1. How well do pathologists agree on cytologic and/or histologic definitions of "definite," "probable" and "possible" cases of lung cancer and "definite" non-case of it.
2. How concordant are the classifications in practice?
3. What justifies the definitions? Notably, what is known about the prospective course conditional on each category and also on the size of the tumor within the category?

Summary

The advent of CT screening for early detection of lung cancer presents an ideal opportunity to address important questions about the pathology of lung cancer. This comes at a time when the World Health Organization (WHO)/ International Association for the Study of Lung Cancer (IASLC) has just completed its new proposal for histologic typing of lung tumors. With this classification two major changes have taken place in lesions that are likely to be encountered in surgical specimens removed from patients who are found to have growing nodules by CT screening. These include atypical adenomatous hyperplasia (AAH) a newly added preinvasive lesion and a new definition of bronchioloalveolar carcinoma (BAC) that requires the tumor to have a purely lepidic pattern without invasive growth. There is little clinical data based on carefully characterized AAH and BAC (according to the new definition) that could potentially be obtained in conjunction with large scale CT screening studies. In addition, there is little data regarding other histologic types of lung cancers as they develop in their early phases that could potentially be obtained by carefull correlation of serial CT scans with surgically resected tumors. For this reason it will be very important to have a well thought oyt pathology component to any protocol for early detection of lung cancer by CT screening.

Overdiagnosis

Overdiagnosis (This is a term that should be changed - easily misleading): "Detection of carcinomas by screening that do not interfere with the life or outcome of the patient." Overdiagnosis is essentially a concept related the screening process and is not the same as a false positive diagnosis of lung cancer by pathologists which is highly unusual. Concordance in the diagnosis of cancer - cytologically and histologically determined is extremely high.

How well do pathologists agree on cytologic and/or histologic definitions of: definite, probable, and possible cases of lung cancer and definitely not lung cancer?

The diagnosis of lung cancer is made with high degree of accuracy by most practicing cytologists and surgical pathologists.

Cytology

The great majority of detected carcinomas will be easily recognized as one of the four major types of lung carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma (SCLC). The new WHO classification is summarized in Table 1.

Histology

The separation of SCLC from non-small cell carcinoma (NSCLC) is the major distinction made in histologic classification of lung cancer since SCLC tends to be widely disseminated at initial diagnosis and is responsive to chemotherapy. (1) In 95% of cases this distinction can be made reliably. In approximately 5% of cases there are problems in interobserver agreement even among expert lung cancer pathologists. (2;3) These problems result from a variety of issues: the continuum of cell morphology from SCLC to large cell carcinoma, small specimens, extensive necrosis or crush artifact, thick sectioning or poor quality staining.

After the separation of SCLC from NSCLC the next most clinically relevant distinction among the various histologic subtypes of NSCLC is the separation of bronchioloalveolar carcinoma from other adenocarcinomas. (1;4) Noguchi, et at demonstrated the absence of lymph node metastases and 100% 5 and 10 year survival in patients with small adenocarcinomas less than 2 cm in size that showed a purely lepidic grouth pattern with or without areas of alveolar collapse. Lymph node metastases and deaths occurred only in patients whose adenocarcinomas showed histologic evidence of invasion. Study of the small CT detected specimens will allow these observations to be amplified and extended. >/p>

Cytology

Preinvasive Lesions: The new WHO/IASLC classification includes three preinvasive lesions: squamous dysplasia and carcinoma in situ, atypical adenomatous hyperplasia (AAH), and diffuse idiopathic neuroendoctrine cell hyperplasia (DIPNECH).(1) Squamous dysplasia and CIS are thought to be precursors to squamous cell carcinoma. AAH is considered a presursor for adenocarcinoma and DIPNECH is very rare condition, which may be associated with the development of carcinoid tumors.

Another potential problem in the differential diagnosis of BAC is the separation from atypical adenomatous hyperplasia (AAH). To help the study pathologist with these early lesions, a system of consultation on difficult ases should be set up. The members of this sub-committee (W.T., D.C., M.N. and A.G.) have agreed to serve as consultants in order to produce a consensus diagnosis on these cases.

Specimens showing squamous preinvasive lesions are uncommonly encountered in the practice of surgical pathology. (1)For this reason, few pathologists have experience in classifying these lesions. In addition, there is continuum of morphologic abnormalities with considerable overlap between the various lesion. In addition, bronchoscopic specimens may be difficult to interpret due to small size, poor sampling or orientation problems due to tangential sectioning. These problems contribute to difficulties with reproducibility.

