Pulmonary Medicine

Other Lung Neoplasms (including benign lung tumors, inflammatory pseudotumor/plasma cell granuloma, neuroendocrine tumors, sarcomas, and metastases to the lungs)

What every physician needs to know:

While lung cancer is the most common cause of malignant lesions in the lungs, many other malignant and benign lung neoplasms may mimic primary lung cancer. It is important to distinguish the different etiologies because treatment varies widely, from observation for granulomas or hamartomas to surgery for malignancies like carcinoid tumor and solitary metastasis. With some malignancies, such as those involving the colon or kidney, the treatment for multiple pulmonary metastases may be resection, but chemotherapy may offer the best option for other malignancies. Therefore, there is a clear need for a definitive diagnosis.

Classification:

Granulomas, the most common cause of benign pulmonary nodules, are usually related to previous infection. The next most common benign tumor is hamartoma, which is mesenchymal tissue composed of varying proportions of smooth muscle, connective tissue, cartilage, and fat. Solitary fibrous tumor, previously called benign localized mesothelioma, is a spindle cell growth thought to be of fibroblastic origin that arises from the pleura. It is not related to asbestos exposure, and most are benign, but local recurrence has been observed in 10% to 15% of cases after resection.

Inflammatory myofibroblastic tumor (IMT), previously called inflammatory pseudotumor or plasma cell granuloma, is a myofibroblastic spindle cell proliferation with an accompanying lymphoplasmacytic infiltrate. IMTs are of intermediate biologic potential for recurrence or spread following removal.

Uncommon primary malignant tumors of the lung include carcinoid (neuroendocrine tumor) and salivary gland tumors of adenoid cystic carcinoma and mucoepidermoid carcinoma. Bronchial carcinoid tumors account for 2% to 5% of all lung malignancies and 20% of all carcinoid tumors. Salivary gland tumors of the tracheobronchial tree are histologically similar to their counterparts in the salivary glands and are less common than carcinoid tumors. Mucoepidermoid carcinomas are the most rare. Primary lymphoma may be localized to the lung. Other rare primary tumors of the lung include various sarcomas, chondroma, meningioma, pleuropulmonary blastoma, neurofibromas, pleomorphic carcinomas, spindle cell carcinomas, giant cell carcinomas and carcinomascomas, and other miscellaneous lesions.

Based on autopsy reports, lung metastases occur in 33% to 50% of all non-lung malignancies. Most metastases are caused by the common malignancies, including breast, lung, colorectal, prostate, and renal cell carcinoma. Other primary malignancies with a tendency for pulmonary metastases include melanoma, sarcomas, and thyroid and germ cell tumors.

Are you sure your patient has a lung neoplasm? What should you expect to find?

The symptoms of either benign or malignant lesions may vary widely. Many patients are asymptomatic, even when the pulmonary lesion is large, while others may be highly symptomatic with a one cm lesion located endobronchially or involving the chest wall. Symptoms are nonspecific and may include cough, hemoptysis, fever/pneumonia, pain, or dyspnea, wheezing, depending on the intrathoracic location of the disease.

Some tumors, such as adenoid cystic carcinoma and bronchial carcinoid, have a propensity for the trachea or major bronchi and may present with wheeze, cough, or hemoptysis. Endobronchial metastases, which are most common with renal cell, melanoma, and lymphomas, are likely to have these same symptoms. Squamous cell carcinomas often present with hemoptysis within 4 to 6 months of symptom onset, due to mucosal irritation and ulceration. Endobronchial obstruction from any of the primary or metastatic tumors may present with symptoms of pneumonia, including fever, sweats, and/or pleurisy. Tracheal tumors, such as primary neurofibromas, are often misdiagnosed as asthma for many months.

Ectopic hormone secretion is rare with these primary or metastatic tumors, but Cushing's syndrome and acromegaly have been reported with bronchial carcinoid tumors. Flushing and diarrhea (carcinoid syndrome) resulting from excessive serotonin production has been reported with bronchial carcinoid tumors, but these patients usually have significant hepatic metastases, and the pulmonary tumor is usually greater than 5 cm. Hypertrophic pulmonary osteoarthropathy as well as digital clubbing may occur with solitary fibrous tumors in up to 20% of cases, but it is otherwise uncommon with pulmonary metastases. Hypoglycemia has also been observed with some SFT.

