Continuing Education Activity

Pulmonary carcinoid tumors are uncommon neuroendocrine epithelial malignancies accounting for less than 1% of all lung cancers. They divide into two subcategories: typical carcinoids and atypical carcinoids. Typical carcinoids and atypical carcinoids are, respectively, low- and intermediate-grade neuroendocrine tumors. Approximately 80% of pulmonary carcinoids occur centrally, and 20% are peripheral. All bronchial carcinoids are malignant and have the potential to metastasize. This activity reviews the cause and pathophysiology of lung carcinoids and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the histopathology of lung carcinoids.
• Review the presentation of lung carcinoid.
• Summarize the treatment options for lung carcinoid.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by lung carcinoid.

Introduction

Pulmonary carcinoid tumors are uncommon neuroendocrine epithelial malignancies accounting for less than 1% of all lung cancers. They divide into two subcategories: typical carcinoids and atypical carcinoids. Typical carcinoids and atypical carcinoids are, respectively, low- and intermediate-grade neuroendocrine tumors. Approximately 80% of pulmonary carcinoids occur centrally, and 20% are peripheral.[1] All bronchial carcinoids are malignant and have the potential to metastasize.[2]

Etiology

The mechanisms of carcinoid tumor development and progression are not clear, but some cases are postulated to develop in the setting of proliferating pulmonary neuroendocrine cells via diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets.[3]

Some studies also showed a relationship of this tumor to smoking but the causation relationship is still not concrete. Air pollutants and certain chemicals have also shown a few risk factors among other studies. Some data shows a high incidence among whites and women as compared to men.[4]

Epidemiology

Carcinoid tumors comprise less than 1% of primary lung cancers.[5] The mean age at presentation is about 50 years, but they can occur at any age from 5 to 90 years. Atypical carcinoids present approximately one decade later than typical carcinoids. About 8% develop in the second decade, making them the most common primary pulmonary tumor of childhood. Typical carcinoids are not correlated to tobacco smoking, although reports of atypical carcinoids are more frequent in smokers.[6] Risk factors of carcinoids include having a family history of carcinoid tumors and carrying multiple endocrine neoplasia type 1 (MEN1) genes.[7] This shows an inherited pattern of the tumor too.

Pathophysiology

Lung carcinoids are a part of the neuroendocrine tumors (NETs) that arise in the lungs. These NETs could show either a typical low-grade, well-differentiated, slow-growing tumor or they may present as atypical high-grade, poorly differentiated carcinomas. However, the NETs share the capacity to synthesize neuropeptides and the presence of submicroscopic cytoplasmic dense-core.[8]

Histopathology

Macroscopic Findings

Central carcinoid tumors are well-circumscribed, round to ovoid, and sessile or pedunculated. There is salt and pepper chromatin and moderate to abundant eosinophilic cytoplasm. They often fill the bronchial lumen.[9] The tumors may grow between the cartilaginous plates into adjacent tissues. Carcinoids range in size from 0.5 to 9.5 cm. Atypical carcinoids are on average larger than typical carcinoids.[9] 

Histopathology

The growth patterns of carcinoid tumors suggest neuroendocrine differentiation. Organoid and trabecular patterns are most common; however, rosette formation, papillary growth, pseudo-glandular growth, and follicular growth may also be present. The tumor cells are usually uniform in appearance, with finely granular nuclear chromatin, inconspicuous nucleoli, and moderate to abundant eosinophilic cytoplasm.[10] The stroma is classically highly vascularized, but extensive hyalinization, cartilage, or bone formation may be encountered.  There are reports of stromal amyloid as well as the prominent mucinous stroma. Typical carcinoids are carcinoid tumors with less than 2 mitoses per 2mm2 and lacking necrosis. Atypical carcinoid generally shows the same range of histological features as typical carcinoid. The defining features are 2 to 10 mitoses per 2mm2 and/or necrosis.[11] Necrosis is usually punctate. Mitoses counting should be in the area of highest mitotic activity in the fields filled with many viable tumor cells as possible and should also be per 2mm2 rather than ten high-power fields.[10]

Immunohistochemistry

Immunohistochemistry may be a necessity for diagnosis, particularly on small biopsies. An antibody panel including chromogranin A, synaptophysin (both with cytoplasmic labeling), and CD56 (mostly decorating cell membranes) is the recommendation. However, none of these markers distinguish typical carcinoids from atypical carcinoids. Most carcinoids are also reactive for pan-cytokeratin antibodies. Some peripheral tumors also stain with TTF1, which is less specific. The Ki67 labeling index is valuable in biopsy or cytology samples, particularly with crush artifacts where the mitotic index is difficult to assess, to avoid misdiagnosing carcinoid tumors as high neuroendocrine carcinomas.[10]

History and Physical

Almost 25 percent of the people with lung carcinoid tumors may not present with any symptoms of the disease. They may be diagnosed incidentally while being tested for another condition.

