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A 60-year-old female with smoking history presents with a right upper lobe lung nodule
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A 60-year-old white female presented to the hospital with complaints of progressively worsening shortness of breath, progressive weakness, chest tightness and lower extremity swelling.
Past medical history was significant for asthma, chronic obstructive pulmonary disease, hypertension, hyperlipidemia, hypothyroidism, gastritis, systemic lupus erythematosus and polymyalgia rheumatica. Her medications included calcium carbonate, celecoxib (Celebrex, Pfizer), loratadine (Claritin, Alavert), omeprazole (Prilosec, AstraZeneca), simvastatin (Zocor, Merck), sitagliptin-metformin, levothyroxine (Synthroid, Abbott), lisinopril, nortriptyline, desvenlafaxine, oxycodone (OxyContin, Purdue Pharma) and hydromorphone as needed.
She was an active smoker and has a 50 pack-year smoking history. Her examination was significant for bilateral expiratory wheezes and bilateral pitting edema.
She underwent an echocardiogram and was found to have an ejection fraction of 20%. She was initiated on diuretics and was scheduled to get a cardiac catheterization. Chest X-ray prior to catheterization showed a right upper lobe infiltrate. A CT scan showed a 16 mm × 16 mm pulmonary nodule in the right upper lobe. There were two additional pulmonary nodules measuring 1.3 mm and 9 mm. There was an increase in size and number of mediastinal lymph nodes, with the largest measuring 1.6 mm and emphysematous changes bilaterally.
A PET/CT scan showed a hypermetabolic right upper lobe lesion corresponding to the nodule identified on CT exam. The additional nodules that were seen in CT scan and the mediastinal lymph nodes were not positive on the PET scan. She underwent a CT-guided fine-needle aspiration biopsy, which showed a cellular neoplasm composed of densely packed, small- to intermediate-sized cells with focal glandular pattern, suggesting a neuroendocrine neoplasm. The stain for chromogranin was negative, whereas the stains for synaptophysin and thyroid transcription factor-1 (TTF-1) were strongly positive.
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There was moderate nuclear pleomorphism, but no necrosis or mitotic activity was found. These features were compatible with a low-grade neuroendocrine carcinoma, but atypical carcinoid could not be excluded because of the limited sample.
She was discharged home after the biopsy and was evaluated a couple of weeks later in the outpatient setting. At that visit, she was on 2 L of nasal oxygen and had an ECOG performance status of 2. Her pulmonary function tests showed severe obstructive ventilator deficit with no improvement of flow rates with a bronchodilator.
Discussion
Bronchial carcinoids are a group of pulmonary neoplasms characterized by neuroendocrine differentiation and relatively indolent clinical behavior. They are now considered to be true malignancies belonging to the neuroendocrine tumor family. They arise from enterochromaffin cells of the bronchial epithelium, which is made up of peptide- and amine-producing cells that have migrated from the embryologic neural crest.
Although carcinoids can arise at any site, the most frequently involved site is the gastrointestinal tract, followed by the lung. They account for approximately 1% to 2% of all lung malignancies in adults. They are the most common primary lung neoplasm of children and typically present in late adolescence. They have a higher incidence in women and in whites. The average age of diagnosis is 45 years for bronchial carcinoids vs. 55 years for atypical carcinoids. Association between bronchial carcinoids and smoking is unclear and causality is not proven yet.
There is a wide spectrum of neuroendocrine tumors of the lung with strikingly different biologic behavior. They range from typical carcinoid — which are low-grade, slowly growing neoplasms that rarely metastasize — to high-grade, poorly differentiated neuroendocrine carcinomas (small cell lung cancer), which behave aggressively with rapid growth and metastases. Atypical carcinoids are intermediate between typical carcinoids and small cell lung cancer.
World Health Organization classification of neuroendocrine carcinomas of the lung divides carcinoids into typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma. Typical carcinoids have less than 2 mitoses per 10 high-power fields and lack necrosis. Atypical carcinoids have 2 to 10 mitoses per 10 high-power fields or necrosis. Typical low-grade carcinoid tumors are composed of cytologically bland cells containing regular round to oval nuclei with finely dispersed chromatin and inconspicuous small nucleoli. The cells usually are polygonal in shape and are arranged in distinct organoid, trabecular or insular growth patterns with a delicate vascular stroma. Atypical carcinoids more often present with hilar and mediastinal nodal metastases and have a higher rate of recurrence.
About three-fourths of tumors arise in the proximal airways and present with symptoms from an obstructing tumor or bleeding. Symptoms include cough, wheeze, hemoptysis, chest pain or recurrent pneumonia. About one-fourth of tumors originate peripherally. They usually are asymptomatic and are discovered on routine imaging. Less than 5% of patients present with symptoms relating to carcinoid syndrome, such as flushing, diarrhea and itching.
