Document ZnOEXY9KdO6gGmj5neJX45aX0

Clinical Commentary EnApnmental Associations and Histopathologic Patterns of Carcinoma of the Lui^: The Challenge and Dilemma in Epidemiologic Studies Introduction i\s early as 1924, Marchesani (1) distin guished 4 types of lung cancer, and this classification was so comprehensive that it remained substantially unchanged for al most 25 yr (2). After this time, new tumor types that did not fit within this simple clas sification were described by pathologists, and, by 1967, the World Health Organiza tion (WHO) recognized 13 histological types of carcinoma of the lung (2). Kreyberg (3). in 1962, proposed classification of lung cancer into 2 groups determined large ly by epidemiologic characteristics of the different cell types. The Group I tumors were squamous cell and small cell carcino mas, usually located centrally in the respira tory tract. The Group II tumors were usual ly peripheral in location and consisted of adenocarcinomas, bronchioloalveolar car cinomas, and large cell carcinomas. At that time, there was a marked difference in smoking habits between the sexes, and GroiaKonsisted of those cell types with a male^^Hominance, whereas Group 11 had a more or less equal sex distribution. In 1971, Kreyberg (4) suggested that the Group I tumors were related to exposure to inhaled carcinogens, e.g., cigarette smoke, radon daughters, and nickel. In addition to the recently revised WHO classification of lung tumors (5), there are 5 classifications in current use: (/) The Sys tematized Nomenclature of Medicine (SNOMED) (6), (2) The International Clas sification of Diseases (ICD-O) (7), (3) The Working Party for Therapy of Lung Can cer (WP-L) (8), (4) The Manual of Tumor Nomenclature (MOTNAQ (9), and (3) The Veterans Administration Lung Cancer Che motherapy Study Group (VALCCSG) (10). The chronological development of these classification systems is outlined in figure 1. The ICD-O, SNOMED, and WHO histo pathologic classifications of lung cancer have similar categories of cell types (table 1). Approximately 90% of all lung carcino mas are included in 4 main histopathologic categories: squamous cell carcinoma, small ceil carcinoma, adenocarcinoma, and large cell carcinoma (16-18). It has been suggested that lung cancer is not a single disease, and the possibility ex ists th^feere are several well-defined histopathc^PI types of lung cancer that tend to have unique characteristics with specific eti ologies (3,13,16,19-21). Numerous studies have been conducted to examine possible SUMMARY An updata of histopathologic classification schemes is provided for carcinoma of the lung and factors that influence proportional distributions of cell types, i.e., sources and prep arations of tissue specimens, observer variability, and use of secondary sources of information. Consideration is given to the natural history and to current knowledge of the demographic char acteristics of cell types of carcinoma of the lung. A review of studies reporting histopethologic associations with environmental exposures suggests that no single type of carcinoma of the lung is specifically associated with exposure to tobacco smoke, arsenic, or beryllium. Furthermore, studies concerned with exposure to asbestos, chloroethers, chromates, nickel, vinyl chloride, end radioactivity lack sufficient information to conclude definitively that only one specific lung cancer cell type Is associated with these exposures. In conclusion, an exclusive association of a single cell type of carcinoma of the lung with exposure to the physical or chemical agents re viewed has not been demonstrated. AM rev respia pis 1M3; 12a:ies-sos causal associations of environmental expo sures, i.e., tobacco smoke, minerals, chemi cals, and radioactive substances, with specific lung cancer cell types. Some investigators have concluded that specific chemical or physical exposures result in a greater pro portion of one or more histopathologic types of carcinoma of the lung as well as an overall increased risk of lung cancer. This report discusses some of the epidemiologic characteristics of the 4 major cell types of lung cancer, factors that may affect histo pathologic diagnoses, and conclusions con cerning proportional distributions of the cell types. Several studies in which lung cancer cell type patterns have been asso ciated with selected environmental ex posures are reviewed.1 It is intended that this review will be useful in the planning, conduct, and interpretation of epidem iologic studies dealing with the histo pathologic types of lung cancer. Natural History, Demographic Characteristics A review of the biological concepts of carci nogenesis, morphogenesis, md multicen tricity of lung cancer is beyond the scope of this report: however, pertinent references have been included in the bibliography (22-29). The natural history of lung cancer is poorly defined because most studies are limited by the late stage of development at which the majority of tumors are diagnosed and by the changes in tumor histopatho logic aspects resulting from radiation and chemotherapy. Lung cancers include a wide1 1 Terms, such as "anaplastic" and "undifferen tiated," which were used in some early publica tions but are not used in curreni nomenclature have been omitted from this text. spectrum of malignant neoplasms that may be endodcrmal, mesodermal, or possibly neuroectodermal in derivation (30), and many are a mixture of cell types. Clinically, tumor behavior may be generalized on the basis of its cell type and degree of differen tiation (31). However, it is not known whether a specific tumor will behave biolog ically in accord with its most differentiated or undifferentiated areas. Several researchers have proposed differ ent theories describing the development of lung cancer. Seydel and associates (32) pro posed that during the early development of lung cancer there is a gradual transition from the