Beware: there are other diseases that can mimic lung neoplasms:

Granulomatous lung diseases are the most common mimickers of pulmonary malignancy, including histoplasmosis, blastomycosis, coccidiodomycosis, and tuberculosis. Actinomycosis is another infectious disease that radiography frequently mistakes for malignancy.

Nodular sarcoidosis may be confused with metastatic disease. Pulmonary vasculitis, especially Wegener granulomatosis, may present with nodular pulmonary disease with or without constitutional symptoms. Cryptogenic organizing pneumonia (formerly known as BOOP) may present with fever, malaise, and a single nodule or multiple pulmonary nodules that are indistinguishable from a primary or metastatic disease.

How and/or why did the patient develop a lung neoplasm?

It has been hypothesized that circulating tumor cells that have a higher predilection to metastasize to the lung express genes that enable the cells to transverse the walls of the capillaries and into the lungs selectively by altering the microenvironment. Smoking is not a predisposing factor for any of the lung tumors other than primary lung cancer, which is covered elsewhere.

Which individuals are at greatest risk of developing a lung neoplasm?

Bronchial carcinoid tumors are more common in women. While there is no clear association between bronchial carcinoid tumors and smoking, multiple studies show that between one third to two thirds are smokers. Malignant germ cell tumors are almost exclusively limited to males, but the etiology of these tumors is unknown.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Pulmonary granulomas are the sequelae of previous infection, and generally all cultures of sputum or blood are negative. In some cases, the fungal serology yields evidence of a prior infection, but those titers usually decrease with time and may become negative. Most bronchial carcinoid tumors do not secrete hormones, but if flushing and/or diarrhea (carcinoid syndrome) is present, a twenty-four-hour urine 5-HIAA level may be elevated, although this is not a sensitive test. Occasionally, urine serotonin may be of value.

Uncommonly, carcinoid tumors may produce ACTH (corticotropin) or CRH (corticotropin-releasing hormone), which results in Cushing syndrome. Rarely carcinoid tumors may produce growth hormone and cause acromegaly. Human chorionic gonadotropin and/or alpha-fetoprotein may be elevated in the serum of patients with germ cell tumors.

What imaging studies will be helpful in making or excluding the diagnosis of a lung neoplasm?

Many of these pulmonary tumors are visible on chest radiographs. However, chest computed tomography (CT) generally provides better details and helps to separate infection from tumor in many cases. For pulmonary metastases, CT may reveal many more lesions than are appreciated on standard x-ray. CT is excellent at detecting major airway lesions that are frequently missed on chest x-ray. In the case of bronchial carcinoid tumors, fluorodeoxyglucose (FDG) positron emission tomography (PET) scan can be avid for atypical masses and have weak uptake for typical tumors. In certain cases of tumors that are enmeshed with the adjacent vasculature, mediastinum, or vertebral environment, MRI may be more useful in determining the tumor architecture.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a lung neoplasm?

A PPD or Quantiferon blood test is helpful in making or ruling out tuberculosis, but neither are absolutely sensitive or specific. Fungal serology is frequently, but not always, positive within a few weeks of the initial infection. For bronchial carcinoid tumors, blood or urine tests for corticotropin,5-HIAA, or serotonin may suggest the diagnosis in the occasional patient with the appropriate clinical syndrome. Blood tests for HCG or AFP are frequently positive in patients with malignant germ cell tumors. The majority of tumors discussed in this chapter have no associated blood, urine, or sputum tests that are high specific or sensitive to a particular diagnosis.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a lung neoplasm?

Fiberoptic bronchoscopy with BAL, brushings, and transbronchoscopic biopsies are likely to make a diagnosis of an infectious agent like histoplasmosis or blastomycosis. If the BAL smears are non-diagnostic, cultures are likely to be positive in seven to fourteen days when the etiology is fungal. Depending on the size of the lesion(s), brushings and/or biopsy may yield a diagnosis of a specific malignancy.

