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case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Jo-Anne O. Shepard, m.d., Associate Editor Sally H. Ebeling, Assistant Editor

Stacey M. Ellender, Assistant Editor Christine C. Peters, Assistant Editor

Case 26-2004: A 56-Year-Old Woman with Cough and a Lung Nodule

Thomas J. Lynch, M.D., Cameron D. Wright, M.D., Noah C. Choi, M.D., Suzanne L. Aquino, M.D., and Eugene J. Mark, M.D.

presentation of case
Dr. Jennifer Temel (Medical Oncology): A 56-year-old woman was evaluated in the thoracic oncology clinic for treatment of nonsmall-cell lung cancer. The patient had been in her usual state of good health until three months before presentation, when a nonproductive cough developed. During the next two months, the cough became productive of yellow, blood-tinged sputum. She saw her primary care physician, and a chest radiograph revealed a nodule, 2.5 cm in diameter, in the upper lobe of the right lung (Fig. 1A). Computed tomographic (CT) scanning of the thorax identified a 2.5-cm nodule in the right upper lobe, with no enlarged hilar or mediastinal lymph nodes (Fig. 1B). An abdominal ultrasound examination, a CT scan of the head, and a bone scan showed no abnormalities. A positron-emission tomographic (PET) scan revealed increased accumulation of fludeoxyglucose F 18 at the apex of the right lung, at a site corresponding to the primary lesion (Fig. 1C); no other areas of accumulation were noted. One month before the patients evaluation in the clinic, bronchoscopy and mediastinoscopy were performed in preparation for a thoracotomy and resection of a suspected bronchogenic carcinoma. Bronchoscopic examination revealed no abnormalities. Mediastinoscopy revealed no nodes on the left side but did show a normal-appearing subcarinal node and a normal-sized, mobile paratracheal node on the right side. Intraoperative examination of a frozen section of a biopsy specimen of the paratracheal node showed metastatic nonsmall-cell lung cancer; the subcarinal node was normal. The thoracotomy was not performed, and the patient was referred to the thoracic oncology clinic at this hospital. An aneurysm of the left middle cerebral artery had been repaired three years previously, and an aneurysm of the right internal carotid artery had been repaired two years previously. The patient had no neurologic deficits. She had smoked one to two packs of cigarettes per day for 38 years but had stopped smoking when her cough developed. She did not drink alcohol. Her only medications were alprazolam as needed for anxiety and a nicotine patch. She had no family history of lung cancer. On physical examination, her vital signs were normal and she appeared comfortable. There was no palpable lymphadenopathy. The lungs were clear on auscultation.
From the Departments of Medical Oncology (T.J.L.), Thoracic Surgery (C.D.W.), Radiation Oncology (N.C.C.), Radiology (S.L.A.), and Pathology (E.J.M.), Massachusetts General Hospital; and the Departments of Medicine (T.J.L.), Surgery (C.D.W.), Radiation Oncology (N.C.C.), Radiology (S.L.A.), and Pathology (E.J.M.), Harvard Medical School. N Engl J Med 2004;351:809-17.
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Figure 1. Radiologic Studies. A chest radiograph shows a 2.5-cm nodule in the right upper lobe (Panel A). A CT scan confirms the presence of a 2.5-cm nodule in the right upper lobe on lung windows (Panel B). The surrounding lung tissue shows moderate centrilobular emphysema. A coronal image from a PET scan obtained with the use of fludeoxyglucose F 18 shows increased metabolic activity in the upper-lobe nodule (Panel C) and in the right paratracheal (Panel D, arrow) and subcarinal lymph-node regions.

