Significance of Multiple Carcinoid Tumors and Tumorlets in Surgical Lung Specimens: Analysis of 28 Patients

doi:10.1378/chest.06-2788

Chest

Volume 131, Issue 6, June 2007, Pages 1635-1643

https://doi.org/10.1378/chest.06-2788 Get rights and content

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.

Section snippets

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

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).

Discussion

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

References (31)

IL Heimburger et al.
Peripheral bronchial adenomas
J Thorac Cardiovasc Surg
(1966)
DS Bonikos et al.
On the origin of the so-called tumorlets of the lung
Hum Pathol
(1976)
MA Miller et al.
Multiple peripheral pulmonary carcinoids and tumorlets of carcinoid type, with restrictive and obstructive lung disease
Am J Med
(1978)
F Darvishian et al.
Carcinoid tumorlets simulate pulmonary metastases in women with breast cancer
Hum Pathol
(2006)
JR Gosney
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors
Chest
(2004)
J Sobota et al.
Multiple bronchial adenomas, Cushing's syndrome and hypokalemic alkalosis: report of a case
Dis Chest
(1964)
J Gosney et al.
Pathology and genetics: tumors of the lung, pleura, thymus and heart
SM Aguayo et al.
Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease
N Engl J Med
(1992)
JH Ryu et al.
Bronchiolar disorders
Am J Respir Crit Care Med
(2003)
MJ Brown et al.
Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT: pathologic correlation
AJR Am J Roentgenol
(1997)

PA Canessa et al.

Pulmonary tumourlets and microcarcinoids in bronchiectasis

Monaldi Arch Chest Dis

(1997)

A Churg et al.

Pulmonary tumorlet: a form of peripheral carcinoid

Cancer

(1976)

F Whitwell

Tumorlets of the lung

J Pathol Bacteriol

(1955)

W Felton et al.

Peripheral and multiple bronchial adenomas

Cancer

(1953)

VD D'Agati et al.

Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature

Cancer

(1985)

Cited by (101)

