SURGERY SECTION - THE JAPANESE EXPERIENCE WITH LIMITED SURGICAL RESECTION IN SCREENING DETECTED TUMORS by Junji Yoshido, MD, PhD

SLIDES & TRANSCRIPTS
Tuesday, June 19

SURGERY SECTION - THE JAPANESE EXPERIENCE WITH LIMITED SURGICAL RESECTION IN SCREENING DETECTED TUMORS

Junji Yoshida, MD, Ph.D.

Slide 1: Introduction

DR. YOSHIDA: Thank you very much. Greetings from the city of Kashiwa, and the National Cancer Center Hospital East. Our institute is located about 20 miles or 30 kilometers northeast of Tokyo, forming one point of a triangle with the National Cancer Center in Tokyo, where the next speaker, Dr. Asamura works, and the Narita Airport. I would also like to thank Dr. Saxman and Dr. Altorki for offering this opportunity. Today, I will be reviewing the interim results of an ongoing small lung carcinoma limited resection clinical trial at our institute, with a brief discussion of the trial background. Our previous study on primary peripheral lung cancers less than 1 centimeter in diameter, with emphasis on the seeming prevalence of the invasive nature of these small tumors. I will also describe Dr. Noguchi's classification for small lung adenocarcinomas, which Dr. Shimosato referred to earlier. As a delegate from Japan, I will also review Dr. Tsubota's extended segmentectomy study, but as time is limited, I will summarize the study in my handout, which doesn't seem to be delivered to you at this time. But I am sure someone will deliver them to you later on.

Slide 2: Primary Peripheral Lung Carcinoma

In 1998, we reported a retrospective review of peripheral lung cancers smaller than 1 centimeter in diameter. Out of 16 small tumors, 7 displayed an invasive nature. We concluded tumor size alone is another positive indicator for limited resection, and Dr. Asamura will report the similar cohort of patients at the Mayo Clinic later. Let's look at the National Cancer Center data set briefly.

Slide 3: Patients

Over 12 years, 1,192 lung cancer patients underwent surgical resection at our institute; 16 of them, 1.3%, had no nodal involvement or distant metastasis clinically had untreated tumors that were peripherally located, and were 1 centimeter or smaller in maximum dimension in the resected specimens.We did a histopathological review based on the WHO criteria (3rd edition).

Slide 4: Small Cell Carcinoma

One of the 16 was a small cell carcinoma shown here. But it had mistakenly been diagnosed before surgery as a squamous cell carcinoma. We believe patients with the small cell carcinoma are not good candidates for limited resection, due to its invasive nature, and metastatic nature. Indeed, the carcinoma had lymphatic vessel invasion, and sentinel node metastasis. He underwent additional chemotherapy and radiotherapy and survived more than six years.

Slide 5: Adenocarcinoma

One well differentiated adenocarcinoma showed lymphatic vessel invasion, venous invasion, and subcarinal nodal metastasis. The patient developed malignant pleural effusion and bone metastasis four months after the resection and died after 21 months. No other patients in our series died of lung cancer.

Slide 6: Vessel Invasion

When we look at vessel invasion, there were three tumors with lymphatic invasion. I described in previous slides the small cell carcinoma, and the well differentiated adenocarcinoma carcinoma with subcarinal node metastasis. This adenocarcinoma carcinoma showed venous invasion. Another well differentiated adenocarcinoma without nodal involvement showed lymphatic invasion.

Slide 7: Histologic Typing

. We need to review Dr. Noguchi's article before going further. But Dr. Shimosato referred to this in the previous session, so let's do it very briefly. Dr. Noguchi classified lung adenocarcinomas more than 2 centimeters in diameter into the six categories as shown here: localized bronchoalveolar carcinoma as LBAC; LBAC with foci of collapse of alveolar structure; LBAC with foci of active fibroblastic proliferation; and three other subtypes.

Slide 8: Survival Curves

In Noguchi's study following lobectomy and lymph node dissection, patients with Type A and B tumors survived five years or more without recurrence, but the Type C tumor patient survival rate was significantly less.

Slide 9: Conclusion

Based on these findings and histologic characteristics and outcomes, Noguchi concluded that Type A and B tumors were in situ peripheral carcinomas, whereas Type C tumors were an advanced stage of Types A and B.

Slide 10: Study

Now back to our study. Six of the 12 adenocarcinomas in our series were classified as Noguchi's Type C. One of them was a tumor with subcarinal nodal metastasis. Another tumor showed lymphatic vessel invasion.

