Early-Stage (I–II) Non–Small Cell Lung Cancer

John P. Christodouleas and Joe Y. Chang

Background

How many lobes are there in the lung? How many segments are there per lobe?

There are 5 lobes in the lung–3 on the right and 2 on the left: RUL, RML, RLL, LUL, and LLL. Lingula is the anatomic equivalent of LML, and is part of the LUL. There are 5 segments per lobe, except for the RUL and RML, which are divided in 3 and 2 segments, respectively, supplied by tertiary bronchi.

Name the 9 N2 nodal stations.

N2 nodal stations:

Station 1: highest mediastinal
Station 2: upper paratracheal
Station 3: prevascular (3A) and retrotracheal (3P)
Station 4: lower paratracheal
Station 5: subaortic (AP window)
Station 6: para-aortic
Station 7: subcarinal
Station 8: paraesophageal
Station 9: pulmonary ligament

Where are the intrapulmonary and hilar nodes located?

Intrapulmonary nodes are nodes along the secondary bronchi, whereas hilar nodes are those along the main stem bronchi. These are all considered N1 nodes.

Name the 5 N1 nodal stations.

N1 nodal stations:

Station 10: hilar
Station 11: interlobar
Station 12: lobar
Station 13: segmental
Station 14: subsegmental

(Note: N1 nodes are all double digits.)

What are the estimated annual # of new lung cancer cases diagnosed in the U.S. and the # of deaths from lung cancers?

In 2009, there were ~219,000 newly diagnosed cases of lung cancers in the U.S., accounting for > 160,000 deaths. This accounts for more deaths than all colorectal, breast, and prostate cancers combined.

Overall, what is the 5-yr survival rate for lung cancer pts?

The overall 5-yr survival rate for non–small cell lung cancer (NSCLC) is 15%.

What are the 3 histologic subtypes of NSCLC in decreasing order of frequency?

Histologic subtypes of NSCLC: adenocarcinoma (50%) > squamous cell carcinoma (35%) > large cell (15%)

In addition to tobacco smoke, what are 3 other environmental exposure risk factors for developing lung cancers?

Environmental exposure risk factors for lung cancer:

Radon
Asbestos (Note: Smoking and asbestos exposures are synergistic in early reports, but more recent studies suggest less than a multiplicative effect.)
Occupational exposure (arsenic, bis-chloromethyl ether, hexavalent chromium, mustard gas, nickel, polycyclic aromatic hydrocarbon)

What is the estimated RR for lung cancer in heavy smokers vs. nonsmokers?

Heavy smokers have a 20-fold excess of lung cancer (American Cancer Society [ACS] cohort study).

What is the risk of lung cancer in former smokers compared to current smokers?

The risk of developing lung cancer in former smokers is around half (9 times vs. 20 times) that of current smokers (ACS cohort study).

What is the risk of lung cancer from passive smoke exposure?

There is an RR of 1.2–1.3 for developing lung cancer from passive smoke exposure.

Approximately what % of smokers develop lung cancer?

<20% of smokers actually develop lung cancer (in the Carotene and Retinol Efficacy Trial, 10-yr cancer risk was 1%–15%).

What histology subtype of NSCLC is least associated with smoking?

Adenocarcinoma is the histologic subtype that is least associated with smoking.

Name 3 histologic variants of adenocarcinoma of the lung.

Bronchoalveolar, acinar, and papillary

Name 2 variants of large cell cancer of the lung.

Giant cell and clear cell

What is the race and gender predilection for NSCLC?

Blacks have the highest incidence of lung cancer. Males also are historically at greater risk, but as females continue to start smoking, the incidence in females is rising.

What is the most common stage at initial presentation?

The most common stage of presentation for lung cancer is metastatic Dz (around one third of pts).

What are the most common sites of DMs for lung cancer?

Bone, adrenals, and brain

What are the para-neoplastic syndromes associated with lung cancers?

Hypercalcemia of malignancy due to PTHrP, syndrome of inappropriate secretion of antidiuretic hormone → ↓Na, Cushing, Lambert-Eaton syndrome, and other neurologic disorders

What is the cause of Lambert-Eaton syndrome? Clinically, how can Lambert-Eaton be distinguished from myasthenia gravis?

Lambert-Eaton syndrome is caused by circulating autoantibodies against presynaptic P/Q calcium channel. Lambert-Eaton strength improves with serial effort, but not myasthenia gravis.

Which histologic subtypes of lung cancer are associated with peripheral and central locations?

Peripheral: adenocarcinoma
Central: SCC

With which histologic subtypes of lung cancer is thyroid transcription factor-1 (TTF-1) staining associated?

Adenocarcinoma, nonmucinous bronchioalveolar carcinoma, and neuroendocrine tumors (i.e., small cell lung cancer, carcinoid). TFF-1 is rare in SCC. A thyroid cancer primary must be excluded.

In NSCLC, what is the role of CT screening for high-risk pts?

This is controversial as of 2010. Lead time bias could be the reason why survival is better. IELCAP (Henschke CI et al., NEJM 2006) reported that out of 27,456 pts screened, 74 pts were found to have cancer (0.3% detection) and 86% were stage I. 10-yr survival was 93% in stage I pts who underwent resection at Dx. 10-yr OS was 82% for all pts diagnosed by CT.

What is the single most clinically significant acquired genetic abnormality in NSCLC?

EGFR mutation in exon 19 (in-frame deletion of 4 aa, LREA) and exon 21 (L858R point mutation); results in a constitutive active receptor.

Among pts with NSCLC, in what particular groups are the EGFR mutations common, and for what do these mutations predict?

In the overall lung cancer population, EGFR mutations are seen in only ~10%, but this occurs at high rates (30%–70%) in nonsmokers, adenocarcinomas, and Asians. These mutations predict for a high response rate to TKIs (gefitnib, erlotnib) of ~80%.

What point mutation in the EGFR gene is associated with TKI resistance?

T790M is the point mutation in the EGFR gene associated with TKI resistance.

What other genetic alteration predicts well for response to TKI?

EGFR amplification (by FISH) is a good predictor for TKI response.

For what does the KRAS mutation or ERCC1 expression predict?

The KRAS mutation or ERCC1 expression predicts for resistance to platinum-based chemo.

Workup/Staging

What is the initial workup for a pt suspected of having lung cancer?

Lung cancer initial workup: H&P + focus on weight loss >5% over prior 3 mos, Karnofsky performance status (KPS), tobacco Hx, neck exam for N3 Dz, CBC, CMP, CT chest to include adrenals or PET/CT, MRI for paraspinal/sup sulcus tumors, Dx of lung cancer rendered by Bx via transbronchial endoscopic or transthoracic FNA, MRI brain for presumed stages II–III, mediastinoscopy or endobronchial ultrasound (EBUS) for suspected hilar or N2 nodes, PFTs prior to Tx, and smoking cessation counseling

What are the 3 most common presenting Sx of NSCLC?

Dyspnea, cough, and weight loss (others include chest pain and hemoptysis)

What is the sensitivity and specificity of sputum cytology for Dx of lung cancer?

Sensitivity <70%, specificity >90%. Accuracy increases with increasing # of specimens analyzed. At least 3 sputum specimens are recommended for the best accuracy.

What is the sensitivity and specificity of FDG-PET compared to CT for the staging of lung cancers?