During investigation of an episode of self-limiting abdominal pain, a 63-year-old Caucasian female never-smoker was found to have an asymptomatic right lower lobe pulmonary mass. A positron-emission tomography/computed tomography (PET/CT) scan revealed the right lower lobe mass to be 25 × 32 mm with a standardized uptake value (SUV) of 10.2, without evidence of hilar or mediastinal lymphadenopathy or of distant metastases.
Additional Case Background
The patient did not have a biopsy of the primary lesion prior to surgery. In an outside facility, a right lower lobectomy via open thoracotomy and selected lymph node staging biopsies were performed. Pathology revealed a 2.3-cm moderately differentiated adenocarcinoma, with negative surgical margins. Lymph node examination revealed malignancy involving one right lower lobe peribronchial lymph node, one subcarinal lymph node, one of two bronchus intermedius lymph nodes, and no disease in a sampled right middle lobe bronchial node, or in an inferior pulmonary vein lymph node (Figure 1). A magnetic resonance imaging (MRI) scan of the brain showed no evidence of intracranial metastases. The tumor was pathologically staged as pT1, N2, M0, or stage IIIA.
Overall, the patient tolerated the surgery well. It is now 5 weeks since her operation. She has already seen one oncologist, who proposed giving her four cycles of carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel) as adjuvant chemotherapy. She has come to the University of Colorado Thoracic Oncology Program seeking a second opinion on her management. Her Eastern Cooperative Oncology Group (ECOG) performance status is zero, and she has no significant past medical history.
Dr. D. Ross Camidge (Medical Oncologist): Dr. Franklin, can you review the patient’s pathology?
Dr. Wilbur Franklin (Pathologist): The right lower lobe specimen containing a 2.3-cm mass was examined. The mass proved to be a well-differentiated papillary adenocarcinoma (Figure 2) consistent with a primary lung cancer. It is increasingly well established that lung adenocarcinomas are heterogeneous in their histologic appearances. One pattern that is the object of ongoing evaluation is referred to as “true papillary.” In this histologic pattern, the usual concave contours of the alveolar surfaces are replaced with irregular, complex vascularized projections (papillary structures) lined by multilayered epithelium. This pattern must be present in > 75% of the cross-sectional area of the tumor to qualify as true papillary.
A second, more common “micropapillary” pattern has been recently described, consisting of avascular cellular tufts projecting from alveolar surfaces. Together these two subtypes occur in up to 37% of lung adenocarcinomas and are more likely to harbor activating mutations in the epidermal growth factor receptor (EGFR) than other adenocarcinomas.
Dr. Scott Kono (Medical Oncology Fellow): Can you comment on the molecular diagnostic panel run on the tumor specimen?
Dr. Franklin: A number of different molecular tests particularly associated with sensitivity or resistance of non–small-cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors have been explored in the past few years. As part of our standard molecular diagnostic panel at the University of Colorado, we now evaluate all NSCLCs for EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number increases by fluorescence in situ hybridization (FISH), and EGFR and KRAS mutational status by direct sequencing techniques. This patient strongly expressed EGFR in nearly all tumors cells, and had a high EGFR copy number (high polysomy) by FISH. Specific exon sequencing for somatic mutations revealed wild-type KRAS (exon 1) and EGFR (exons 19-21).
Although the significance of the different analytic techniques and test results continues to be debated, the most clinically significant test in an untreated patient currently relates to the presence or absence of an activating mutation in the EGFR. Such activating mutations have been associated with dramatically increased sensitivity to EGFR tyrosine kinase inhibitors such as erlotinib (Tarceva) in the advanced disease setting, as well as with an overall improved prognosis. Activating EGFR mutations such as exon 19 deletions are more common in adenocarcinomas than in other NSCLC variants, especially the papillary subtype. However, the fact that an activating EGFR mutation is not exhibited in this patient reinforces the idea that histologic and demographic factors are only guides to the likelihood of such sequence abnormalities being present. They are not a replacement for molecular testing.
Dr. Camidge: Dr. Weyant, can you comment on whether a standard approach exists for lung and mediastinal lymph node (MLN) sampling in relation to surgery for lung cancer?
Dr. Michael Weyant (Thoracic Surgeon): MLN sampling plays a critical role in evaluating NSCLC, as nodal status has direct therapeutic and prognostic significance. Unfortunately, no single standard exists among surgeons with regard to sampling mediastinal lymph nodes. In a recent American College of Surgeons survey, only 27% of lung cancer patients underwent preoperative mediastinoscopy, and only 58% had MLNs removed at the time of resection. The rates of MLN sampling differed significantly among centers, with academic centers having the highest rate, followed by community comprehensive cancer centers, and then community cancer centers.
