1. Solitary Pulmonary Nodule DrMotwakilImam Sudan

2. Background A solitary pulmonary nodule is defined as a discrete, well-marginated, rounded opacity less than or equal to 3 cm in diameter that is completely surrounded by lung parenchyma, does not touch the hilum or mediastinum, and is without associated atelectasis or pleural effusion

3. A 1.5-cm coin lesion in the left upper lobe in a patient with prior colonic carcinoma

4. Patients with solitary pulmonary nodules are usually asymptomatic; however, solitary pulmonary nodules pose a challenge to both clinicians and patients. Whether detected serendipitously or during a routine investigation, a nodule on a chest radiograph raises several questions: Is the nodule benign or malignant? Should it be investigated or observed? Should it be surgically resected?

5. Most solitary pulmonary nodules are benign, but they may represent an early stage of lung cancer. Lung cancer is the leading cause of cancer death in the United States, accounting for more deaths annually than breast, colon, and prostate cancers combined. Lung cancer survival rates remain dismally low at 14% at 5 years.

6. Pathophysiology Generally, a pulmonary nodule must reach 1 cm in diameter before it can be identified on a chest radiograph. For a malignant nodule to reach this size, approximately 30 doublings would have occurred. The average doubling time for a tumor is 120 days (range 7-590 d). A lesion at this growth rate may be present for 10 years before discovery. A solitary pulmonary nodule may be secondary to a wide differential of causes. However, greater than 95% are malignancies (most likely primary), granulomas (most likely infectious), or benign tumors (most likely hamartoma).

7. Epidemiology Frequency United States Approximately 150,000 cases are detected each year as an incidental finding. The prevalence of solitary pulmonary nodules ranged from 8-51%.[2] Approximately 40-50% of solitary pulmonary nodules are malignant. Most of these are adenocarcinoma (47%), followed by squamous cell carcinoma (22%); small cell lung cancer makes up only 4% of malignant solitary pulmonary nodules. Mortality/Morbidity Most solitary pulmonary nodules are benign, but they may represent an early stage of lung cancer. Although lung cancer survival rates remain dismally low at 14% at 5 years, early lung cancer can be associated with a 5-year survival rate of 70-80%. Age Risk of malignancy increases with age. For individuals younger than 39 years, the risk is 3%. The risk increases to 15% for individuals aged 40-49 years, to 43% for persons aged 50-59 years, and to more than 50% for persons older than 60 years.

8. Solitary Pulmonary Nodule Clinical Presentation

9. History Most patients with solitary pulmonary nodules are asymptomatic; the nodules are typically detected as an incidental finding. The following features are important when assessing whether the nodule is benign or malignant. History of malignancy History of smoking Occupational risk factors for lung cancer: Exposure to asbestos, radon, nickel, chromium, vinyl chloride, and polycyclic hydrocarbons can lead to the development of a solitary pulmonary nodule. Travel: Travel to areas with endemic mycosis (eg, histoplasmosis, coccidioidomycosis, blastomycosis) or to areas with a high prevalence of tuberculosis (TB) can lead to the development of a benign solitary pulmonary nodule. History of TB or pulmonary mycosis.

10. Causes Bearing in mind that the major distinction that must be made is between neoplastic and inflammatory lesions, solitary pulmonary nodules may have the following causes: Neoplastic (malignant or benign) Bronchogenic carcinoma Adenocarcinoma (including bronchoalveolar carcinoma) Squamous cell carcinoma Large cell lung carcinoma Small cell lung cancer Metastasis Lymphoma Carcinoid Hamartoma Connective-tissue and neural tumors - Fibroma, neurofibroma, blastoma, sarcoma

11. Inflammatory (infectious) Granuloma - TB, histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis, nocardiosis Lung abscess Round pneumonia Hydatid cyst Inflammatory (noninfectious) Rheumatoid arthritis Wegener granulomatosis Sarcoidosis Lipoid pneumonia Congenital Arteriovenous malformation Sequestration Bronchogenic cyst Miscellaneous Pulmonary infarct Round atelectasis Mucoid impaction Progressive massive fibrosis

12. Solitary Pulmonary Nodule Differential Diagnoses

13. Differentials Arteriovenous Malformations Aspergillosis Atelectasis Blastomycosis Carcinoid Lung Tumors Coccidioidomycosis (Pulmonology) Histoplasmosis Hydatid Cysts Lung Abscess Lung Cancer, Non-Small Cell Lung Cancer, Oat Cell (Small Cell) Nocardiosis Pancoast Tumor Rheumatoid Arthritis Sarcoidosis Tuberculosis Wegener Granulomatosis

14. Solitary Pulmonary Nodule Workup

15. Laboratory Studies Laboratory studies have a limited role in the workup of solitary pulmonary nodules (SPNs). Anemia or an elevated sedimentation rate may indicate an underlying neoplastic or infectious process. Elevated levels of liver enzymes, alkaline phosphatase, or serum calcium may indicate metastases from a solitary bronchogenic carcinoma or extrapulmonary malignancy. Patients who have histoplasmosis or coccidioidomycosis may have high levels of immunoglobulin G and immunoglobulin M antibodies specific to these fungi.

