at the University of Wales
Swansea
Link to slide seminar diagnoses and discussion
William D. Travis, M.D. Armed Forces Institute of Pathology, Washington, D.C.
Tumor classification systems need to be updated periodically as progress is made in understanding of the clinical, epidemiological, histogenetic and molecular aspects of various tumors. It has been 30 years since the first classification of lung tumors was proposed by the World Health Organization (WHO)1 and 17 years since the WHO classification was updated in 1981.2 During the subsequent period substantial progress has been made in our understanding of lung tumors. In 1988, a major change in 1981 WHO proposal for subclassification of small cell carcinoma (SCLC) was suggested by the pathology panel of the International Association for the Study of Lung Cancer (IASLC).3 In 1994 the WHO adopted the IASLC pathology panel to comprise the core membership of the WHO committee to develop a new revised classification of lung and pleural tumors. In addition to the IASLC pathology panel members, an extended panel of reviewers were asked to serve on the WHO committee to help develop this new classification (Table 1). This is a brief preliminary overview of the new classification proposed by the WHO pathology panel (Table 2).4 The formal blue book "Histological Classification of Lung and Pleural Tumors" with more detailed discussion and illustrations should be published in 1998.4 This classification is also adopted by the IASLC. Due to the work by the IASLC pathology panel and the support contributed by the IASLC to this project, we refer to it as the "WHO/IASLC Histological Classification of Lung and Pleural Tumors" (Table 2).
Tumor classification systems provide the foundation for tumor diagnosis and patient therapy.5 Therefore they provide a critical basis for epidemiologic and clinical studies. In developing this classification we tried to adhere to the principles of reproducibility, clinical significance, and simplicity. We also tried to minimize the number of unclassifiable lesions.2 Whenever possible, changes in classification were based on newly available published data. However, in some cases, such data was not available and decisions had to be made based on the collective experience and wisdom of the panel members. In general, certain time-honored terms were retained unless new concepts had emerged necessitating a change.
In addition to the categories of squamous dysplasia and carcinoma in situ, two additional lesions were added to the category of preinvasive lesions: atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.
Many publications on the subject of atypical adenomatous hyperplasia suggest that it is a precursor to adenocarcinoma.6-10 Multiple terms have been used for this lesion including alveolar cell hyperplasia, atypical alveolar hyperplasia, bronchioloalveolar cell adenoma, alveolar atypical hyperplasia and atypical alveolar cuboidal cell hyperplasia. However, most studies have examined these lesions as incidental findings in lung specimens resected for lung cancer. Therefore the opportunity to investigate the biology of this lesion as a precursor to carcinoma has been limited. The concept that AAH is a precursor to invasive carcinoma is largely an assumption based on the concurrent finding of these lesions in the lung parenchyma adjacent to lung carcinomas, primarily adenocarcinomas. In addition, some have attempted to identify AAH within the same mass of carcinoma as it merges with an adenocarcinoma. Only rare cases have been documented where AAH was identified and there was subsequent progression to invasive carcinoma. Extensive multicentric AAH appears to be a potential setting for progression to occur,9 although a recent study suggests that the prognosis of lung carcinoma is not affected by the presence of coexisting AAH.6
Diffuse idiopathic neuroendocrine cell hyperplasia is a very rare lesion that can be associated with multiple carcinoid tumors.11 Neuroendocrine cell hyperplasia occurs most commonly as a reactive hyperplasia in the setting of airway fibrosis and/or inflammation.12,13 Up to two-thirds of patients with peripheral carcinoid tumors may have neuroendocrine cell hyperplasia in the adjacent bronchiolar epithelium.14 A subset of these patients will have airway fibrosis and a smaller number may have obstructive pulmonary function. In 1992, Aguayo et al identified a small group of patients who presented with interstitial lung disease characterized by obstructive pulmonary function and histologic evidence of bronchiolar fibrosis associated with neuroendocrine cell hyperplasia.11 Some of these patients also had multiple tumorlets and some had carcinoid tumors.11 Since neuroendocrine cells produce bombesin and other mediators that can act as a fibroblast growth factor, it was proposed that the neuroendocrine cells are the cause of the fibrosis rather than a secondary reaction to the airway fibrosis. These observations suggest that diffuse idiopathic neuroendocrine cell hyperplasia is a condition in which neuroendocrine cell hyperplasia may progress to carcinoid tumors.
