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April, 2020
Case of the Month

Clinical History: A 66-year-old woman with a history of resected pleomorphic sarcoma of the back status-post irradiation underwent surveillance imaging and was noted to have pulmonary nodules that were increasing in size. Chest CT showed numerous nodules in the left lower lobe (largest = 6 mm) and several smaller nodules in other lobes worrisome for metastatic disease. However, the nodules were not PET-avid. She underwent wedge resection followed by completion lobectomy (Figures 1-5). She is a non-smoker.


Q1. Which of the following is the best diagnosis based on these images?

  1. Neuroendocrine proliferations
  2. Metastatic pleomorphic sarcoma
  3. Melanoma
  4. Sarcomatoid carcinoma

Q2. The most likely immunohistochemical profile of these nodules is:

  1. Cytokeratins (-), TTF-1 (-), synaptophysin (-)
  2. Cytokeratins (-),TTF-1 (-), S-100 (+), MART-1 (+)
  3. Cytokeratins (+),TTF-1 (+), synaptophysin (+)
  4. Cytokeratins (+/-), TTF-1 (+/-), synaptophysin (+/-)

Q3. According to the current WHO classification, which of the following features best differentiate between typical carcinoid tumor and atypical carcinoid tumor?

  1. Mitotic rate and necrosis
  2. Ki-67 and p53
  3. Pleomorphism and lymph node metastasis
  4. Lymphatic invasion and spread through air spaces

Answers to Quiz

Q2. C
Q3. A


Carcinoid tumor with multiple carcinoid tumorlets and neuroendocrine hyperplasia.


The lobectomy specimen shows multiple peribronchiolar neuroendocrine proliferations (Figure 1), some of them forming groups with pale cytoplasm confined within the basement membrane (Figure 2), while others showed invasion beyond the basement membrane associated with stromal fibrosis; these were all < 5 mm (Figure 3). At least two other nodules were ≥ 5 mm and at high magnification showed classic morphologic features of carcinoid tumor (Figure 4). Areas of solid cell nests were found within the adjacent alveolar spaces beyond the boundary of the main tumor mass representing “spread through air spaces” (Figure 5).

The spectrum of neuroendocrine proliferation in the lung ranges from neuroendocrine hyperplasia (clusters restricted to basement membrane), carcinoid tumorlets (< 5 mm) and carcinoid tumor (≥ 5 mm), mostly restricted to airways. The presence of isolated tumorlets is considered an incidental finding. However, multiple carcinoid tumorlets with diffuse neuroendocrine hyperplasia are seen most commonly in chronic lung disease, such as chronic bronchitis or emphysema as a reactive process, which may not lead to carcinoid tumor. Occasionally, in specimens containing a resected carcinoid tumor, neuroendocrine hyperplasia and tumorlets are seen in the background lung. Rarely, the neuroendocrine proliferation may cause small airway obstruction and peribronchiolar fibrosis leading to airflow limitation, progressing to respiratory failure. This syndrome of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) is considered preneoplastic due to progression to carcinoid tumors. The differential diagnosis includes minute meningothelial-like nodules, which are primarily differentiated from carcinoid tumorlets based on their perivenular location, presence of whorls and intranuclear inclusions, lack of fibrosis and absence of keratin/neuroendocrine markers. The other differential diagnosis is metastases as in this patient due to the presence of multiple lesions on imaging. This may lead to potential diagnostic pitfalls during intra-operative consultation. The presence of air trapping on expiratory CT-imaging along with multiple nodules would help the diagnosis in favor of DIPNECH. But up to 50% of patients with DIPNECH are asymptomatic for a long time. Sometimes, the interval between the onset of clinical symptoms and diagnosis may be more than a decade, which makes the diagnosis extremely challenging. Our patient has not developed any respiratory symptoms yet but remains on close clinical monitoring.

Take home message for trainees: Multiple pulmonary neuroendocrine proliferations may mimic metastatic lesions.


Benson, RE, et al. Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics 2013;33:1631-49.

Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med 2010;134:1628-38.

Travis WD, et al. WHO classification of tumours of the lung, pleura, thymus and heart. WHO classification of tumours, 4th edition, volume 7, 2015.


Raghavendra Pillappa, M.D
Assistant Professor of Pathology
Pulmonary Pathologist
Director, Immunohistochemistry
Department of Pathology
Virginia Commonwealth University
Richmond, VA
2019 PPS Lifetime Achievement Award
Professor Elisabeth Brambilla
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