16. Imaging Studies Chest radiography and computed tomography

17. Chest radiographs can provide information regarding size, shape, cavitation, growth rate, and calcification pattern. All of these radiologic features can help determine whether the lesion is benign or malignant. However, none of these features is entirely specific for lung carcinoma.

18. CT scanning of Advantages include better resolution of nodules and detection of nodules as small as 3-4 mm. CT scan images also help better characterize the morphologic features of various lesions. Multiple nodules and regions that are difficult to assess on chest radiographs are better visualized on CT scan images

20. Several radiologic characteristics, both on CT and radiography (although CT is superior), may help establish the diagnosis or suggest if a lesion is benign or malignant. These include (1) size, (2) growth rate, (3) presence of calcification, (4) border characteristics, (5) internal characteristics, and (6) location.

21. Size: Although a well-defined nodule of smaller size that is clearly visible on chest radiographs may be calcified and benign, small lesions may very well be early-stage bronchogenic carcinoma. A lesion greater than 4 cm in diameter is very likely a bronchogenic carcinoma, although exceptions include lung abscess, Wegener's granulomatosis, lymphoma, round pneumonia, rounded atelectasis, and hydatid cyst.

22. Rate of growth: Serial chest radiographs facilitate estimation of the growth rate of a nodule.

23. In general, doubling times of less than 1 month suggest infections; doubling times of more than 18 months suggest benign processes such as granuloma, hamartoma, bronchial carcinoid, and rounded atelectasis. If a nodule remains the same size for 2 years, it is very likely benign; however, further follow-up monitoring may be indicated. In one restrospective series, a volume doubling time of < 400 days at 3 month and 1 year followup was strongly predictive of malignancy.

24. Calcification: Chest radiographs may demonstrate calcification, which often indicates that the lesion is benign. The 5 patterns of calcification usually observed in benign lesions are diffuse, central, laminar, concentric, and popcorn. A stippled or eccentric pattern is associated with malignancy.

28. Border characteristics A very irregular edge or corona radiata may indicate a bronchogenic carcinoma. A well-defined, smooth, nonlobulated edge may indicate a benign lesion or metastasis, whereas lobulation and notching may indicate bronchogenic carcinoma. Cavitation with a thin, smooth wall may indicate lung abscess or a benign lesion, whereas thick-walled cavitations imply an underlying malignant neoplasm.

31. The CT halo sign (ie, ground-glass attenuation surrounding a nodule on CT scan image) most commonly indicates infection with an invasive Aspergillus species. Other less common possibilities include TB, cytomegalovirus infection, or herpes simplex infections.

32. Internal characteristics: Several characteristics within the nodule itself can indicate a specific cause. Demonstration of fat within the lesion is specific for a hamartoma

34. Ground-glass opacities may represent a benign lesion, such as atypical adenomatous hyperplasia, or malignancy, such as bronchoalveolar carcinoma (BAC).Importantly, malignant ground-glass opacities often grow slower and may require longer follow up.

35. Subsolid nodules (nodules with both solid and ground glass component) are frequently peripheral adenocarcinomas of the lung. Specifically, atypical alveolar hyperplasia typically manifests as pure ground glass lesions less than 5cm; BAC is usually greater than 5cm; lesions with mixed solid component and ground glass correlate with adenocarcima, mixed subtype. The presence of air bronchograms within the solitary pulmonary nodule makes bronchogenic carcinoma or metastasis unlikely, although they may be observed with bronchoalveolar carcinoma or lymphoma. Invasion of the adjacent bone by the nodule is pathognomic of bronchogenic carcinoma.

36. Location Nodules that are attached to pleura, vessels or fissures are likely benign.

37. Positron-emission tomography Whether positron-emission tomography (PET) scanning will be useful depends on (1) the clinical pretest probability of malignancy, (2) nodule morphology, (3) the size and position of the nodule, and (4) the scanning facility available.

38. Because malignant nodules have increased glucose metabolism compared with benign lesions and healthy lungs, enhancement of the lesion makes it likely to be malignant. Injection of analogue 18-F-2 fluorodeoxyglucose (FDG) is used to assess the metabolic activity. Although visual analysis findings may match SUV calculations, an SUV of less than 2.5 is considered indicative of a benign lesion.