normal bronchial respiratory cili ated epithelial lining to squamous metapla sia to carcinoma-in-situ and, finally, to lo cally invasive carcinoma, all over a period of 5 to 10 yr. Auerbach and coworkers (33) believe the pathogenesis of bronchogenic carcinoma is a continuum beginning with a few mildly atypical mucosal cells and prog ressing gradually to a localized area of se verely atypical mucosal cells and, finally, to invasive carcinoma. They also suggest that the progressive mucosal atypia occurs over a period of many years and that carcinomain-situ remains as such for several years before invasion occurs. Furthermore, they indicate that at each step the process is po tentially reversible. Auerbach (34) believes that this sequence of progressive mucosal atypia leading to invasive lung cancer ap pears to be the same, regardless of the cell type of the carcinoma. Yesncr (35) was one of the first to pro pose a unified concept of the histopatho logic criteria of lung carcinomas and, over the past 20 yr, he has continued to refine this concept. In his studies of heterogene ous carcinomas, he describes a transition from small cell to large cell carcinomas and 195 SNOYSMTEENMCLAATTIUZERED Or PATMOLOCT (SNOP) 0965)" manual of tumor nomenclature and COP INC (fOTNAC) <US>la manual of tumor NOMENCLATURE and CODING (MOTNACi * 0966),' EICHtH REVISION OF INTERNATIONAL classification or DISEASES OCO-8) 0967) NltfTH REVISION OF INTERNATIONAL CLASSIFICATION OF DISEASES (ICD-9) (revU*d;l?75. pvOlith*d:l977)1! HISTOLOGICAL TYPING OteFnLtUaNtCiveTU.MO(WUNROS), 0958) HISTOLOGICAL Typing OF LUNC TUMOURS (WHO) 09670 VETERANS * ADMIN ISTRATION LUNC cancer chemother apy STUOY GROUP (VALCCSG) 09650* WORKING PARTY FOR THERAPY OF LUNC CANCER (WP-L) (1972,diicOn* tirtuad 1976) OF MEDICINE (SNOMEO) (97fe`77) INTERNATIONAL CLASSIFICATION OF DISEASES FOR ONCOLOfiV (ICQ-O) 03760 \ SNOYSMTEENMCLAATTIUZERED Qf MEDICINE (SNOMEO) 0973)* HISTOLOGICAL TTPlNC OF LUNG TUMOURS (WHO) 0982)5 Fig. 1. Chronology and relationships among histologic classifications of carcinoma of the lung. The Man ual of Tumor Nomenclature (MOTNAC) was first compiled end published in 1951 and revised in 1966 with the addition of the histologic code from Sections 8 and 9 of The Systematized Nomenclature of Pathology (SHOP, 1965) and the topographic code from Sections 140-99 in the Eighth Revision of the International Classification of Diseases (ICD-8,1967). The SNOP was the first histologic code designed for computerization and used a 4-field organizational system, i.e., topography, morphology, etiology, and function. The SNOP wes restructured and expanded into The Systematized Nomenclature of Medicine (SNOMED, 1976-77) with the addition of 2 fields: disease and procedures. The SNOMED was revised in 1979, and the morphology section dealing with neoplasms is identical to The International Classification of Diseases for Oncology (ICD-0,1976), except that the ICD-0 provides for more subtypes. The ICD-0 repre sents an extension of Chapter 11 (Neoplasms) of The Ninth Revision of the International Classification ot Diseases (ICD-9,1975,1977) and permits coding by topography, histology (morphology), and behavior as well as histologic grading and differentiation. Particular effort was made tn developing the ICD-0 to use compatible terms for neoplasms listed In The International Histologic Classification of Tumours series also published by WHO. The Histological Typing of Lung Tumours (tentative version, 1958; pub lished, 1967) is the first of a series of "blue books" published by the World Health Organization (WHO) entitled The International Histological Classification of Tumours. The first revision ot the WHO classifica tion of lung tumors was published In 1982. The Veterans' Administration Lung Cancer Chemotherapy Study Group (VALCCSG) modified the WHO tentative (1958) histological classification in 1965. The Patho logy Panel of the International Workshop tor Therapy ot Lung Cancer devised a classification in 1972, The Working Party for Therapy of Lung Cancer (WP-L), which was compatible both with the WHO Histologi cal Typing of Lung Tumours (1967) and the VALCCSG classifications. The WP-L was discontinued in 1976 because chemotherapy was determined to be of little value (13) and the Lung Cancer Study Group (LCSG) replaced it in 1977. The LCSG uses a modified and condensed version of the WP-L from large cell carcinoma to squamous cell carcinoma and adenocarcinoma. The maturational transition from small cell carcino ma to squamous and adenocarcinoma, as described by Yesner (figure 2), is at variance with the theory that small ceil carcinomas are derived from neuroectoderm. Large cell carcinoma, proposed by Yesner as a transi tional stage in the maturation process, has been described as an ill-defined or "waste basket" category (36-39). Most important ly, Yesner (40) proposed that the reporting of cell types for lung carcinomas be done with two codes, "one for the predominant and the other for the secondary pattern. Other theories related to cell derivation and transition have been proposed, i.e., a single cell derivation for squamous and small cell carcinomas (41), a morphologic continuum within the general group of small cell ana plastic carcinomas (42), and a transition be tween the small cell carcinomas (43). These latter theories neither confirm nor refute Yesner's hypothesis, but they are indicative of the need for continued investigation.2 1 1 Lukeman (44) believes carcinomas may arise in any portion of the lung and may or may not resemble their progenitors. He suggests that this results in the polymorphism seen in lung tumors. Carr and Lukeman (13) propose that almost all cells in the respiratory tract are capable of pro ducing adenocarcinomas when the neoplastic process becomes initiated, and, therefore, the di agnosis of adenocarcinoma is meaningless because the term reveals nothing about the histogenesis