Neurologic examination revealed no abnormalities. Laboratory-test results were normal, except for a slightly elevated level of alkaline phosphatase (116 U per liter).

and mediastinal contours and densities are normal. A CT scan shows a spiculated nodule in the apex of the right lung (Fig. 1B). There is centrilobular emphysema of the surrounding lung parenchyma. There is no evidence of enlarged lymph nodes in the right hilum or mediastinum. differential diagnosis PET scanning of the thorax with the use of Dr. Suzanne L. Aquino: The chest radiograph obtained fludeoxyglucose F 18 shows increased uptake of at the other hospital shows an ill-defined, 2.5-cm this radioactive agent in the nodule in the right nodule in the right upper lobe (Fig. 1A). The hilar upper lobe (Fig. 1C) a finding that suggests the

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presence of a malignant tumor. Although it was not noted at the time, in retrospect it is apparent that there was an increase in fludeoxyglucose F 18 uptake in the right paratracheal and subcarinal lymph-node regions (Fig. 1D) a finding that suggests metastatic disease in the lymph nodes. There are no other areas of increased fludeoxyglucose F 18 uptake. This scanning technique has a sensitivity of 92 to 95 percent and a specificity of 88 to 90 percent for detecting cancer in pulmonary nodules.1-3 False negative results may occur in slowly growing tumors, such as bronchioloalveolar carcinomas4 and carcinoid tumors,5 and in nodules less than 1 cm in diameter. Any nodule that shows increased uptake of fludeoxyglucose F 18 should be considered potentially neoplastic, and a biopsy should be performed. Nodules without increased metabolic activity should be followed with repeated radiography to ensure that their size remains stable. Because PET scanning performed with the use of fludeoxyglucose F 18 measures the rate of metabolism, other diseases with increased metabolism can resemble cancer, especially if the lesions have a nodular appearance. This explains the slightly lower specificity of the technique for detecting a malignant condition.1-3 False positive interpretations may occur with granulomas, pneumonias, and inflammatory lesions such as rheumatoid nodules.6-9 Since the detection of abnormal lymph nodes on CT scans is based purely on size, a small lymph node involved with tumor would be interpreted as benign if it was less than 1 cm in diameter. PET scanning performed with fludeoxyglucose F 18 has improved the radiologic staging of lung cancer, with a sensitivity of 91 percent, a specificity of 86 percent, and negative and positive predictive values of 95 percent and 74 percent, respectively.10-13 As with the detection of a primary tumor, the major limitations are false positive findings in lymph nodes affected by other diseases, such as silicosis or granulomatous diseases. Therefore, to confirm the presence of cancer, most experts recommend biopsy of any lymph nodes that show increased fludeoxyglucose F 18 uptake. Dr. Thomas J. Lynch: Dr. Wright, can you tell us about your surgical approach for this patient? Dr. Cameron D. Wright: In this clinical setting, I thought the most likely diagnosis preoperatively was nonsmall-cell lung cancer. She was of the appropriate age (older than 55 years), had a history of smoking, had no history of previous inflammatory lung illness, and had emphysema, hemoptysis, and

a spiculated, solitary pulmonary nodule, as revealed on a PET scan. Given these factors, the chance that her diagnosis was lung cancer was greater than 90 percent. There are pitfalls for the surgeon in the preoperative assessment of mediastinal lymph nodes. Small nodes that are considered benign according to CT criteria can be microscopically positive for cancer, and large nodes are sometimes only inflammatory. Enlarged nodes that are pathologically benign are found most commonly when there is an obstructive pneumonia caused by a tumor in the bronchus, usually a squamous-cell cancer. In contrast, large nodes with peripheral lung lesions almost always contain cancer. If both the CT scans and the PET scans are read as negative, it is highly likely that the nodes will be negative for cancer. If either set of scans is positive (or if both are), it is necessary to sample the lymph nodes to obtain a tissue-based diagnosis. The uncertainty is highlighted in this case, since the retrospective interpretation of the PET scan suggested that both the right paratracheal and the subcarinal nodes were positive but on biopsy only the paratracheal node was positive. To ascertain whether a patient is a candidate for preoperative chemotherapy or radiotherapy, invasive staging of the mediastinum must be performed. Since this patients PET scan was originally read as showing no evidence of metastasis, we planned a one-day operation consisting of surgical staging of the mediastinum with a mediastinoscopy, and if the findings were negative, a thoracotomy. Most nodal groups that are important in lung cancer14,15 the paratracheal, subcarinal, and tracheobronchial angle nodes can be readily accessed by a mediastinoscopy. Nodes on the left side of the aortic arch (para-aortic and subaortic) are accessed by an anterior mediastinotomy, which can be done at the same time. It is now possible, when necessary, to access the inferior mediastinal nodes by endoscopic fine-needle aspiration guided by ultrasonography. The staging of lung cancer is based on the size of the tumor (T1 through T4), the location and number of positive lymph nodes (N0 through N3), and the absence or presence of distant metastases (M0 or M1). This patient has a tumor that is T1 (diameter, <3 cm, without invasion of the pleura), N2 (involvement of ipsilateral, mediastinal, and subcarinal lymph nodes), and M0 (no distant metastases). Lung cancer is also staged as IA or IB, IIA or IIB, IIIA or IIIB, or IV, depending on the combination of TNM findings. This patients tumor is considered

