rodgers-Sullivan, RF, Weiland, LH, Palumbo, PJ, et al Pulmonary tumorlets associated with Cushing’s syndrome.Am Rev Respir Dis1978;117,799-806. [PubMed]
 
Sauer, W, Dearing, W, Flock, E Diagnosis and clinical management of functioning carcinoids.JAMA1958;168,139-147
 
Fessler, MB, Cool, CD, Miller, YE, et al Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly.Respirology2004;9,274-277. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Top, A: Unenhanced CT with 5-mm sections shows multiple (> 100) bilateral well-circumscribed lung nodules. The nodules were uncalcified, and there was mild hilar adenopathy. Center, B: Macroscopic photograph of lung wedge biopsy showing multiple small nodules. Bottom, C: Low-power photomicrograph illustrating bronchiolocentric carcinoid tumorlets (hematoxylin-eosin, original × 40).Grahic Jump Location
Figure Jump LinkFigure 2. Low-power photomicrograph illustrating range of hyperplasia with carcinoid tumorlet (chromogranin, original × 40).Grahic Jump Location
Figure Jump LinkFigure 3. Intermediate-power photomicrograph illustrating peribronchiolar fibrosis resulting in luminal narrowing in obliterative bronchiolitis (hematoxylin-eosin, original × 200). Similar findings were seen in a patient who lacked evidence of significant airflow limitation.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Findings in 28 Patients With Multiple Carcinoid Tumorlets/Tumors*
* 

N/D = not done; N/A = not assessable; Mod = moderate.

Table Graphic Jump Location
Table 2. Detailed Clinical Findings in Patients With Multiple Carcinoid Tumorlets and Tumors*
* 

Data are presented as No. (%) unless otherwise indicated.

Table Graphic Jump Location
Table 3. Detailed Pathologic Findings in Patients With Multiple Carcinoid Tumorlets and Tumors*
* 

Data are presented as No. (%) unless otherwise indicated.

Table Graphic Jump Location
Table 4. Summary of Reported Cases of Diffuse Neuroendocrine Cell Hyperplasia/Multiple Tumorlets*
* 

NA = not available; AWD = alive without disease.

References

Gosney, J, Travis, WD (2004) Pathology and genetics: tumors of the lung, pleura, thymus and heart. Travis, W Brambilla, E Muller-Hermelink, Het al eds.World Health Organization classification of tumors,76-77 IARC. Lyon, France:
 
Aguayo, SM, Miller, YE, Waldron, JA, Jr, et al Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease.N Engl J Med1992;327,1285-1288. [PubMed] [CrossRef]
 
Ryu, JH, Myers, JL, Swensen, S Bronchiolar disorders.Am J Respir Crit Care Med2003;168,1277-1292. [PubMed]
 
Brown, MJ, English, J, Muller, NL Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT: pathologic correlation.AJR Am J Roentgenol1997;168,1561-1562. [PubMed]
 
Canessa, PA, Santini, D, Zanelli, M, et al Pulmonary tumourlets and microcarcinoids in bronchiectasis.Monaldi Arch Chest Dis1997;52,138-139. [PubMed]
 
Churg, A, Warnock, ML Pulmonary tumorlet: a form of peripheral carcinoid.Cancer1976;37,1469-1477. [PubMed]
 
Heimburger, IL, Kilman, JW, Battersby, JS Peripheral bronchial adenomas.J Thorac Cardiovasc Surg1966;52,542-549. [PubMed]
 
Whitwell, F Tumorlets of the lung.J Pathol Bacteriol1955;70,529-541. [PubMed]
 
Felton, W, Liebow, A, Lindskog, G Peripheral and multiple bronchial adenomas.Cancer1953;6,555-567. [PubMed]
 
Bonikos, DS, Archibald, R, Bensch, KG On the origin of the so-called tumorlets of the lung.Hum Pathol1976;7,461-469. [PubMed]
 
D’Agati, VD, Perzin, KH Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature.Cancer1985;55,2472-2476. [PubMed]
 
Hausman, DH, Weimann, RB Pulmonary tumorlet with hilar lymph node metastasis: report of a case.Cancer1967;20,1515-1519. [PubMed]
 
Miller, MA, Mark, GJ, Kanarek, D Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease.Am J Med1978;65,373-378. [PubMed]
 
Miller, RR, Muller, NL Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors.Am J Surg Pathol1995;19,653-658. [PubMed]
 
Sheerin, N, Harrison, NK, Sheppard, MN, et al Obliterative bronchiolitis caused by multiple tumourlets and microcarcinoids successfully treated by single lung transplantation.Thorax1995;50,207-209. [PubMed]
 
Darvishian, F, Ginsberg, M, Klimstra, D, et al Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer.Hum Pathol2006;37,839-844. [PubMed]
 
Fabbri, N, Rocca, T, Navarra, G, et al “Carcinoid tumorlets”: case report and review of the literature.Ann Ital Chir1998;69,509-511. [PubMed]
 
Akashiba, T, Matsumoto, K, Kosaka, N, et al Multifocal peripheral bronchial carcinoid tumour.Respirology1999;4,199-201. [PubMed]
 
Lee, JS, Brown, KK, Cool, C, et al Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features.J Comput Assist Tomogr2002;26,180-184. [PubMed]
 
Arioglu, E, Doppman, J, Gomes, M, et al Cushing’s syndrome caused by corticotropin secretion by pulmonary tumorlets.N Engl J Med1998;339,883-886. [PubMed]
 
Armas, OA, White, DA, Erlandson, RA, et al Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease.Am J Surg Pathol1995;19,963-970. [PubMed]
 
Cohen, AJ, King, TE, Jr, Gilman, LB, et al High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells.Am J Respir Crit Care Med1998;158,1593-1599. [PubMed]
 
Skinner, C, Ewen, SW Carcinoid lung: diffuse pulmonary infiltration by a multifocal bronchial carcinoid.Thorax1976;31,212-219. [PubMed]
 
Kay, S Histologic and histogenetic observation on the peripheral adenoma of the lung.Arch Pathol1958;65,395-402
 
Gosney, JR Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors.Chest2004;125(5 suppl),108S
 
Sobota, J, Reed, R Multiple bronchial adenomas, Cushing’s syndrome and hypokalemic alkalosis: report of a case.Dis Chest1964;46,367-371. [PubMed]
 
Pirie, FJ, Motala, AA, Amod, A, et al Cushing’s syndrome caused by ectopic ACTH secretion from pulmonary tumourlets.S Afr Med J2001;91,952-954. [PubMed]
 
Ozbey, N, Bozbora, A, Kalayci, G, et al Cushing’s syndrome caused by ectopic corticotropin secretion by multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type.J Endocrinol Invest2000;23,536-541. [PubMed]
 
Rodgers-Sullivan, RF, Weiland, LH, Palumbo, PJ, et al Pulmonary tumorlets associated with Cushing’s syndrome.Am Rev Respir Dis1978;117,799-806. [PubMed]
 
Sauer, W, Dearing, W, Flock, E Diagnosis and clinical management of functioning carcinoids.JAMA1958;168,139-147
 
Fessler, MB, Cool, CD, Miller, YE, et al Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly.Respirology2004;9,274-277. [PubMed]
 
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