of the cancer. They believe that the morphologic variations noted in many lung adenocarcinomas are not necessarily related to variations of a sin- Spenccr (45) observed that lung cancer may occur peripherally or centrally and that the distribution varies by cell type. He noted that peripheral tumors account for about one third of all squamous cell carcino mas, one fifth of all small cell carcinomas, and three fourths of all adenocarcinomas. Squamous cell and small cell carcinomas occur mainly in large, central bronchi, while adenocarcinomas are chiefly located peripherally and may be associated with chronic interstitial fibrosis or focal lung scars. Large cell carcinomas tend to be pe ripheral and subpleural in location. Carci nomas involving the conducting airways of the lung, e.g., squamous cell carcinoma, have been associated with a response to re petitive injury and chronic inflammation. The pathogenesis of small cell carcinoma is not well understood and the mechanisms of development of adenocarcinomas and large cell carcinomas of the lung are equally ob scure. Squamous cell carcinomas generally grow more slowly and less often give rise to distant metastases than do small cell carci nomas. which metastasize early and widely. Adenocarcinomas tend to grow slowly but have a high metastatic potential (46). Increases in the relative frequencies of squamous cell carcinoma (47) and adeno carcinoma (19, 48, 49) have been reported. It is not clear if the reported increases are due to changes in histopathologic criteria, increased incidence of lung cancer in women, changes in modes of therapy, and/or to environmental exposures. Demographic Aspects (Age, Sex, and Race) Age influences the incidence rate of lung cancer, and the rate may be proportional to the fifth or sixth power of age (50, 51). In one case series, 87% of lung cancers in men occurred in those 50 yr of age and older, and 75% of the men were 50 to 69 yr of age (52). Proportional distributions of lung cancer cell types also reflect the effect of age. The proportions of both squamous cell carcinoma and adenocarcinoma increased with age in a study of 901 cases of lung can cer diagnosed by autopsy in Los Angeles (48). Approximately 30% of the lung can cer cases, however, were described as large cell, poorly differentiated, or undifferenti ated and, because of the lack of specificity of these terms, age trends of lung cancer cell types cannot be clearly determined. In a combined autopsy and surgical series of lung cancer cases identified between 1952 and 1962, 70% of the 1,324 white, male veterans studied within each of the 4 major categories of cell types were 60 to 79 yr of age (53). Diagnosis of a primary site was gle ceil or clones developing from that precursor cancer cell, but possibly from a number of ceils in the respiratory tract that are capable of re sponding to the neoplastic stimulus. They sug gest that gland formation is an expression of only one aspect of the growth pattern. R&S 117012 .ML OOMMEN1AH) TABLE 1 CATEGORIES WITHIN MAJOR CLASSIFICATIONS OF LUNG CANCER: INTERNATIONAL CLASSIFICATION OF DISEASES FOR ONCOLOGY (ICD-O), SYSTEMATIZED NOMENCLATURE OF MEDICINE (SNOMED), AND WORLD HEALTH ORGANIZATION (WHO) 1976 (7) and SNOMED 1979 (6) WHO 1982 (5) 8070/3* Squamous carcinoma, NOSt 8074/3 Spindle cell type 8041/3 Small cell carcinoma, NOS 8042/3 Oat cell carcinoma 8043/3 Small cell, fusiform type 8140/3 Adenocarcinoma, NOS 8550/3 Acinar cell carcinoma 8260/3 Papillary adenocarcinoma, NOS 8250/3 Bronchioloalveolar adenocarcinoma 8230/3 Solid carcinoma, NOS 8012/3 Large cell carcinoma, NOS 8031/3 Giant ceil carcinoma 8310/3 Clear cell carcinoma 8560/3 Adenosquamous carcinoma 1. Squamous cell carcinoma Variant: a. Spindle cell carcinoma 2. Small cell carcinoma a. Oat cell carcinoma b. Intermediate celt type C. Combined oat cell carcinoma^ 3. Adenocarcinoma a. Acinar adenocarcinoma b. Papillary adenocarcinoma c. Bronchioloalveolar carcinoma d. Solid carcinoma with mucus formation 4. Large cell carcinoma Variants: a. Giant cell carcinoma b. Clear cell carcinoma 5. Adenosquamous carcinoma * Ttw 4-dlglt code number signifies the histologic type end the fifth digit after the slash indi cates the behavior code 1/3 s Malignant, primary site). t Not otherwise specified. * Multiple coding necessary, e.g., 8042/3 Oat cell carcinoma plus 8070/3- Squamous cell carcinoma. uivocal in 21 % of the cases in this study, d the relative frequency of lung cancer II typesmight have been affected by the esenc^^Bhese equivocal cases. Kreybo^52), in an autopsy series of lg cancer in Norway during the years 50 to 1964, reported a close similarity of : mean ages at diagnosis for squamous 1 carcinoma (males, 58.8 yr, versus feiles, 55.6 yr), small cell carcinoma ales, 56.1 yr, versus females, 58.6 yr), d adenocarcinoma (males, 58.3 yr, versus nales, 59.8 yr). However, the proportions :hin the age groups differed markedly ble 2). The proportion of squamous cell rcinoma increased consistently with age im 11.59b in men 30 to 39 yr of age to .4% in men 60 to 69 yr of age. The pro portion of small cell carcinoma was highest (23.2%) in men 40 to 49 yr of age and then showed a consistent decrease to only 8.3% in men 70 yr of age and older. The largest proportion of adenocarcinomas was found in men less than 40 yr of age; a slight in crease occurred in those 70 yr of age and older. Women had relative frequencies of lung cancer cell types similar to those in men. Auerbach and associates (54) reported no age trend for either small or large cell carcinomas in an autopsy series of 662 men, but the proportion of squamous carcinoma tended to increase with age and the propor tion of adenocarcinoma tended to decrease. Three of these studies of lung cancer cell types by age groups are from autopsy series and are thus limited by factors determining f $% Polygonal util eol t 8mal cvl Fig. 2. Carcinoma of the lung: maturatlonal