Radiological–pathological correlation in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): imaging and histopathology
2024, Clinical Radiology
To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological–radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH.
Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered.
There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development.
CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.
A multi-lesional analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a single-centre analysis
2024, Clinical Radiology
To conduct a multi-lesional computed tomography (CT) analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) patients to determine volumetric changes in lesions over 5 years.
A retrospective case-note review was undertaken to identify 16 patients with histological and radiological features of DIPNECH between 2012–2021. Area and volume were calculated for 17 sets of lesions identified on high-resolution CT. Clinical data were extracted from electronic patient records, which included demographic data, outpatient clinic letters, histology reports, and imaging reports.
One hundred and twenty-eight lesions were identified in 16 patients (one male, 15 female) and followed-up annually over a median 1,985 days (range 1,450–2,290). At year 1 follow-up, lesion area ranged from 1–48 mm^2, and lesion volume ranged from 8–18,380 mm³; lesion area ranged from 1–45mm² and lesion volume ranged from 11–17,800 mm³ and year 5. Half (8/16) of the patients had concomitant typical carcinoid tumours and one patient had an atypical carcinoid tumour. No statistically significant correlation (p<0.05) was found between lesion cross-sectional area or volume and duration of follow-up (years and days). No metastatic spread was observed at the time of analysis.
No significant increase was observed in the size of over 100 lesions in patients with DIPNECH over a 5-year period and no metastasis occurred during the study period affirming the relatively indolent course of the disease.
Pulmonary Carcinoid Tumorlet in the Explanted Lungs for Lung Transplantation: A Case Series of 15 Patients
2023, Transplantation Proceedings
Pulmonary carcinoid tumorlet (PCT) is defined as small proliferation of neuroendocrine cells that invade the adjacent basement membrane. It is often associated with chronic pulmonary inflammatory processes. However, the characteristics of PCT in end-stage lung diseases remain unclear.
We conducted a retrospective cohort study of the explanted lungs after transplantation at our institution between January 1999 and October 2020. Patients who underwent re-transplantation were excluded.
Pulmonary carcinoid tumorlet was incidentally discovered in the explanted lungs from 15 patients (1.1%) out of 1367 lung transplants performed during the study period. Nine patients (60.0 %) were women, with a median age of 59 years (IQR: 57-62) at transplant. Underlying pulmonary indications for lung transplantation were chronic obstructive pulmonary disease (9/15, 60.0%), interstitial lung disease (2/15, 13.0%), pulmonary vascular disease (2/15, 13.0%), alpha-1 antitrypsin deficiency (1/15, 7.0%), and bronchiectasis (1/15, 7.0%). Of the patients who underwent bilateral lung transplantation (13/15, 86.7%), PCT was found in the right lung in 10 patients (10/13, 76.9%). Thirteen patients had one lesion, 1 patient had 2 lesions and 1 patient had multiple lesions.
Our study shows that PCT is generally uncommon, but when it occurs, it occurs more frequently on the right side and in female patients with end-stage pulmonary disease. Chronic obstructive pulmonary disease may be a predisposing factor for developing PCT.
Prognostic Significance of Pulmonary Multifocal Neuroendocrine Proliferation With Typical Carcinoid
2022, Annals of Thoracic Surgery
The clinical significance of multifocal pulmonary neuroendocrine proliferation (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with typical carcinoid (TC), is still debated.
We evaluated a retrospective series of TC with long-term follow-up data prospectively collected from 2 institutions and compared the outcome between TC alone and MNEP plus TC. Several baseline covariates were imbalanced between the MNEP plus TC and TC groups; therefore, we conducted 1:1 propensity score matching and inverse probability of treatment weighting in the full sample. In the matched group, the association of clinical, respiratory, and work-related factors with the group was determined through univariable and multivariable conditional logistic regression analysis.
A total of 234 TC patients underwent surgery: 41 MNEP plus TC (17.5%) and 193 TC alone (82.5%). In the MNEP plus TC group, older age (P < .001), peripheral tumors (P = .0032), smaller tumor size (P = .011), and lymph node spread (P = .02) were observed compared with the TC group. Relapses occurred in 8 patients in the MNEP plus TC group (19.5%) and 7 in the TC group (3.6%). After matching, in 36 pairs of patients, a significantly higher 5-year progression-free rate was observed for the TC group (P < .01). Similar results were observed using inverse probability of treatment weighting in the full sample. The odds of being in the MNEP plus TC group was higher for those with work-related exposure to inhalant agents (P = .008), asthma or bronchitis (P = .002), emphysema, fibrosis, and inflammatory status (P = .032), or micronodules on the chest computed tomography scan and respiratory insufficiency (P = .036).
The association with MNEP seems to represent a clinically and prognostic relevant factor in TC. Hence, careful preoperative workup, systematic pathologic evaluation, including nontumorous lung parenchyma, and long-term postoperative follow-up should be recommended in these patients.
Neuroendocrine neoplasms of the lung
2022, Practical Pulmonary Pathology: A Diagnostic Approach