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locally advanced (stage IIIA). The expected one-year and five-year survival rates for this patient are 64 percent and 23 percent, respectively.16 There are several prognostic factors in stage N2 lung cancer, but the most important consideration is whether enlarged mediastinal nodes are seen either on a standard posterior-anterior radiograph or on a CT scan; these clinically positive nodes are also known as clinical N2 disease. Patients with such nodes who undergo surgical resection and postoperative adjuvant treatment have a five-year survival rate of only 5 percent, as compared with patients whose lymph nodes are positive but not enlarged (five-year survival rate, 20 to 30 percent).17,18 Other poor prognostic variables include the involvement of nodes at multiple sites and extracapsular growth of tumor in the lymph node. Clinically, this patients disease was N0 because no enlarged nodes were seen on routine radiographs. Because the intraoperative frozen section showed a positive node, I thought she might benefit from preoperative chemoradiotherapy, so I elected not to proceed with the planned thoracotomy.

pathological discussion
Dr. Eugene J. Mark: The right paratracheal lymphnode specimen from mediastinoscopy was submitted for analysis; it consisted mostly of metastatic large-cell carcinoma (Fig. 2A). The cells had large, pleomorphic nuclei, and several cells had very large nucleoli with clumped chromatin and prominent nucleoli. There was no gland formation or keratinization to indicate adenocarcinoma or squamouscell carcinoma (Fig. 2B). The subcarinal node did not contain tumor cells. The standard histologic classification of the common carcinomas of the lung is shown in Table 1. This patient had an undifferentiated large-cell carcinoma. The role of the pathologist in the evaluation of carcinomas of the lung is given in Table 2.19-21 The histologic type should conform to the standard classification. The grade is often given but has not proved to be an independent factor in prognosis. The most important issue is the staging, which includes an assessment of the size of the tumor, the relationship of the tumor to the pleura, the presence or absence of lymph-node metastases, and the adequacy of resection margins, particularly at the bronchus. Immunopathological markers are sometimes useful in distinguishing a primary lung cancer from

Figure 2. Lymph-Node Biopsy Specimen (Hematoxylin and Eosin). There are nests of carcinoma cells (Panel A) adjacent to fibrotic tissue. At higher magnification the cells are large, with no glandular or squamous differentiation (Panel B).

Table 1. Standard Histologic Classification of Lung Cancer and Its Variants. Squamous-cell carcinoma Papillary Small-cell Basaloid Adenocarcinoma Acinar Papillary Bronchioloalveolar Solid with mucus Large-cell carcinoma Neuroendocrine Clear-cell Lymphoepithelial Rhabdoid Small-cell carcinoma

a metastasis (Table 3). The most commonly used markers are thyroid transcription factor 22,23 and cytokeratins of various molecular weights. Thyroid transcription factor is largely restricted to lung and thyroid cancer. The expression of cytokeratins of

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Table 2. Pathological Considerations in the Diagnosis of Lung Cancer. Histologic classification Histologic grade (optional) Stage of tumor Size of primary tumor Extent of pleural invasion Status of lymph nodes Status of resection margins Investigational variables Cellular reaction Blood-vessel or lymphatic invasion Effects of therapy

Table 3. Immunopathological Markers of Cancer. Marker Keratin (broad spectrum) Carcinoembryonic antigen Keratins 7 and 20 Expression All carcinomas Adenocarcinoma Lung cancer (positive for keratin 7); gastrointestinal cancer (positive for keratin 20) Lung and thyroid cancers Mesothelioma Pancreatic cancer Breast cancer Prostate cancer Small-cell carcinoma