39. FDG-PET scans are quite helpful in detecting mediastinal metastases, thus improving staging of noninvasive lung cancer. FDG-PET scans have several limitations because the false-positive findings occur in other metabolically active pulmonary nodules, which are either infectious or inflammatory. Tumors that have lower metabolic rates, such as carcinoid and bronchoalveolar carcinoma, may be difficult to distinguish from background activity. Finally, the FDG-PET scan has lower sensitivity for nodules smaller than 20 mm in diameter and may miss lesions smaller than 10 mm.

40. Single-photon emission computed tomography . SPECT scanning is less expensive than PET scanning, but both modalities have comparable sensitivity and specificity. SPECT imaging is performed using a radiolabeled somatostatin-type receptor binder, technetium Tc P829. SPECT imaging has not been evaluated in a large series of patients; in a smaller series, the sensitivity fell significantly for nodules less than 20 mm in diameter.

41. Procedures Biopsy Biopsy of solitary pulmonary nodule can be performed bronchoscopically or via transthoracic needle aspiration (TTNA).

42. Solitary Pulmonary Nodule Treatment & Management

43. Medical Care Lesions that have typical benign features, such as lack of change over 2 years or a benign pattern of calcification, especially in low-risk patients, do not require further workup. On the other hand, lesions that are strongly suggestive of malignancy (eg, >3 cm diameter) or those with documented growth should be referred for surgical resection.Management decisions for lesions with intermediate probability are more complex.

44. In 2005, the Fleischner Society published guidelinesfor follow-up imaging of solitary pulmonary nodules (SPNs). They specified different strategies based on patient risk factors and the size of the nodule.

45. Low-risk patients Less than or equal to 4 mm - No further investigation 4-6 mm - CT scanning at 12 months 6-8 mm - CT scanning at 6-12 months and 18-24 months Greater than 8 mm - CT scanning at 3, 9, and 24 months; contrast-enhanced CT scanning; positron-emission tomography (PET) scanning; and/or biopsy High-risk patients Less than or equal to 4 mm - CT scanning at 12 months 4-6 mm - CT scanning at 6-12 months and 18-24 months 6-8 mm - CT scanning at 3–6 months, 9–12 months, and 24 months Greater than 8 mm - Same as low-risk patients

46. Previous chest radiographs should be reviewed to determine if the lesion has been stable over 2 years. If so, no further follow up is necessary, with the exception of pure ground-glass lesions on CT scans, which can be slower growing. For lesions with a benign pattern of calcification, further testing is not necessary.

47. Management of indeterminate lesions greater than 8-10 mm depends on clinical probability of malignancy, as follows: Low probability - Serial CT scanning at 3, 6, 12, and 24 months Intermediate probability - 18-Fluorodeoxyglucose (FDG) PET scanning, contrast-enhanced CT scanning, transthoracic needle aspiration (TTNA), and/or transbronchial needle aspiration (TBNA) (Thoracoscopic diagnosis is recommended for patients who wish to have a surgical diagnosis if the lesion is in the peripheral third of the lung.) High probability - Surgical resection

48. Management of pure ground glass lesions or lesions with mixed ground glass and solid components is more controversial and no formal guidelines have been made.

49. Surgical Care When a lesion is likely to be malignant, surgical resection—not TTNA or observation—is often used.

50. The 2007 ACCP guidelines recommend that patients who have indeterminate lung nodules with a high probability of malignancy undergo thoracoscopic wedge resections if the lesion is in the peripheral third of the lung. This is because of the relatively low morbidity and mortality associated with the procedure compared with thoracotomy.If frozen sections show evidence of malignancy, anatomic resection with mediastinal lymph node sampling or dissection may be performed.

51. Localization using methylene blue injection or wire placement has facilitated successful resection of smaller nodules with video-assisted thoracoscopic surgery (VATS). Intraoperative ultrasonography is also suggested as a means of nodule localization during VATS.

52. For proven malignant solitary pulmonary nodule, lobectomy is preferred over wedge resection or segmentectomy because of the lower rate of recurrence and trend toward increased 5-year survival with lobectomy.

53. Solitary Pulmonary Nodule Follow-up

54. Prevention Avoiding certain exposures may help prevent certain causes of solitary pulmonary nodule formation. Possible avoidable exposures include the following: Risk factors for malignancy Smoking Occupational exposures (eg, asbestos, radon, nickel, chromium, vinyl chloride, polycyclic hydrocarbons) Travel to areas endemic for mycosis (eg, histoplasmosis, coccidioidomycosis, blastomycosis) or to areas with a high prevalence of tuberculosis .

55. Complications Most solitary pulmonary nodules are benign, but they may represent an early stage of lung cancer. While lung cancer survival rates remain dismally low at 14% at 5 years, early lung cancer (ie, diagnosed when the primary tumor has a diameter smaller than 3 cm can be associated with a 5-year survival rate of 70-80%. Accordingly, the only chance for cure of early lung cancer manifesting as solitary pulmonary nodule is prompt diagnosis and management.

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