Since adenocarcinoma is now the predominant histologic subtype in many countries,15,16 issues relating to subclassification of adenocarcinoma are very important.
Adenocarcinoma subclassification was one of the most difficult problems faced in revising the classification of lung carcinomas. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity.17 In fact mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar and solid adenocarcinoma with mucin formation.
Another problem has been the imprecise application of criteria for diagnosis of bronchioloalveolar carcinoma. Since it has been shown that patients with solitary, non-invasive bronchioloalveolar carcinomas measuring less than 2.0 cm, can be cured,18 we have restricted the definition of this tumor to only non-invasive tumors. If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, it would be classified as an adenocarcinoma, mixed subtype with predominant bronchioloalveolar pattern and either a focal acinar, solid or papillary pattern depending on which pattern is seen in the invasive component. Criteria for diagnosis of bronchioloalveolar carcinoma have varied widely in the past and the tumor described above would have been labeled as bronchioloalveolar carcinoma in many series. This definition is much more restrictive than previously used by many pathologists.
Several variants of adenocarcinoma are recognized in the new classification including well-differentiated fetal adenocarcinoma,19-21 mucinous ("colloid") adenocarcinoma,22 mucinous cystadenocarcinoma,23 signet ring adenocarcinoma,24 and clear cell adenocarcinoma.25
Since 1981 there has been substantial evolution of concepts of NE lung tumor classification. These issues are discussed in more detail in Chapter B-3. Large cell neuroendocrine carcinoma (LCNEC) is now recognized as a histologically high-grade non-small cell carcinoma.26 It has a very poor prognosis similar to that of small cell carcinoma (SCLC). Atypical carcinoid is recognized as an intermediate grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and the high grade SCLC and LCNEC.27 In addition, it has become well recognized that neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10-20% of common non-small cell lung carcinomas (NSCLC) that do not have any neuroendocrine morphology.28-31 These tumors are not formally recognized within the WHO/IASLC classification scheme since the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.
In addition to the general category of large cell carcinoma, several uncommon variants are recognized including LCNEC,26 basaloid carcinoma,32,33 lymphoepithelioma-like carcinoma,34,35 clear cell carcinoma,25 and large cell carcinoma with rhabdoid phenotype.36 Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma and rarely adenocarcinomas may have a basaloid pattern. However, in tumors without either of these features, they are regarded as a variant of large cell carcinoma. 32,33
Although immunohistochemical, ultrastructural and molecular studies can all be helpful in analyzing these tumors, we have proposed a classification scheme based solely on light microscopy.
This is a very difficult group of tumors to classify for several reasons. First they are rare tumors and few pathologists have the opportunity to study very many cases. Spindle and giant cell carcinomas and carcinosarcomas comprise only 0.4% and 0.1% of all lung malignancies respectively.15 In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation.37,38 Biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid or sarcomatous elements based on clinical and molecular data.21,39,40
It is rare to encounter a pure spindle or giant cell carcinoma.37 More commonly these patterns are mixed with other histologic subtypes of lung carcinoma and frequently the spindle cell and giant cell pattern are seen together. Carcinosarcoma is arbitrarily defined as a biphasic tumor with carcinomatous and sarcomatous components only if the latter demonstrate heterologous elements such as malignant bone, cartilage, or skeletal muscle. Pleomorphic carcinoma is diagnosed in a biphasic tumor showing carcinomatous as well as spindle and/or giant cell components even if epithelial differentiation cannot be demonstrated in the spindle cell component by immunohistochemistry or electron microscopy.
While immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification of lung tumors, we have attempted to establish a classification that is simple, practical and able to be used even in surgical pathology laboratories where these techniques may not be available.