Thyroid transcription factor 1 Calretinin and WT-1 CA 19-9 Estrogen and progesterone receptors Prostate-specific antigen Neuroendocrine markers (neuronspecific enolase, synaptophysin, chromogranin)

various molecular weights in tumors mirrors that of the normal epithelium that the tumor arises from or differentiates toward, and is useful in the diagnosis of metastases from the gastrointestinal tract as well as the distinction of carcinomas of the lung these patients the disease can be cured by surgery, but the majority die from metastatic cancer. Stratefrom diffuse malignant mesothelioma. gies that incorporate systemic chemotherapy offer the best chance of controlling distant metastatic discussion of management disease in both clinical N2 and minimal N2 lung Dr. Lynch: In summary, this 56-year-old woman has cancer. A key question that we faced in the managenonsmall-cell lung cancer, with clinical stage N0 ment of this case was how to optimally incorporate or N1 disease and pathological stage N2 disease systemic chemotherapy and radiotherapy into her a combination that is sometimes called minimal N2 treatment: Should they be given after surgery (adjudisease. What is the optimal approach to care for vant) or before surgery (neoadjuvant)? Before 2003, the role of adjuvant chemotherapy this patient? Treatment of stage IIIA nonsmall-cell lung for completely resected lung cancer, with or withcancer is one of the most controversial topics in the out positive lymph nodes, was unclear. Four years management of lung cancer. The most important ago, when treatment decisions for this patient were initial distinction is to classify the disease as either being made, the data available did not support its clinical N2 or clinical N1 or N0. Currently, oncolo- use. A 1995 meta-analysis found that cisplatingists use the presence of lymph nodes on CT scans based adjuvant chemotherapy was associated with or chest radiographs as the criterion for clinical N2 a 5 percent improvement in overall survival, but the disease. A question for the near future is whether number of patients treated was too small to allow PET scanning will change the preoperative staging an assessment of statistical significance.26 A study classification. I suspect that patients whose disease in which the combination of cisplatin, etoposide, is considered positive on the basis of PET scanning and radiotherapy was compared to radiotherapy and negative on the basis of CT scanning will have alone after complete resection of stage II or III non a prognosis that is somewhere between that of pa- small-cell lung cancer27 failed to show a benefit tients with clinical N2 disease and minimal N2 dis- from adjuvant chemoradiotherapy. In 2003 and 2004, the results of two larger trials ease. The increasing use of simultaneously registered PET and CT may make this distinction more were reported. One trial found that three cycles of platinum-based chemotherapy resulted in a 2 to clear.24 For patients with clinical N2 disease, there is 3 percent rate of absolute improvement in overall wide agreement that surgery alone does not provide survival as compared with surgery alone, a finding an acceptable cure rate.25 For patients with clinical that did not reach statistical significance; however, N0 or N1 disease who have pathologically involved the number of patients in this study was not large N2 nodes, also known as minimal N2 disease, there enough to permit detection of a 5 percent differare several reasonable options. In nearly a third of ence in survival.28 The second trial was the largest