The most common presenting symptoms of bronchopulmonary carcinoid tumors are:

• Coughing or wheezing
• Hemoptysis
• Symptoms referable to the consequences of collapse or pneumonia distal to airway obstruction.[1] Sometimes the patients present with stridor.

Since this tumor is primarily a carcinoid tumor, the patient's may present with symptoms of carcinoid syndrome:

• Facial flushing
• Shortness of breath
• High blood pressure
• Weight gain
• Hirsutism
• Asthma-like symptoms

Small carcinoids may be asymptomatic and only discovered, incidentally.

Most cases are endocrinologically silent at the clinical level. Clinical syndromes secondary to peptide production are uncommon, they include carcinoid syndrome, Cushing syndrome, and acromegaly.[1]

Evaluation

Biochemical Evaluation

Plasma chromogranin A measurement, blood count, electrolytes, liver, and kidney function are tests indicated in the diagnostic process and follow-up of carcinoids[12].

Specific tests are performed when symptoms suggesting hormonal secretion are present. They include[13]:

• Urinary dU-5-hydroxy indol-acetic acid in patients with carcinoid syndrome
• Serum cortisol, 24-hour urine free cortisol
• ACTH level determination in patients with Cushing’s disease
• Plasma GHRH and insulin growth factor (IGF)-I are indicated in patients with signs of acromegaly

Bronchoscopy

Since lung carcinoids are usually centrally located and visible at endoscopic evaluation, bronchoscopy plays a significant role in their diagnosis.[14] Bronchoscopic evaluation and biopsy are the gold standard for the diagnosis of pulmonary carcinoids; however, there is a risk of hemorrhage. 

Radiological Assessment

Carcinoids can are detectable on a standard chest x-ray in 40% of the cases. However, the gold standard for radiological detection of lung carcinoids is a CT scan. On both, chest x-ray and CT scans, the mass is usually well-defined, round, and sometimes slightly lobulated. Calcification can occur in central carcinoid tumors. When bronchial involvement is present, secondary distal effects include atelectasis, bronchiectasis, and, hyperlucency on CT scan.[15]

Fluorodeoxyglucose (FDG) positron emission tomography (PET) may distinguish carcinoid tumors from atypical carcinoids; this technique may be most helpful in discerning carcinoids from high-grade neuroendocrine tumors such as small cell or large cell neuroendocrine tumors.[16] Carcinoids exhibit a low-to-moderate activity on PET scanning.

Octreotide single-photon emission CT and other novel imaging techniques such as gallium-labeled somatostatin analogs may be more sensitive at the detection of lung carcinoids.[17] Imaging for somatostatin receptors using Indium-111-labeled-octreotide may increase the sensitivity for diagnosis, staging, and follow-up for recurrence.[18]

Treatment / Management

Surgery

The treatment of choice for patients with lung carcinoids is surgical resection.[13] Extensive resections are necessary in the treatment of atypical carcinoids and cases of destruction of distal lung parenchyma. Lobectomy (sleeve or wedge resection) is the surgical technique of choice. Bronchoplastic procedures are often required since carcinoids often arise from the main bronchi or lobar bronchi. A wedge resection is favored in peripheral carcinoids and is often sufficient.[1]

Adjuvant Therapy

There is no consensus on adjuvant therapy in pulmonary carcinoids.[1] The National Comprehensive Cancer Network guidelines recommend adjuvant cisplatin and etoposide with or without radiation in stage III atypical carcinoids.[1] The European Neuroendocrine Tumor Society advocates adjuvant treatment in atypical carcinoids with positive lymph nodes, but no adjuvant therapy for typical carcinoids.[1]

Differential Diagnosis

The differential diagnoses of pulmonary carcinoids include[10]:

• Metastatic carcinoids from elsewhere especially those originating from the gastrointestinal tract
• Small cell lung carcinoma
• Salivary gland-type tumors
• Metastases of lobular breast carcinoma, paraganglioma, and glomangioma
• Tumorlets

Staging

Typical Carcinoids

In pulmonary carcinoid tumors, the classification system designates typical carcinoids as low grade.[19] Most typical carcinoids are stage 1a.[19]

Atypical Carcinoids

In pulmonary carcinoid tumors, the classification system designates atypical carcinoids as intermediate grade. Atypical carcinoids are usually at a higher stage at presentation than typical carcinoids.[19]

Enhancing Healthcare Team Outcomes

The distinction between atypical carcinoid and typical carcinoid is the most important prognostic factor. Atypical carcinoid has a worse prognosis than typical carcinoid. Atypical carcinoids are more likely to metastasize than typical carcinoids. Typical carcinoid tumors metastasize to hilar nodes in 10% to 15%.[20] Distant metastases are less common. They occur in fewer than 3% of patients and involve the liver, lung, brain, adrenal, or bone.[21] For atypical carcinoid tumors, metastatic disease is present in 20% of patients.[22] Age and nodal involvement are poor prognostic factors in patients with atypical carcinoids.[22] Five-year survival rates for patients with typical carcinoids and atypical carcinoids are approximately 90% and 60% respectively.[1]