—  SPECIALTY CONFERENCE  —

Pulmonary Pathology

Case 2 - Multiple Carcinoid Tumors and Tumorlets with
Diffuse Pulmonary Neuroendocrine Cell Hyperplasia

William D. Travis
Armed Forces Institute of Pathology
Washington, DC


Click on each slide thumbnail image for an enlarged view
Clinical History
A 60 year old woman was found to have a right middle lobe lung mass on chest x-ray while undergoing follow-up for a non-invasive, papillary, transitional cell carcinoma of the bladder. She had mild progressive dyspnea and a slight, productive cough. Pulmonary function showed mild obstruction and decrease in the diffusing capacity. She had a 70 pack year history of smoking but had quit for one year. At thoracotomy, multiple pulmonary nodules were found in the right middle lobe and removed surgically. Three of the nodules measured 1.0, 0.7 and 0.6 cm in diameter. A right middle lobectomy was performed.


Case 2 - Figure 1 - The airways in the lung parenchyma surrounding the carcinoid tumor (right lower corner) show mild fibrosis and bronchiolectasis. Increased cellularity is focally appreciable at this low magnification
Case 2 - Figure 2 - Immunohistochemistry for bombesin (gastrin releasing polypeptide) shows strong staining of the tumor and also the bronchiolar mucosa in surrounding airways with linear and nodular patterns. This reflects neuroendocrine cell hyperplasia and tumorlets.
Case 2 - Figure 3 - Medium magnification of the carcinoid tumor shows spindle cell morphology.



Case 2 - Figure 4 - The spindle-shaped tumors cells have finely granular nuclear chromatin. An organoid nesting pattern is seen. No mitoses or necrosis are seen.
Case 2 - Figure 5 - This bronchiole shows a nodular clusters of neuroendocrine cells with infiltration of the bronchiolar wall.
Case 2 - Figure 6 - Tumorlets are seen on both sides of this blood vessel. Above the cells are proliferating along airspaces. Below they are forming a nodule.



Case 2 - Figure 7 - Neuroendocrine cell hyperplasia consisting of nodulear clusters of neuroendocrine cells (also known as neuroendocrine bodies) at the base of the mucosa.
Case 2 - Figure 8 - Immunohistochemistry for bombesin (gastrin releasing polypeptide) shows strong staining of a linear pattern of neuroendocrine cells in the bronchiolar mucosa.

Discussion
This case represents an example of multiple carcinoid tumors and tumorlets with diffuse pulmonary neuroendocrine cell hyperplasia. It was discovered as an incidental radiographic finding in a patient who had mild pulmonary symptoms and mild obstruction. Since three of the nodules of neuroendocrine cells were 0.5 cm or greater, they are regarded as carcinoid tumors according to the 2004 WHO Classification of Lung Tumors. [1] Most of the remaining airways in the specimen have neuroendocrine cell hyperplasia or tumorlets (measuring less than 0.5 cm). This is not as apparent on H&E examination as it is on immunohistochemistry for GRP (Bombesin) and chromogranin. Neuroendocrine cell hyperplasia consisted of scattered single cells, neuroendocrine bodies and linear arrays of neuroendocrine cells. Although the patient was a smoker, the extent of the neuroendocrine proliferation in this case far exceeds that previously described in smokers. [2] Therefore this case is interpreted as an example of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), which has been recognized since the 1999 WHO classification as a rare precursor lesion for pulmonary carcinoid tumors. [1, 3, 4]

This case provides a introduction to the topic of DIPNECH that is defined by the 2004 WHO as a generalized proliferation of scattered single cells, small nodules (neuroendocrine bodies), or linear proliferations of pulmonary neuroendocrine (NE) cells that may be confined to the bronchial and bronchiolar epithelium, include local extraluminal proliferation in the form of tumourlets, or extend to the development of carcinoid tumours. It is sometimes accompanied by intra- and extraluminal fibrosis of involved airways, but other pathology that might induce reactive NE proliferation is absent. DIPNECH is very rare with less than 50 reported cases.