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randomized trial reported to date for patients with resected lung cancer.29 In this study, more than 1800 patients with stage I, II, or IIIA lung cancer were randomly assigned after surgery to either observation or to one of four cisplatin-based chemotherapy regimens. At five years, the overall survival was 44.5 percent in the group that received adjuvant chemotherapy as compared with 40.0 percent in the group that did not get adjuvant treatment a statistically significant difference. This trial was large enough to demonstrate a benefit of the magnitude that is clinically meaningful to patients. Thus, for this patient with minimal N2 disease, surgical resection followed by three or four cycles of adjuvant cisplatin-based chemotherapy would be a reasonable treatment option. Had these data been available when this patient presented, she would have considered this option. Trials of neoadjuvant therapy followed by surgery for stage IIIA nonsmall-cell lung cancer have involved both chemotherapy and combined chemotherapy and radiotherapy strategies. Phase 2 studies of chemotherapy followed by surgery (and often postoperative radiotherapy) have reported cure rates of between 15 percent and 20 percent.30,31 This compares favorably with the 5 percent to 9 percent survival rate reported for patients with clinical N2 cancer who were treated with surgery alone. However, the comparison is not completely fair, since patient selection could result in differences in known prognostic factors. Two small, randomized trials reported in the early 1990s32,33 showed a clear benefit associated with chemotherapy followed by surgery as compared with surgery alone; however, both studies included patients with T3N0 disease, which probably has biologic features and a pattern of recurrence that differ from those of N2 disease. A larger, randomized trial34 showed a trend toward improved outcomes with chemotherapy as compared with surgery alone, but the difference did not reach statistical significance because of the small number of patients in the study. Dr. Choi will discuss the use of combined chemotherapy and radiotherapy followed by surgery for stage IIIA nonsmall-cell lung cancer. Dr. Noah C. Choi: Important questions in planning the appropriate multimodality therapy for a patient such as this with stage IIIA (N2) nonsmall-cell lung cancer include the following: What is the role of radiotherapy relative to chemotherapy in downstaging the tumor so that it can be resected? What is the proper sequence for the use of radiotherapy

among the other treatments? How can toxic effects from radiation be minimized? A randomized, phase 3 clinical trial published in abstract form in the early 1990s compared preoperative chemotherapy plus radiotherapy with chemotherapy alone in patients with stage IIIA (N2) and IIIB (T4) nonsmall-cell lung cancer.35 The response rate, resection rate, and rate of freedom from progression for preoperative, concurrent chemoradiotherapy as compared with chemotherapy alone were 67 percent versus 44 percent, 52 percent versus 31 percent, and 40 percent versus 21 percent, respectively; all the differences were statistically significant. My colleagues and I conducted a phase 2 study in which 42 patients with stage IIIA (N2) non small-cell lung cancer were treated with two courses of preoperative cisplatin, vinblastine, and fluorouracil, with concurrent radiation given in two fractions per day, followed by surgery and another course of postoperative chemoradiotherapy.36 The tumor could be resected with negative margins in 81 percent of the patients. The overall survival rates were 66 percent, 37 percent, and 37 percent at two, three, and five years, respectively. Pathological examination of the surgical specimen showed downstaging of the tumor in 67 percent of the cases. The degree of tumor down-staging translated into a survival benefit: five-year survival rates after surgery were 79 percent, 42 percent, and 18 percent for postoperative tumor stages 0 (T0N0) and I (N0), stage II (N1), and stage IIIA (N2), respectively. The Southwest Oncology Group, in another phase 2 study, used a regimen of cisplatin and etoposide given concurrently with 45 Gy of radiation, followed by surgical resection. The five-year survival rate among patients with stage IIIA (N2) disease was 35 percent.37 Thus, the combination of chemotherapy and radiotherapy has the potential advantage of enhancing local control while delivering drug doses that can affect distant metastatic spread. Randomized trials of chemotherapy compared with chemoradiotherapy are needed to determine which strategy is better before surgical resection. The targeting of radiotherapy has improved during the past 30 years, with the advent of threedimensional conformal radiation, intensity-modulated radiation, and proton-beam radiation. These techniques permit the delivery of radiation to the tumor with normal tissue spared, and they allow the delivery of radiation concurrently with chemotherapy without undue toxic effects.38,39 At the time