transi tion of cells. Modified from Yesner (40). the availability and selection of cases for autopsy (48, 52, 54). It is predicted that the peak incidence of squamous cell and small cell carcinomas may diminish in Great Bri tain with the death of the generation now older than 60 yr of age (45). Inclusion of female lung cancer cases in series predominantly made up of male cases distorts the relative frequencies of cell types. The comparison of cell types of lung carcinoma in men and women discloses a preponderance of squamous cell carcinoma in men and of adenocarcinoma in women (table 3). Methods varied greatly among the studies reviewed by Modan (20) in table 3, and the wide ranges in percentages of cell types reported in men and women are evi dent. The Mayo Clinic series of lung cancer cell types in men and women, whether smokers or nonsmokers, agrees in part with Modan's findings (55). However, relevant background information, such as method of ascertainment, sources of tissue speci mens, histologic classification, and reli ability and validity, were not reported in the TABLE 2 NUMBER AND RELATIVE FREQUENCIES (%) OF LUNG CANCER CELL TYPES IN AN AUTOPSY STUDY OF MALES IN NORWAY, 1950 TO 1974, BY AGE* Age Groups in Years Total <29 30-39 40-49 50-59 60-69 II Type <) uamous cell carcinoma tall cell carcinoma adenocarcinomas Adenocarcinoma 3ronchioloalveoiar carcinoma 3ronct)(^^tpnd tumor rcInoid^^F cell types 473 123 122 103 10 9 45 763 (V.) 62.0 16.1 16.0 13.5 1.3 1.2 5.9 100.0 (n) <%) 0 0 5 50.0 2 20.0 3 30.0 5 50.0 10 100.0 </) <%) 3 11.5 4 15.4 8 30.8 4 15.4 1 3.8 3 11.5 11 42.3 26 100.0 </) (*A) (/t) (V.) (/) (%) 53 53.5 201 64.2 177 69.4 23 23.2 53 16.9 38 14.9 14 14.1 46 14.7 35 13.7 13 13.1 40 12.8 32 12J> 1 1.0 4 1.3 2 0.8 0 2 0.6 1 0.4 9 9.1 13 4.2 5 2.0 99 100.0 313 100.0 255 1004) Adapted from Krtytoco <52). >70 <n) <%) 39 65.0 5 8.3 14 23.3 14 23.3 0 2 3.3 60 1004) R&S 117013 -r* ti, TABLE 3 RANGES AND MEDIAN VALUES FOR PROPORTIONS (%) OF CELL TYPES IN MEN AND WOMEN IN SELECTED STUDIES OF LUNG CANCER 1952 TO 1976* Male? Femalet Histologic Cell Type Range Median Range Median Squamous cell carcinoma Small cell carcinoma Adenocarcinoma Large cell carcinoma 17.9-68.9 41.3 2.9-43.1 18.6 0-63.6 19.4 0-44.6 11.0 3.2-34.1 17.9 10.2-66.7 45.1 0-25.0 0.3 0-19.0 0 * Adapted from Modan <20). Tha percentages In many studies do not add up to 100 because not all categories are Included or appear In the original text 1 Studies of males from 10 countries (24 studies): U.S.A., 11: Norway, 3; U.K., 3: Austria, 1; Finland, 1; Iceland, 1; Israel, 1; Italy, 1; Singapore, 1; Uganda, 1. - Studies 01 females from 8 countries (IB studies): U.S.A^ 6; U.IL, 3; Noway, 2; Austria, 1; Finland, 1; Iceland. 1; Israel, 1; Singapore. 1. Studies in which the number of men and women totaled less than 100 were not included In the ranges for women. Mayo Clinic study; hence, interpretation of their report is restricted. Belcher (56) has suggested that the rela tive frequencies of lung cancer cell types in Europeans are different from those in nonEuropeans. Furthermore, the proportion of adenocarcinoma reportedly is higher in Tai wan, Tokyo, Hong Kong, Jamaica, and Kampala than that observed in European countries. Belcher also suggests that the site of origin of lung cancer differs geographi cally, with peripheral carcinomas account ing for over half the cases in the Far East and only 25% of the cases in Europe. These differences, however, may reflect differ ences in autopsy rates as well as environ mental exposures. Hinds and coworkers (57), in a review of tissue slides of 291 cases of lung cancer in women in Hawaii from 1968 to 1978, re ported no difference in the distribution of cell types between Japanese and Chinese women. Lung cancers in Hawaiian women, however, were more commonly squamous cell or small cell types, whereas two thirds of the Japanese and Chinese women had adenocarcinoma. The tissue slides in this study were reviewed by 2 of the authors using the WHO classification, but the sources of specimens were not stated. Factors That Affect Lung Cancer Celt Type Distributions Accurate and consistent classification of lung cancer is,important for both clinical and epidemiologic studies. However, such classification is complicated by numerous factors, including the changing nomencla ture. As classification systems have evolved, different nomenclature has been used, thus limiting comparisons among studies. Vin cent and coworkers (19) found that apply ing the WP-L criteria to cases diagnosed during the period from 1962 to 1968 re sulted in increases in small cell carcinoma (17.0 to 22.1'%), adenocarcinoma (8.7 to 17.0%), and large cell carcinoma (5.2 to 17.0%) and decreases in squamous carcino ma (51.6 to 41.2%) and undifferentiated carcinomas (12.8 to 1.4%). Sobin (58) pre dicts that stria application of the revised WHO criteria (5) will recategorize undiffer entiated squamous carcinomas as large cell carcinomas. Also, Sobin believes that more large cell solid tumors containing mucus formation will be classified as adenocarci noma. The large cell carcinoma category will have the poorly differentiated adeno carcinomas showing mucus formation, but it will gain the very poorly or undifferenti ated squamous carcinomas. Techniques in Obtaining and Preparing Tissue Specimens The techniques of obtaining and preparing tissue specimens affect their quality and, subsequently, the accuracy of the histo pathologic diagnosis. Because lung cancers may contain more than one cell type, each of varying differentiation, inadequate tissue sampling may result in misleading findings. For example, in the autopsy series reported by Willis (59), 23% of the lung cancers were mixed or combined cell types, whereas 77% were single cell types. Although he exam ined an average of 6 tissue seaions of each carcinoma, he believed that some of the homogeneous tumors might have shown heterogenicity if