The pathologic diagnosis of neuroendocrine tumors of the lung requires integration of histologic and cytologic findings with clinical and radiologic consideration. Despite advances in diagnosis, challenges remain in their accurate classification. A search of relevant literature in PubMed was conducted with terms that included neuroendocrine, lung, and the terms in the chapter subheadings of individual entities combined with lung. In addition, a review of archived cases in the file of Weill Cornell Pathology was conducted.
Neuroendocrine tumors, including preinvasive lesions, were described from the perspective of classification, clinical presentation, pathology, ancillary studies, molecular findings, and treatment impact. New information focused on diagnostic criteria for large cell neuroendocrine carcinoma including overlap with small cell carcinoma and adenocarcinoma, mitotic counting, specificity of CD56, utility of INSM1, and potential diagnostic pitfalls. Molecular advances have led to new insights on the origin and classification of neuroendocrine tumors, especially of neuroendocrine carcinomas. The integration of clinical and radiologic findings to enhance diagnostic certainty was addressed.
Emerging knowledge supports the classification of neuroendocrine tumors into low, intermediate, and high grade categories. Use of Ki-67 to distinguish high from low grade lesions is established but not as a replacement for mitotic counting in well-preserved samples and excisions. Molecular data in large cell neuroendocrine carcinoma show some heterogeneity in this category with potential treatment implications. New data support the observation that most carcinoids and atypical carcinoids do not progress into higher grade lesions; however, this may occur in a small subset of cases. In addition, there appear to be atypical carcinoid tumors with mitotic rates higher than 10 in 2 mm²; their biologic behavior needs to be better defined. The consideration of rare entities in the differential diagnosis of neuroendocrine tumors is prompted by unusual epidemiology, histology, and clinical presentation.
Lung carcinoid tumors with Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) exhibit pejorative pathological features
2021, Lung Cancer
Citation Excerpt :
Despite the absence of significant influence of DIPNECH on overall survival (OS), probably due to the relative low number of patients and event occurrence (death), we surprisingly found statistically higher amount of atypical carcinoid histology. This striking result is rather unexpected, as it was usually assumed, in previous series of comparable size, that carcinoid tumors associated with DIPNECH syndrome were preferentially typical and peripheral [22,2,7]. To our knowledge, it is the first study to report a higher AC/TC ratio in a well characterized series of DIPNECH patients.
Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) is a rare disease often associated with carcinoid tumors. We aimed at evaluating the impact of DIPNECH on characteristics and prognosis of patients who underwent radical treatment of pulmonary carcinoid tumors.
We reviewed all patients operated on for curative-intent resection of carcinoid tumor in our department from 2001 to 2020. Cases exhibiting both pathological and radiological features of DIPNECH, as assessed by respective thoracic expert physicians, were analyzed separately.
172 cases of resected carcinoid tumors were identified, including 25 (14.5 %) harboring pathological criteria of DIPNECH and radiologic features like mosaic attenuation (92.0 %), multiple nodules < 5 mm (76.0 %), and mucoid impactions (32 %). In DIPNECH patients, major pulmonary resections were usually performed (92.0 %) and resected tumors were mostly classified as pT1 (92 %). Mean Ki67 staining was 3.7 ± 5.2 %. The early postoperative period was mostly uneventful (96.0 %) and 5-year survival was 92.9 ± 6.9 %. Compared to non-DIPNECH cases, we found that patients were older (mean 65.6 ± 9.3 versus 54.1 ± 17.9, p = 0.002), more frequently female (84.0 % versus 56.5 %, p = 0.009), and exhibiting diabetes mellitus (45.8 % versus 18.5 %, p < 0.001) or hypertension (45.8 % versus 24.1 %, p = 0.039). The rate of atypical carcinoid tumors was significantly higher in DIPNECH patients (40.0 % versus 19.9 %, p = 0.027), as well as rate of mediastinal lymph-nodes involvement (pN2+) (36.0 % versus 4.1 %, p < 0.001). At multivariate analysis, only DIPNECH pattern and atypical histology were independent factors of pN2 invasion which was the only predictor of poorer prognosis on Log-Rank test.
Carcinoid tumors with proven DIPNECH are associated with negative pathological features and may deserve a dedicated perioperative management.

View all citing articles on Scopus

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.

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Chest

ORIGINAL RESEARCHLUNG CANCERSignificance of Multiple Carcinoid Tumors and Tumorlets in Surgical Lung Specimens: Analysis of 28 Patients

Background

Methods

Results

Conclusions

Section snippets

Study Group

Clinical Data

Results

Discussion

J Thorac Cardiovasc Surg

Hum Pathol

Am J Med

Hum Pathol

Chest

Dis Chest

Pathology and genetics: tumors of the lung, pleura, thymus and heart

Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease

N Engl J Med

Bronchiolar disorders

Am J Respir Crit Care Med

Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT: pathologic correlation

AJR Am J Roentgenol

Pulmonary tumourlets and microcarcinoids in bronchiectasis

Monaldi Arch Chest Dis

Pulmonary tumorlet: a form of peripheral carcinoid

Cancer

Tumorlets of the lung

J Pathol Bacteriol

Peripheral and multiple bronchial adenomas

Cancer

Carcinoid tumorlets of the lung with metastasis to a peribronchial lymph node: report of a case and review of the literature

Cancer

ORIGINAL RESEARCH
LUNG CANCER
Significance of Multiple Carcinoid Tumors and Tumorlets in Surgical Lung Specimens: Analysis of 28 Patients