Atypical carcinoid symptoms — such as disorientation, anxiety tremor, periorbital edema, lacrimation, salivation, hypotension, tachycardia, diarrhea, dyspnea, asthma and edema — can be seen in bronchial carcinoids.
Ectopic production of adrenocorticotropic hormone (ACTH) can be seen in typical and atypical bronchial carcinoids and can cause Cushing’s syndrome. Bronchial carcinoid is the most common cause of ectopic ACTH production. Foregut carcinoids generally have low serotonin content because they lack aromatic amino acid decarboxylase and cannot synthesize serotonin. Bronchial carcinoids arise from the foregut and, hence, elevated plasma or urinary hormone levels are rarely detected. Serum levels of chromogranin A are lower with bronchial carcinoids, and conversely, increased chromogranin A levels are seen in nonmalignant conditions.
Diagnosis
Diagnosis is made by imaging and biopsy. Pulmonary carcinoids are generally staged using the tumor, node and metastases (TNM) classification for bronchogenic lung carcinomas. Typical carcinoid tumors most commonly present as stage I tumors, whereas atypical carcinoids usually present at stage II (bronchopulmonary nodal involvement) or stage III (mediastinal nodal involvement).
Approximately 80% of typical bronchial carcinoids express somatostatin receptors by immunohistochemistry and may be imaged with OctreoScan (Mallinckrodt). However, specificity is limited because scintigraphy is positive in many other tumors, granulomas and autoimmune diseases. OctreoScan also can identify metastatic disease outside the lung. However, since extrathoracic metastatic disease is rare with bronchial carcinoid tumors, it is not routinely indicated. The role of PET in carcinoids is controversial, as these tumors are usually small and they are often hypometabolic.
Typical bronchial carcinoids have an excellent prognosis. Five-year survival rates are 87% to 100%, and 10-year survival rates are 82% to 87%. Atypical carcinoids have a higher incidence of local recurrence and distant metastasis. Five-year survival rates are 30% to 95% and 10-year survival rates are 35% to 56%. Studies have not shown an adverse outcome of nodal disease in typical carcinoids, whereas in atypical carcinoids, certain series show an adverse influence of nodal metastases on prognosis.
Treatment
Surgery is the treatment of choice for carcinoid tumors and often is curative. Because carcinoids do not spread submucosally, a small surgical margin is considered adequate. A complete mediastinal lymph node dissection is indicated during surgical resection, if possible. Adjuvant therapy is not indicated for completely resected, typical bronchial carcinoids, even in the presence of nodal metastases because of their favorable outcome. In contrast, in patients with atypical carcinoids with mediastinal (N2) disease, postoperative chemotherapy, radiation therapy or both have been suggested. There are no prospective trials that directly address the benefit of adjuvant therapy for patients with bronchial carcinoids. Although carcinoid tumors are relatively radiation-resistant, radiation therapy can be considered for palliation of symptoms in locally unresectable tumors. Long-term follow-up of patients is needed because local or distant disease recurrence may occur several years after initial treatment.
For patients with surgically unresectable but nonmetastatic disease, options include radiation therapy and palliative endobronchial resection of the obstructing tumor. In patients with limited liver metastases, surgical resection is recommended. Although not curative, this can lead to increased survival due to the indolent nature of these tumors. Nonsurgical treatment options for liver metastases include embolization, chemoembolization, radiofrequency ablation and cryoablation. For patients with advanced metastatic disease who are symptomatic, first-line therapy with a somatostatin analogue is a reasonable option. In rapidly progressing cases, chemotherapy regimens used for small cell lung cancer — such as cisplatin and etoposide — are recommended. Molecular-targeted agents such as mTOR inhibitors (eg, everolimus [Afinitor, Zortress; Novartis]) and small molecule tyrosine kinase inhibitors (eg, sunitinib [Sutent, CPPI CV]) have shown to improve outcomes in advanced pancreatic neuroendocrine tumors, but the role in bronchial carcinoids is less certain.
Given our patient’s poor pulmonary reserve and ongoing cardiac issues, she was not considered to be a candidate for resection. She had three separate nodules in the right upper lobe along with mediastinal adenopathy, which is not a typical presentation for carcinoid. She did not have any symptoms relating to her carcinoid. It was decided to address her cardiac issues first and repeat imaging in the near future before further treatment can be planned.
References:
- Carretta A. Lung Cancer. 2000;29:217-225.
- Fink G. Chest. 2001;119:1647-1651.
- Wirth LJ. Lung Cancer. 2004;44:213-220.
For more information:
- Ramya Varadarajan, MD, is a consultant at Regional Hematology and Oncology PA at Helen Graham Cancer Center in Newark, Del. She is a member of the HemOnc Today Editorial Board. Disclosure: Dr. Varadarajan reports no relevant financial disclosures.