additional tissue seaions had been taken. Necrotic, inflammatory, or ulcerative areas in surgical and autopsy tis sue specimens may also obscure findings. Bronchial biopsies may be misclassified, frequently as undifferentiated small (oat) cell carcinoma, because of a "crush artifact" that has been observed in 20 to 25% or more of bronchial biopsies (13). The length of time from tissue biopsy until fixation may also affea specimen quality. Kreyberg (3) noted a greater number of combined cell types in autopsy series and attributed this to autolytic changes. Use of histochemical staining will also influence identification of various cell types. Herman and Crittenden (48) reported that with special stains for mucin the proportion of adenocarcinoma in an autopsy series increased from 10.6 to 29.0%; hence, the quality of prepared tis sue specimens refleaed techniques in use at the time the specimens were prepared. Histopathologic studies of lung cancer per formed prior to the 1960s are limited be cause they lack present-day techniques of obtaining, preparing, examining, and clas sifying specimens. Sources of Specimens Numerous investigators have suggested that the source of tissue specimens for histo pathologic diagnosis may influence the fre quency of diagnosis of the cell types of lung cancers (10, 30, 53, 54, 60-69). Sources of tissue specimens are daermined by various diagnostic and therapeu tic praaices as well as the availability of autopsy specimens. The clinical mode of presentation and diagnostic techniques used may affect the deteaion of types of lung cancer. Centrally located tumors, such as squamous and small cell carcinomas, are more likely to provoke symptoms than pe ripheral tumors. The avidity with which bronchoscopy is done for persons with "central" symptoms will affea the deteaion of squamous and small cell carcinomas. Ex tensive or routine use of chest roentgeno grams for early deteaion of respiratory dis eases may lead to increased diagnosis of peripherally located tumors, such as adeno carcinoma. Thus, the style of medical care or policies of health departments or large companies could influence the detection and reporting of lung cancer ceil types in different geographic regions or industries. The treatment of lung cancer includes surgical excision, chemotherapy, or both. Because squamous cell carcinoma is thought to respond best to surgical excision (70), it constitutes a large proportion of the cell types in surgical series of lung cancer. Small cell carcinoma, the most lethal cell type, ex hibits the most rapid doubling time of the major cell types and is usually treated with chemotherapy (71, 72). Consequently, small cell carcinoma is more often found in series of lung cancers derived from biopsies, cy tologies, and autopsies. In Stage 1 adeno carcinoma of the lung, surgery is the treat ment of choice, whereas radiotherapy is the preferred choice for Stage III lesions (71). Adenocarcinomas, therefore, are seen more frequently in both surgical and autopsy se ries than in biopsy series. The anatomic lo cation, and particularly the stage of the lung cancer, also influences the choice of therapy. At least 50% of lung cancers have been found to be inoperable at the time of diagnosis (55, 73). Therefore, a series of surgically rcseaed carcinomas represents at most only 50% of the cases. In addition, patients with inoperable lung cancers may not have an autopsy because the diagnosis is already known. Additional faaors that may determine whether an autopsy is per formed are: type of hospital, rarity of the disease, and primary mode of therapy. These various faaors limit the value of an autopsy series in a review of lung cancer cell types. Herrold (53) concluded that neither surgical nor autopsy series alone are repre sentative of the distribution of lung cancer cell types in that each has its own selection bias. R&S 117014 I CLINICAL COMMENTARY '* S oP) N+ pN o 2 Av o Sp "5w> tf --w t0^>? 3c < <B o s6 SBh- 2x>|5 -* re o s|sl * S- 2 m w *- t` h. ^ V r* P) <" P) * o p> c> t- o> pH o K - -2 Ills I rr5* ^O *> r- 2 *6 5= 0| S' -jre rs > I) g t S Sz =re 4> ?g* 2i8i s *" 2 oS <e > Z &o ?S5 c 6" i "I E te I M C& ^ W -- Y X on P) N s? E fc *1 <n h. O) 'i ?X Rc> r=e 5'S ' in 0811 If 5s j! ii . o If*i*s Iis= s O O1 #s =1= i | X o-- >;re= * -&8 * K = B) < J O o J E f Z * I S: | 199 Our review of lung cancer cell type distri butions reported in various studies indicates that the relative frequencies of cell types in these studies are affected by the source of tissue specimens (tables 4 and 5). Biopsy and cytology series (table S) have higher proportions of squamous cell carcinoma (range, 36 to 49%) and small cell carcinoma (range, 17 to 34%), reflecting their central, more accessible location. Surgical series (ta ble 5) are predominantly squamous cell car cinoma (range, 44 to 74%), indicating that surgical excision is the preferred treatment for this cell type. Autopsy series (table 5) have a predominance of small cell carcino ma (range, 24 to 37%) with wider or lower ranges in the proportion of squamous cell carcinoma (range, 17 to 35%) and adeno carcinoma (range, 25 to 27%). Observer Variability Histopathologic diagnoses may vary among pathologists, even though they use a simi lar, clearly defined, classification system. A study by Feinstein and associates (75), among 5 pathologists who reviewed 50 lung cancers, revealed a between-observer vari ability of 2 to 42% (most marked for poorly differentiated specimens), and a within-observer variability of 2 to 20%. Weiss and as sociates (76) reported only 40% unanimity among 3 pathologists in a review of 161 cases of lung cancer. The poorest agree ment, 25%, occurred with small cell cardnoma. A 10-yr reevaluation of data col lected during 1953 to 1959 by Yesner and coworkers (77) of 449 lung cancers in dicated 63% agreement between the origi nal and review diagnoses. A recent review of tissue biopsies