Nevertheless, immunohistochemistry and/or electron microscopy are required for definitive diagnosis of large cell neuroendocrine carcinoma and malignant mesothelioma. The intent of our emphasis on light microscopy is not meant to discourage the use of these techniques. The distinctive immunostaining characteristics of certain tumors can be very useful such as HMB-45 positivity in clear cell tumors and lymphangioleiomyomatosis and EMA staining in sclerosing hemangiomas.
The advent of molecular biology has also allowed a new depth of insight into the understanding of many lung tumors. It has allowed molecular demonstration of the neoplastic nature of certain lesions such as alveolar adenoma,41 chondroid hamartoma,42,43 and inflammatory pseudotumors (inflammatory myofibroblastic tumor).44 It has also provided insights into genetic abnormalities that have contributed to histologic classification of lung tumors and preinvasive lesions.40,45-48
Similar to our comments on immunohistochemistry and electron microscopy, our emphasis on light microscopic criteria for diagnosis of lung tumors is not intended to discourage the use of molecular techniques as diagnostic aids and research tools.
Most lung tumors can be classified by light microscopic criteria. Although special techniques are necessary to classify a few tumors the advantage of the emphasis on light microscopic criteria for most tumors in this classification system is the potential for widespread and worldwide application.
Hopefully future studies will clarify some of the difficult problems in lung tumor classification, especially for preinvasive lesions, adenocarcinoma subtyping, large cell neuroendocrine carcinoma and carcinomas with pleomorphic, sarcomatoid or sarcomatous elements.
Chair
William D. Travis, M.D.* Washington, D.C.
Coordinators
Thomas V. Colby, M.D.* Scottsdale, AZ
Bryan Corrin MD, MRCPath* London, ENGLAND
Yukio Shimosato, M.D.* Tokyo, Japan
Core Panel Members
Emilio Alvarez Fernandez, M.D.* Madrid, SPAIN
Professor E. Brambilla, M.D.* Grenoble, FRANCE
Samuel P. Hammar,M.D.* Bremerton, WA, USA
Dr. Philip S.Hasleton* Manchester, ENGLAND
Fred R. Hirsch, M.D., Ph.D.* Copenhagen, DENMARK
Bruce Mackay, M.D., Ph.D.* Houston, TX, USA
Helmut Popper, M.D.* Graz, AUSTRIA
Richard H. Steele, MB, ChB, PhD, FRCPA, FAFOM* Woolloongabba, AUSTRALIA
Contribution on Preinvasive lesions by:
Wilbur Franklin, M.D. * Denver, CO, USA; Chair, International Association for the Study of Lung Cancer/National Cancer Institute SPORE Pathology Working Group for Classification of
Preinvasive Epithelial Abnormalities of Lung
Extended Panel of Reviewers
Seena Aisner, M.D.* Newark, NJ, USA
Andrew Churg, M.D. Vancouver, British Columbia
CANADA
Louis P. Dehner, M.D. St. Louis, MO, USA
Adi F. Gazdar, M.D.* Dallas, TX, USA
Douglas W. Henderson, MBBS, MRCPath, FRCPA Bedford Park, SOUTH AUSTRALIA
N.A. Jambhekar, M.D. Parel Bombay, INDIA
Michael N. Koss, M.D. Los Angeles, CA, USA
Prof. Dr. Klaus-Michael Muller Bochum, GERMANY
Prof. Nicolai Petrovitchev Moscow, RUSSIA
Dr. Paulo SaldivaSao Paulo, BRAZIL
Mary Sheppard, BSc, MD, MRCPath* London, ENGLAND
Dr. Sjoerd Sc. Wagenaar Amsterdam, THE NETHERLANDS
Dr. Li Wei-hua Beijing, P.R. CHINA
* IASLC Pathology Panel Members
1.3.1 Squamous cell carcinoma
1.3.2 Small cell carcinoma
1.3.3 Adenocarcinoma
1.3.4. Large cell carcinoma
Variants
1.3.5. Adenosquamous carcinoma
1.3.6.Carcinomas
with pleomorphic, sarcomatoid or sarcomatous elements
1.3.7 Carcinoid tumor
1.3.8 Carcinomas of salivary gland type
1.3.9 Unclassified carcinoma
3.1 Benign
3.2 Malignant
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