AAH is a bornchiloalveolar proliferation that falls short of non-mucinous bronchioloalveolar carcinoma. (1;5-7) AAH is usually less than 0.5 cm in size. Larger lesions may be difficult to separate from adenocarcinoma. (6) It is encountered most often as incidental histologic finding in lung specimens removed for other reasons, most often in 5-21% of lung carcinoma resection specimens. (7-10) Histologically AAH is a nodular lesion, consisting of monotonous, slightly atypical cuboidal to low columnar epithelial cells proliferating along the alveolar walls. Grading of AAH is discouraged and AAH should not be diagnosed in continuity with frankly malignant carcinomas. There is little documentation taht patients without carcinoma that are found to have AAH will progress to develop adenocarcinoma. For this reason such patients should be managed conservatively careful follow-up but without surgical invervention, chemotherapy or radiation.

How concordant are the classifications in practice?

Not all pathologists use the same classifications. The new 1999 WHO/IASLC classification was just published, but it is not widely known and will take some time for pathologists to begin to utilize it.

The major problems in lung cancer histologic classification are summarized above.

What justifies the definitions? Notably, what is known about the prospective course conditional on each category and also on the size of the tumor within the category?

As outlined above the major clinical and survival differences are found between SCLC and NSCLC. After this distinction the most impoartant separation is between BAC and other adenocarcinomas.

Gross Processing of Lung Carcinomas, Especially Small Size (<2 cm)

The early detection of lung carcinoma by spiral CT screening provides an impoartant opportunity for radiologic pathologic correlation. This is particularly important since little is known about the progression of adenocarcinomas from a purely lepidic growth pattern to invasive adenocarcinoma. This is the most important separation among the various types of NSCLC, allowing for identification of potentially curable BAC. However, for this diagnosis to be established it requires through histologic sampling of the lesion. For small lesions 2 cm or less the entire tumor should be processed. For larger lesions one section per centimeter should be sampled and if the initial sections show a purely lepidic growth pattern, additional sections should be taken to exclude an invasive component.

For tumors removed under a protocol for spiral CT, the tumors should be sampled and mapped carefully allowing for reconstruction of the tumor patterns in comparison with 3 dimensional radiographic images.

Consideration should be given to formatting protocols similar to those used for mapping of whole prostatectomy specimens for prostate cancer.

Any protocol for CT screening should have a mandatory tissue registry to be kept at the primary institution where the pathologic materials will be kept with the surgical resection specimens. Funding mechanisms should be in place for obtaining protocol based material from those specimens examined in pathology departments other than the primary institution.

Table 1

References

1. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with L.H. Sobin and pathologists from 14 Countries. Histological Typing of Lung and Pleural Tumors, Third Edition ed. Berlin: Springer, 1999.
2. Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R. Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases. Hum. Pathol. 1985; 16:569-79.
3. Vollmer RT, Ogden L, Crissman JD. Separation of small-cell from non-small-cell lung cancer. The Southeastern Cancer Study Group pathologists' experience. Arch.Pathol.Lab.Med. 1984; 108: 792-4.
4. Noguchi M, Morikawa A, Kawasaki M, Matsuno Y, Yamada T, Hirohashi S et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 1995; 75:2844-52.
5. Noguchi M, Shimosato Y. The development and progression of adenocarcinoma of the lung. Cancer Treat.Res. 1995;72:131-42.
6. Kitamura H, Kameda Y, Ito T, Hayashi H. Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma [In Process Citation]. Am.J.Clin.Pathol. 1999; 111:610-22.
7. Miller RR. Bronchioloalveolar cell adenomas. Am J Surg Pathol. 1990; 14:904-12.
8. Weng SY, Tsuchiya E, Kasuga T, Sugano H. Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer. Virchows Arch.A.Pathol Anat.Histopathol. 1992; 420:463-71
9. Carey FA, Wallace WA, Fergusson RJ, Kerr KM, Lamb D. Alveolar atypical hyperplasia in association with primary pulmonary adenocarcinoma: a clinicopathological study of 10 cases. Thorax 1992; 47:1041-3.
10. Nakanishi K. alveolar epithelial hyperplasia and adenocarcinoma of the lung. Arch.Pathol.Lab.Med. 1990; 114:363-8.