of lung cancers of 476 pa tients was conducted by 3 pathologists, 2 of whom agreed upon the major cell type for 94% of the cases, but all 3 agreed on only 67% of the cases (78). The rates of agree ment were 89% for small cell carcinoma, 86% for squamous cell carcinoma, 76% for adenocarcinoma, and 40% for large cell cardnoma. TABLE 5 RANGE OF OBSERVED FREQUENCIES (V.) FOR LUNG CANCER CELL TYPES BY SOURCE OF SPECIMEN' Source of Specimens Cell Type Range In Frequency <V.) Biopsy and cytology Surgical Autopsy Squamous cell Small cell Adenocarcinoma Squamous cell Small cell Adenocarcinoma Squamous cell Small cell Adenocarcinoma 36-49 17-34 2-29 44-76 3-13 8-33 17-35 24-37 25-27 Sec table 4. R&S 117015 V 200 CLINICAL COMMENTARY Sources of Information There are various sources from which histo pathologic information may be obtained, e.g., death certificates, physicians' reports, medical records, and pathology reports. In formation in each of these sources is col lected for one or more specific purposes, most likely unrelated to epidemiologic studies. It is important, therefore, that in formation obtained from any of these sources and intended for use in an epidemi ologic study be carefully interpreted. Each source is of limited, but differing, value. The Third National Cancer Survey, 1969 to 1971, obtained information concerning 20,167 microscopically confirmed cases of lung cancer (all races, both sexes) from medical records (98% of the cases) and death certificates and cancer registries (2% of the cases) (79). Cell types were coded using the MOTNAC system and the relative frequencies were: 35% for squamous cell carcinoma (8,073), 13.6% for small cell car cinoma (8,043), 15.0% for adenocarcinoma (8,143), 27.7% for carcinoma not otherwise specified (8,013), and 8.7% for others. The reliability of secondary information on lung cancer cell types was examined in an early study by Haenszel and associates (80) who, using a sample of 247 male lung cancer deaths, compared physicians' reports with information obtained from original sources. In this comparison, adenocarcinoma was overdiagnosed by 60% and the squamous cell-undifferentiated group was under diagnosed by about 20%. As a result of this analysis, Haenszel and associates concluded that access to the initial tissue diagnoses is essential for determination of the cell type of lung cancer. Environmental Exposures Associated with Specific Cell Types Specific lung cancer cell type may be an im portant variable in identifying and inter preting associations between specific envi ronmental exposures and the development of disease. Unfortunately, the histopathology and pathogenesis of occupationally associated lung cancers are poorly documented, and the intensity and duration of exposure are not easily determined long after the exposure has occurred. Further more, mixed exposures in the workplace, cigarette smoking, age, use of inappropriate comparison groups, use of histopathologic specimens obtained from different sources, differences in early classification schemes, small numbers of cases, and mixing data of different races and sexes, compromise the interpretations of many study results. It is possible that differences in particle size and the intensity of an exposure may have an effect on the relative frequency of lung cancer cell types in addition to the overall risk of lung cancer. Yesner (81) has suggested that the greater the insult to dif ferences in the proximal bronchi, the more malignant is the tumor that results. He cites the occurrence of small cell carcinoma, one of the most malignant of tumors, in a study of uranium miners that demonstrated a dose-response effect for this lung cancer cell type. The almost exclusive pattern of small cell carcinoma in lung cancer cases among moderate and heavy exposures to bis(chloromethyl) ether (BCME) also sug gests a dose-response effect. Abe and associates (82) observed that heavier ex posure to chromate dust was associated with a higher incidence of small cell car cinoma. They suggested that when exposure to a respiratory carcinogen is less intense and of long duration, squamous cell car cinoma might become the predominant cell type of lung cancer in occupational ex posures. The potency of an agent may also be a factor. Lung cancer cell types have been reported in studies of acrylonitrile, cadmium, and mustard gas exposures. However, to date, acrylonitrile and cadmium have not been established as respiratory carcinogens. The evidence of increased risk of respiratory tract tumors after exposure to mustard gas is compromised in some studies by a ques tion of preferential reporting of cases (83). The lung cancer cell types identified in studies of these 3 substances are not dis cussed in this report. Smoking Studies conducted during the past decade suggest that association between a single cell type of lung cancer and smoking re mains equivocal (84). A survey of cell types of 1,041 primary lung cancers in U.S. veter ans disclosed a significant association be tween cigarette smoking and Kreyberg's Group I (squamous cell carcinoma and small cell carcinoma--both predominantly centrally located); however, no correlation was found between the cell type and the amount of tobacco smoked (53). Smoking histories were obtained by mailed question naires. Over a 10-yr period, Weiss and coworkers (85) followed 6,136 men and found that well-differentiated squamous cell car cinoma, small cell carcinoma, and adeno carcinoma all displayed a dose-response relation to smoking. By contrast, poorly differentiated squamous cell carcinoma (34% of the total lung cancers in the study) failed to demonstrate a dose-response pat tern. Yesner and associates (77) concluded that the proportion of squamous cell carci noma seemed unrelated to the amount of reported cigarette smoking, although the proportions of small cell carcinoma re flected a positive relationship. Auerbach and associates (54), in a study of 662 U.S. male veterans with lung cancer, found that smoking habits, calendar year of diagnosis, and age at death all appeared to be related to the cell type of lung cancer; however, the differences were generally small, and no consistent patterns were evi dent. Vincent and coworkers (19), in a i study of lung cancer in 584 men and 56 j women at the Roswell Park Memorial lnsti- tute, reported that cell type did not appear SB influenced by the amount of smoking at tributed to the patient, except that non smoking patients had a significantly higher proportion of peripheral tumors (adenocar cinomas and bronchioloalveolar carcino mas) than their smoking counterparts. In 4 of these 5 large studies concerning smoking and cell types of lung cancers, the sources of the specimens were either not re ported or were mixed (19, 53, 77, 85). Au topsy specimens were used in one study (54). Some proportion of the specimens in each of the studies was obtained in the 1950s or 1960s. Validity or reliability results on histopathologic diagnoses were reported in all 5 studies. Minerals Asbestos. Early studies of persons with lung cancer who had been exposed to asbestos reported high proportions of adenocarcino ma (86, 87). Nevertheless, as early as 1961, Whitwell and coworkers (74) proposed that some of the association between lung cancer cell types and environmental expo sures was artifactual because histopatho logic diagnoses are often based on bronchi al biopsy specimens and, thus, reflea a high frequency of carcinomas that occur in the larger, more accessible bronchi, i.e., squa mous and small cell carcinomas (74) (table 4). In their autopsy study of lung cancer in 88 male asbestos workers, Whitwell and co workers (68) also demonstrated a high pro portion of adenocarcinoma (table 6). How ever, in order to evaluate the influence of asbestosis on cell type, the investigators compared the proportion of adenocarcino ma among 28 workers with mild asbestosis (25%) with that in 48 workers with moder ate to severe asbestosis (38%). They found that the apparent difference was not signifi cant (68). Another autopsy series by Warnock and Churg (88) also demonstrated a high proportion of adenocarcinoma. Again, the source of specimens, in this case, autopsy, may have influenced the relative frequency of cell types in these latter 2 studies. Three additional studies of lung cancer cell types in persons exposed to as bestos (87, 89, 90), were based on a variety of sources of tissue specimens. In 2 of these studies the sample size was small (Hourihane and McCaughey (87), n = 17; Hasan and associates (89), n = 12); therefore, these findings do not resolve the issue. A more re cent comparison of lung cancer cell types, obtained from a general hospital series, in dicated no difference in the proportion of cell types for asbestos-exposed shipyard workers versus nonasbestos-exposed workers (table 7) (91). It is important to note that R&S 117016 ItCAL COMMENTARY TABLE 6 NUMBER AND RELATIVE FREQUENCIES (%) OF LUNG CANCER CELL TYPES REPORTED FOR PERSONS EXPOSED TO ASBESTOS Hourlhane & McCaughey (87) 1966 Kannerstein & Churg <90) 1972 Whitweil and associates (68) 1974 Wamock A Churg (88) 197S Hasan and associates (89) 1978 e period ssification rces of pecimen Not specified Not specified Pathologic material Not specified WHO 66% autopsy 1962-72 WHO Autopsy Not specified WHO Autopsy 1945-72 Not specified 42% sutopsy, 58% surgery, etc. e of xposure Not specified Asbestos workers Asbestos workers 50% mixed occupations, 50% unknown 80% shipbulldii 20% nonship- building oking istory 71% smokers, 30% smokers 23% nonsmokers 70% nonsmokers 6% unknown Not specified 88% smokers, 22% unknown Not 48% smokers 57% smokers 93% smokers specified 4% nonsmokers 43% unknown 48Vo unknown Gender Men Women Men Men Women Men Women unspecified 1 type lamous cell all ceil inocarinoma ge cell ier# w (%) 5 29 4 24 6 35 0 2 12 W (%) 2 20 1 10 6 60 0 1 10 (O) (%) 11 22 11 22 11 22 6 12 11 22 (n) (%) (n) (%) 9 22 23 26 2 22 3 33 30 34 0 16 18 3 33 0 1 11 <n) (%) 8 35 29 11 49 14 14 (n) (%) 2 29 1 14 3 43 0 1 14 <> (%) 4 33 2 17 6 50 0 0 Other cell types Include: undlfferentlsted, 2; adenocanthoma, l; combined, 8, and unclassified, 3; simples, 13; mixed, 4; combined, 2. s study is the only study reviewed where 1 type distributions for asbestos-exposed d nonexposed lung cancer cases were napar^^jHie data in table 7 were not blishc^Hid were provided on request Blo^^rsonal communication, 1980). higher proportion of adenocarcinoma is :n in the "never employed" (unexposed) imp when compared with the "exposed" Dup (9 versus 5%). Thus, the question reuns whether the apparent proportions of enocarrinoma found in various studies : artifactual or whether they are truly repentative of lung cancer cell type distribuns resulting from exposure to asbestos. senic. The association of exposure to >enic and various arsenic ores with an in cased risk of lung cancer stimulated uopathologic studies of lung cancer cell types among miners and smelter workers. The proportional distribution of lung cancer cell types identified during the period 1957 to 1963 among 25 workers in South African gold mines that contain large quantities of arsenopyrite (mispickel) was squamous cell carcinoma (289b), small cell carcinoma (30%), and anaplastic carcinoma (52%) (92). The lack of specificity of the latter designation precludes drawing con clusions regarding associations of cell types. A high incidence rate of lung cancer in Silver Bow and Deer Lodge counties in Montana led to the First U.S. study of the histopathologic cell types of lung cancer among workers in copper mines and a cop per smelter (93). The investigators specu lated that the excess lung cancer among the smelter workers was related to air pollu tants containing arsenic, whereas the excess among the miners was associated with expo sure to decomposed quartz used for sanding