Dr. Kono: Can you describe the different operative approaches used in evaluating MLNs?
Dr. Weyant: The gold standard in evaluating NSCLC for MLN metastases is cervical mediastinoscopy, at which time stations 2L, 2R, 4L, 4R, and 7 are sampled (Figure 1). Video-assisted thoracoscopic surgical (VATS) procedures may be used to access additional lymph node basins and augment the cervical mediastinoscopy. Ultrasound-guided transbronchial or transesophageal lymph node biopsies are also potentially useful new techniques. Cervical mediastinoscopy can be performed either as a separate procedure or during the same surgical setting with the use of frozen sections, to be reviewed by an experienced pathologist.
Dr. Kono: This patient’s preoperative PET/CT scan showed no evidence of mediastinal or hilar lymphadenopathy. Although the technology is continually evolving, preoperative PET/CT scans have recently been reported to have a sensitivity and specificity of 85% and 80%, with a negative predictive value of 95% in evaluating mediastinal disease. Dr. Weyant, given the increasing use of preoperative PET/CT scanning and its high negative predictive value, how would you use this information to guide the timing and type of procedures to choose for assessing the mediastinum?
Dr. Weyant: One of the functions of MLN assessment is to determine in which patients a thoracotomy would be futile, due to the presence of multistation N2/N3 disease. In these situations, either radical radiotherapy or chemoradiotherapy would usually be considered the more appropriate approach. Although no definite rules exist, in the presence of a negative preoperative PET/CT scan, given that the chances of involved lymph nodes are low, it would be reasonable to avoid a second anesthetic procedure and to perform MLN assessments at the time of the primary lung surgery.
Lymph Node Sampling vs Dissection
Dr. Kono: Our patient did not undergo preoperative mediastinoscopy. Can you comment on MLN sampling at the time of surgical resection?
Dr. Weyant: Preresection mediastinoscopy with MLN assessment is critical in the operative setting, even with a negative preoperative PET scan. As a standard approach, we examine the lymph nodes obtained at mediastinoscopy by frozen section early on during the operative procedure. If the mediastinal nodes are positive we generally abort the surgery and await final pathologic review and discussion at our multidisciplinary tumor board.
A patient may have a VATS resection of a small previously undiagnosed lung nodule that turns out to be a primary lung cancer. In this setting, I would perform an ipsilateral VATS mediastinal lymph node sampling at the time of the VATS lobectomy. If there is concern or a need to obtain contralateral mediastinal nodes, a subsequent mediastinoscopy can then be performed.
Considerable evidence suggests that at the time of tumor resection, the more lymph nodes assessed, the better the outcome for patients with early-stage disease.[10,11] In part, this simply reflects accurate staging of N0 disease, but there is ongoing debate about the relative merits of purely prognostic mediastinal lymph node sampling (MLNS) vs the potentially additional therapeutic benefit offered by mediastinal lymph node dissection (MLND).
MLNS has been defined as sampling nodes from stations 2R, 4R, 7, and 10R (Figure 1) in right-sided tumors, and stations 2L, 4L, 5, 6, 7, 10 L in left-sided tumors. Conversely, MLND has been defined in right-sided tumors as removal of all lymphatic tissue bound by the right upper lobe bronchus, innominate artery, the superior vena cava, and trachea. In left-sided tumors, the area is bound by the phrenic nerve, vagus nerve, aortic arch, and left mainstem bronchus. For tumors on either side, all lymphatic tissue at stations 7, 8, 9, 11, and 12 are removed.
The major fear relating to inadequate MLN assessment is for stage migration, or basing treatment on a presumed clinical stage, when the pathologic stage is actually higher. MLNS or MLND alleviates this fear and allows for stage-appropriate treatment. A theoretic concern about MLND is a higher operative mortality compared to MLNS, due to the extensive nature of the procedure. However, multiple observational studies and randomized controlled trials have shown no significant difference in mortality rate between MLND and MLNS.
Dr. Kono: Do you feel this patient had “adequate” lymph node sampling?
Dr. Weyant: This patient did not have adequate lymph node sampling. Despite having a negative preoperative PET scan, a more thorough attempt at lymph node sampling should have been performed. The operative note describes several lymph nodes being sampled, specifically N1 lymph nodes at levels 11 and 12 and the most easily accessible N2 lymph nodes at levels 7 and 9. However, the important right paratracheal (level 4) and the contralateral level 4 areas were not sampled. It is important to note that approximately 30% of lower lobe tumors manifest mediastinal lymph node involvement without hilar involvement.