Aguayo, et al described DIPNECH in 1992 [5], but cases with its clinical and pathological features appear in the literature from the early 1950s. [6, 7] Aguayo speculated that the NE proliferation was a primary lesion and that the associated small airway fibrosis in these patients was due to expression of GRP (bombesin) by the NE cells. GRP is known to be a fibroblast growth factor and he proposed that the NE cells were the underlying cause of the airway fibrosis. This hypothesis is contrary to the prevailing concept that most NE cell proliferations and tumorlets in the lung are reactive lesions seen in the setting of conditions associated with airway inflammation and/or fibrosis such as bronchiectasis or idiopathic pulmonary fibrosis.

Clinical Features
DIPNECH typically presents in the fifth or sixth decades of life and there appears to be a female predominance. [5, 7, 8, 9] Patients present with slowly progressive dry cough and dyspnea, often over many years. Pulmonary function tests show an obstructive or mixed obstructive/restrictive pattern of impairment with reduced diffusing capacity.

Chest radiographs may be normal, but computerized tomographic scanning (particularly with an expiration study) demonstrates a mosaic pattern of air trapping, sometimes with nodules and thickened bronchial and bronchiolar walls. [8, 10] Multiple nodules that correspond to tumourlets or carcinoid tumours may be present. [5, 8]

Patients with DIPNECH typically have a favourable clinical course. Rare patients have required lung transplantation due to severe obstructive airway disease. The carcinoid tumors that occur in DIPNECH so far have all been typical carcinoids.

Pathologic Features
Small tan or white sharply circumscribed nodules representing tumourlets (<5mm) and small carcinoid tumors (5mm or larger) may be seen grossly. Larger carcinoid tumours resemble carcinoids seen in other settings with a tan-white or yellow circumscribed nodule. DIPNECH usually affects one or both lungs diffusely, but in surgical biopsies, one typically only has a small sample of the lung to examine histologically.

Histologically the lung demonstrates extensive proliferation of NE cells. [3, 5, 7, 9] NE cell hyperplasia and tumorlets are centered on airways. NE cell hyperplasia consists of increased numbers of individual cells, small clusters (or NE bodies), or linear arrays of NE cells. The bronchiolar wall sometimes is fibrotically thickened and the airway lumens may be constricted or occluded either due to fibrosis and/or NE cell proliferation. The diagnosis of DIPNECH requires exclusion of inflammatory or fibrous airway lesions that might cause a secondary NE cell hyperplasia.

Tumorlets are formed when the NE cells proliferate with extension beyond the structure of the airway wall typically forming millimeter-sized nodules measuring less than 5 millimeters. When the NE nodules are 0.5 cm or larger, the lesions are called carcinoid tumors.

The cells seen in the NE cell proliferation of DIPNECH are similar to those found in the normal lungs of adults. [11, 12] No distinguishing molecular features are recognized, but the loss of heterozygosity found in carcinoid tumors at the 11q13 region that closely approximates to the MEN1 tumour suppressor gene is rare in tumourlets. [13] Cohen AJ, et al demonstrated high expression of neutral endopeptidase in DIPNECH. [14]

Differential Diagnosis
There are no clinically and/or radiologic features that would allow for the diagnosis of DIPNECH without surgical lung biopsy. The presenting clinical findings of cough, dyspnea, mixed obstructive/restrictive pulmonary impairment and a nodular pattern of pulmonary infiltration could be seen in many diffuse parenchymal lung disorders. The finding of a mosaic pattern of air trapping on expiration CT could be seen in small airway disorders due to a wide variety of causes.

The pathologic differential diagnosis includes NE cell hyperplasia and or tumorlets that can occur as a secondary lesion in a wide variety of inflammatory and fibrotic lung conditions such as bronchiectasis and chronic lung abscess. [15, 16, 17, 18] DIPNECH must also be distinguished from the NE cell hyperplasia that can be seen in the normal lung adjacent to up to 75% of peripheral carcinoid tumors. [9]

References

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  2. Aguayo SM. Pulmonary neuroendocrine cells in tobacco-related lung disorders. Anat.Rec. 1993; 236:122-7; discussion 127-8.
  3. Gosney JR. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors. Chest 2004; 125:108S
  4. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with L.H.Sobin and pathologists from 14 Countries. Histological Typing of Lung and Pleural Tumors. Berlin: Springer, 1999:
  5. Aguayo SM, Miller YE, Waldron JA, Jr., et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N.Engl.J.Med. 1992; 327:1285-8.
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  14. Cohen AJ, King TE, Jr., Gilman LB, Magill-Solc C, Miller YE. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am.J.Respir.Crit Care Med. 1998; 158:1593-9.
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