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this patients care was planned, these techniques were not standard, and she was treated with a twodimensional technique. Dr. Lynch: Finally, we need to consider whether surgery is needed after chemotherapy or chemoradiotherapy. In a recent multicenter study, patients with histologically proven N2 disease were randomly assigned to either induction chemoradiotherapy (cisplatin, etoposide, and 45 Gy of radiation) followed by surgery or to chemoradiotherapy alone.40 The initial data indicate that induction chemoradiotherapy followed by surgery was superior in terms of the time to progression and the rate of survival at five years (38 percent vs. 33 percent). However, the trial was small and this difference, though potentially clinically meaningful, was not statistically significant. Both neoadjuvant chemoradiotherapy and chemoradiotherapy alone offer results that are superior to those of surgery alone for clinical N2 disease. In the case under discussion, the decision was made to administer neoadjuvant chemoradiotherapy followed by surgery. Today, this strategy might well still be the treatment of choice, but it would certainly be reasonable to offer treatment with definitive chemoradiotherapy without surgery or to operate initially and follow up with adjuvant chemotherapy. Dr. Temel: Therapy was begun with concurrent chemotherapy and radiation to the tumor region in the right lung. She was treated with 45 Gy of radiation to the right lung and hilus and the right paratracheal region in 25 fractions over a period of six weeks. She also received carboplatin at a dose calculated to result in an area under the concentration time curve of 6.0 mg per milliliter per minute in a three-week cycle and paclitaxel at a dose of 50 mg per square meter of body-surface area each week. The patient had mild nausea, which was well controlled with ondansetron. She had mild esophageal mucositis and alopecia. Restaging studies showed a decrease in the size of the mass in the right upper lobe from 2.5 cm to 2.0 cm and no evidence of metastatic disease. Dr. Wright: After the induction therapy, both pulmonary-function studies and laboratory studies should be performed to make sure that there is a good functional as well as a hematologic recovery, which will enable the patient to tolerate surgery. Because it usually causes hilar fibrosis, induction chemoradiotherapy often increases the difficulty of subsequent surgery. The surgeon treats the original volume of disease even if there has been a complete

Figure 3. Specimen of Resected Lung after Chemoradiotherapy (Hematoxylin and Eosin). There is necrotic tumor containing cholesterol clefts (Panel A) adjacent to desmoplastic inflammation and fibrosis. There is emphysema (Panel B) with free-floating fragments of alveolar walls.

response on radiography, because there can still be microscopic residual disease in either the lymph nodes or lung. Close attention is given to the bronchial stump after induction therapy, and it is covered with a vascularized flap to prevent development of a bronchopleural fistula. The surgeon will do a complete mediastinal lymphadenectomy, both for therapeutic reasons (to remove any residual cancer in the lymph nodes) and for restaging. It is preferable not to perform a right pneumonectomy in patients who have received induction therapy, because of the possibility of higher-than-expected postoperative mortality. Patients whose tumors can be removed either by lobectomy or by left-sided pneumonectomy have a perioperative mortality rate similar to that of patients who have not received preoperative therapy. Twelve weeks after this patients initial mediastinoscopy, I performed a right thoracotomy, with a right upper lobectomy and mediastinal lymphadenectomy. Dr. Mark: The lung resected after radiotherapy

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and chemotherapy contained necrotic tumor; no definitely viable cells remained and there was only a single focus of possibly viable cells. Cholesterol clefts and necrosis were surrounded by inflammation and fibrosis (Fig. 3A). Blood vessels were inflamed with intimal fibrosis, which could have been caused by the cancer itself, by the radiation, or in this case, by both. Free-floating fragments of alveolar walls in the parenchyma apart from the tumor indicated there was emphysema as a consequence of the patients smoking (Fig. 3B). The lymph-node dissection specimens (paratracheal and subcarinal) had no evidence of cancer cells. Dr. Temel: Two months after the operation, the patient received two additional cycles of full-dose carboplatin and paclitaxel. Forty-two months after the completion of therapy, she had no evidence of recurrent disease. Dr. Lynch: This patients case illustrates the need for multidisciplinary management of nonsmallcell lung cancer. Although this patient was doing
references
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well 42 months after the diagnosis, overall survival in this disease is still poor, and novel approaches need to be studied. Future trials in locally advanced nonsmall-cell lung cancer will incorporate new molecular agents. A key issue will be the identification of patients who are likely to benefit from biologic therapy. An example is the recent demonstration that activating mutations in the epidermal growth factor receptor predict responses of non small-cell lung cancers to the tyrosine kinase inhibitor, gefitinib.41 Ultimately, a successful care plan for a patient with stage IIIA nonsmall-cell lung cancer will need to include maximal local treatment with surgery, radiotherapy, or both in addition to systemic treatment that targets residual microscopic tumor.

anatomical diagnosis
Large-cell undifferentiated carcinoma of the lung, stage IIIA (T1N2M0).

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