Slide 11: Limited Resection

So 7 of the 16 tumors, even though they were smaller than 1 centimeter in diameter, showed an invasive nature. It remains unclear whether the invasive nature would end in a favorable result following limited resection, but we must be aware that even though they are small tumors, limited resection might leave cancer cells in the patient. It is evident that tumor size alone is not a positive indicator for limited resection in lung cancer patients. The lung cancer study group performed the only prospective randomized trial on limited resection versus lobectomy as Dr. Rusch presented. They concluded lobectomy was the proper surgical treatment, because limited resection resulted in worse outcomes. So the question arises, are there any indicators for limited resection? Or is it always contraindicated? Although Dr. Noguchi's conclusion was speculative, Japanese researchers were encouraged to find evidence that Type A and B tumors are in situ carcinomas. If they are truly in situ carcinomas, limited resection is the management of choice for Types A and B. As a result, at our institute, we are doing a prospective clinical trial of limited resection for probable in situ adenocarcinoma in the lung periphery. Here is the study design and interim results.

Slide 12: Trial Objectives

The objective is to confirm limited resection efficacy in patients with Noguchi's Type A and B tumors. Noguchi's classification is confirmed by intraoperative frozen section examination.

Slide 13: Eligibility Criteria

What are the eligibility criteria? Enrollment requires patients with a tumor smaller than 2 centimeters in diameter, diagnosed with suspected clinical T1 and N0 carcinoma, in lung periphery based on a CT scan, they have to have a high resolution CT scan suggestive of a Type A or B tumor. The findings include ground glass opacity, lack of pleural indentation and vascular convergence. Written informed consent is obtained from each participant.

Slide 14: Exclusion Criteria

Patients with a malignancy history within the past five years, and those unfit of lobectomy and systematic lymph node dissection were excluded. The primary endpoint is five year disease-free survival.

Slide 15: Treatment Sequence

This is the treatment flow chart. A wedge or segmental resection is performed, and the pathologist examines the specimen immediately by frozen section. If the tumor is confirmed Type A or B, and the margin is larger than 1 centimeter, the patient is closed up and followed on an outpatient basis. If the margin is not sufficient, additional margins is resected. If the tumor is a primary malignancy, but not Types A or B, lobectomy and lymph node dissection are performed. As you can imagine, it is very difficult to perform Noguchi's classification from a simple frozen section.

Slide 16: Frozen Section Diagnosis

We tried EVG (Elastica van Gieson) staining the section, and found it is a great aid in distinguishing Type A and B from Type C tumors. The EVG staining reveals whether the elastic fibers in the alveolar wall are intact or not. If the elastic fibers are destroyed by tumor cells, the tumor is a Type C.

Slide 17: Adenocarcinoma

This slide is similar to the one based on Noguchi's work. The data set is adenocarcinomas 3 centimeters or smaller in diameter, resected at our institute from 1987 through 1992. Patients without stromal destruction, as shown by EVG staining survived five years without recurrence. We believe EVG staining is a powerful adjunct in the frozen section evaluation.

Slide 18: Interim Results

This prospective protocol study started in August 1998, and 39 patients have been enrolled as of May 2001. There are 18 men and 21 women. At admittance, age ranged from 40 to 74, with a median age of 64 years. Tumor sizes ranged from 5 millimeters to 2 centimeters, with an average of 1.2 centimeters. Twenty-four patients underwent wedge resection, 3 segmentectomy, 12 lobectomy and lymph node dissection; 17 procedures were performed only by a three port access.

Slide 19: Interim Results

There was one Type A tumor, 16 Type B tumors, 13 Type C tumors, 4 atypical adenomatous hyperplasias, 4 fibrosis, and 1 granuloma. In one case, the initial frozen section diagnosis of Type B was revised to Type C. As a prospective pathologic study where we didn't do any further treatment. No morbidity or mortality has occurred. So far, there has been no recurrence. This is an ongoing study, however the interim results appear encouraging. With a bit less than three years into this study, it is still early for strong conclusions, but Dr. Noguchi's criteria appear useful, and his conclusions, valid.

Slide 20: Summary 1

Summarizing my presentation, peripheral lung cancers can be invasive, even if they are smaller than 1 centimeter. So tumor size alone is not an indication for a limited resection in lung cancer patients.

Slide 21: Summary 2

Type A and B tumors by Dr. Noguchi's classification may be in situ carcinomas. A limited resection is likely to have a positive outcome. EVG staining is a powerful adjunct in the frozen section evaluation for Noguchi's subtypes. Thank you very much.