Bronchoscopic diagnosis is much greater if an endobronchial lesion is visualized. If bronchoscopy is non-diagnostic, transthoracic needle biopsy yields a tissue diagnosis 80% to 90% of the time with most malignant lesions. Solitary fibrous tumors and inflammatory myofibroblastic tumors are difficult to diagnose using a needle biopsy. A number of the lesions discussed can be diagnosed only with a VATS biopsy or definitive resection.

The advent of image guided bronchoscopy has enabled the trained pulmonologist to sample peripheral pulmonary legions. One specific randomized trial reported increased diagnostic yield with the use of virtual bronchoscopic navigation up to 80 % from 67%. Another studied showed no difference.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a lung neoplasm?

The presence of noncaseating granulomas on biopsy is helpful in suggesting an infectious or granulomatous disease. The presence of these granulomas is unusual when the etiology is a malignant tumor. Similarly, the presence of positive immunohistochemical staining for S-100 is significant for a neurofibroma. In the case of solitary fibrous tumors, pathologists attempt to define tumors as either benign or malignant based on the amount of mitotic activity, presence of necrosis, tumor size, increased cellularity, nuclear pleomorphism, and stromal invasion. Ultimately, the diagnosis of a primary malignant or benign tumor depends on the pathological interpretation of an adequate biopsy or resected specimen.

If you decide the patient has a lung neoplasm, how should the patient be managed?

When the clinician is certain of the diagnosis and they are not causing symptoms, many benign lesions like granulomas and hamartomas can just be observed. Most other benign or malignant solitary neoplasm are best treated with surgical resection. Many solitary metastic lesions are best treated surgically, as it is often uncertain preoperatively whether the solitary lesion is an isolated metastasis or a new primary lung cancer.

Surgery may also be indicated for multiple pulmonary metastases, such as renal cell, colon cancer, and sarcomas, but that decision is best made on a case-by case basis. For patients with malignant neoplasms who are medically unfit for surgery, consideration should be given to stereotactic body radiotherapy (SBRT) if the lesion is 5 cm or smaller. Occasionally, several metastatic nodules may be treated simultaneously with SBRT.

What is the prognosis for patients managed in the recommended ways?

Typical bronchial carcinoid tumors are generally cured with resection with a ten-year survival of 80% to 90%. Atypical carcinoid tumors have an overall five-year survival rate of 50%. Literature studies show that radical excision with mediastinal lymph node sampling is most effective for typical carcinoid tumor, while lobectomy with mediastinal lymph node dissection is recommended for atypical carcinoid. Adenoid cystic carcinomas may be cured with surgery, but they have a tendency toward multiple local recurrences before developing distant metastases. The five- and ten-year survival rate for patients with resectable disease are 70% and 60%, respectively versus survival rates of 50% and 30%, respectively, for patients with unresectable disease.

Solitary fibrous tumors are generally cured with resection, but approximately 10% may develop local recurrence. Similarly, IMTs are generally cured only with local resection, and they have a 90% 5-year survival, but recurrence locally or distant disease has been well documented. In patients who are not surgical candidates, there is inconsistent data with the use of glucocorticoids, radiotherapy, and chemotherapy. In certain patients with an Anaplastic lymphoma kinase (ALK) tyrosine kinase mutation, crizotinib has shown some benefit. Solitary pulmonary metastases, especially metastatic colon or renal cell carcinoma, have a 25% to 35% 5-year survival rate.

Results of resection of other solitary metastases or multiple metastases vary greatly, depending on the biology of the primary tumor and subsequent sites of metastases. Some metastatic pulmonary lesions, especially germ cell tumors, breast cancer, and other malignancies, respond to systemic treatment when a driver mutation, such as the BRAF mutation in melanoma and the EGFR mutation in lung adenocarcinoma, has been identified.

What other considerations exist for patients with lung neoplasms?

There are no genetic predispositions to the neoplasms discussed in this section, with the possible exception of bronchial carcinoid tumors, which are occasionally associated with MEN1. Most bronchial carcinoid tumors occur in patients who do not have MEN1.

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