streets in wintertime. Tissue slides and blocks obtained from the pathology files of 2 pathologists serving these counties were examined independently by 4 pathologists using the VALCCSG classification. The predominant cell type reported was squa mous cell carcinoma (table 8) in which a large proportion (71 %) among the smelter workers was poorly differentiated. The control group comprised 45 cases of lung cancer in men who had not worked longer than a year in either the smelter or the mine. The relative frequency of lung cancer cell types was similar in the control group to the frequencies in the smelter workers and miners. Observer variability, if evaluated, was not reported. The International Agency for Research on Cancer criticized the study R&S TABLE 7 HISTOLOGIC DISTRIBUTION FOR LUNG CANCER CASES IN COASTAL GEORGIA STUDY (91) BY HISTORY OF EMPLOYMENT IN SHIPBUILDING AND SOURCE OF CELL TYPE IDENTIFICATION* Source of Identification Death Certificates Brunswick Hospital Savannsh Hospitals Total ng Cancer II Type History of Employment In Shipbuilding Yes No Yes No Yes No Yes No uamous cell carcinoma aall cell carcinoma lenocarctooma mcer ^^mclnoma NOS* 'tai U 6 (14)t 3(7) 1 <2) 33(77) 43(100) 20(14) 5(3) 6(4) 113 (78) 144 (100)5 11 (38) 3(10) 1 (3) 14(48) 29(100) 38(36) 13 (12) 10(9) 46(43) 107 (100) 7(30) 1(4) 3(13) 12(52) 23(100) 45(40) 9(8) 15 (13) 42(38) 111 (100) 24(25) 7(7) 5(5) 59(62) 95(100) 103(28) 27(7) 31(9) 201 (55) 362(100) ` Oat* In table war* auppliad by William Blot parson*! communication, Match 10,1980. t Humbert In parentheeee are percentage*. * Not otherwloe specified. $ Exclude* i meeometloma. 4.M4. Ui a < X 8 0) -4 o_L 00 ar t5to 1<50 O O r 5 :: ^O zQ ioe fE? map) m o tf> *> o cm *e; j*? S- * zo zo ,, * o* "8 E x: U O II o in cm s s| s "1 c & & sl ^ ^o' nc^po X" 5 Sc I* EB c3 9 < * 3T s V Voo--)I a. m a 2 - = < tn o < > as" ^ *> cEo na n Xl <3 tco= & EC 1 s* SS rt ,o N 1E j=e eiOfl) m^! KVNPN 8 non CO O CD CO *J ST O oV* o ' o ^"o o COSP--D s oCn7M, fIfni S oW ui 5 " 5 Be "o >.0 go- o"" Ift-?w = E tn Qa. Oo 6--S I2l - lf> i i a. " SI |E | 2 i! sIs a= I a I O s w oE v M z w fc; a. C eo H O CO o ~ ,c _ 3 aow ooK. S2Oc O MCM1 N i X5 oC CP 8 = o uc -- p2* " 8 " *E 11 I ??cOo' cCo <^ -j O3c ic ic 1'5 o because the sample was not random and the proportion of the total lung cancers in the area represented by study subjects was not stated (94). Lung cancer cell types of 18 copper smel ter workers were identified from medical files in Sweden, and specific cell types were reported, e.g., squamous cell carcinoma (95). The majority of cell types, however, were qualified as poorly differentiated to undifferentiated. These qualifications, plus the secondary source of information, make these findings inconclusive. A carefully designed case-comparison study of 42 U.S. copper smelter workers for the period 1950 to 1974 reported a signifi cantly higher proportion of adenocarcino ma and a high proportion of small cell car cinoma (table 8) (96). The patient's age, year of diagnosis, smoking history, occupa tion, as well as source of specimens and their condition and preparation, histopatho logic classification, and "blind" examina tion of tissue slides were all carefully con sidered. About one fourth of the lung cancers in both study cases and compeers had no tissue available for cell typing. An autopsy diagnosis was obtained for 15 smelter workers and 12 compeers, and a surgical di agnosis was obtained for 13 smelter workers and 15 compeers. Cell types of lung cancer by source of specimen were not reported. Beryllium. Smith and Suzuki (97) found small cell carcinoma to be the predominant cell type (60%) in biopsies of 10 workers ex posed to beryllium, 1942 to 1968, and aden ocarcinoma to be the predominant cell type (47%) in autopsies of 15 other workers (table 8). Pathology specimens were not re ceived for 20 (44%) persons similarly ex posed, and their cell types may not be dis similar to those reviewed. Epidemiologic evidence that occupational exposure to beryllium may lead to an increased risk of lung cancer is limited, and the risk of expo sure to beryllium compounds in the general population appears to be small (94). Chromate. Based on worldwide studies summarized by Hueper (86), the National Academy of Science concluded that lung cancers in chromate workers do not demon strate a predominance of a specific cell type (98). More recently, Abe and associates (82) reported 13 squamous cell and 5 small cell carcinomas identified in 20 cases of lung cancer among workers in a chromate fac tory in Japan (table 8). The investigators suggested that the carcinogenicity of chro mate compounds may reside in the hcxavalent rather than the trivalent materials and noted that the greater the occupational ex posure, the greater the proportion of small cell carcinoma observed. Furthermore, Abe and associates suggested that when expo sure to a carcinogen is less intense but of long duration squamous cell carcinoma might become the predominant cell type among occupationally related lung cancer. All 18 of the workers with defined cell types tUNICAL' COMMENTARY 203 veTe smokers, but those with squamous cell :arcinoma smoked more heavily than those vith small cell carcinoma. The sources of pecimens and histologic classification used n this^hiy were not reported. VickeMxghi studies of the histopathologic tspects of respiratory cancers in nickel vorkers revealed 49 lung cancers of which quamous cell, anaplastic, and pleomorphic larcinomas were the most common cell ypes (99). Five of the studies were pub* ished prior to 1960, two in the mid-to-late 960s, and one report was a personal comnunication in 1972. A sputum surveillance urogram of 282 male nickel workers in a Canadian nickel sinter plant, 1973 to 1974, denuded by cytologic examination 11 vorkers with abnormal sputum (100). Five )f the men, all smokers, later developed quamous cell carcinomas diagnosed from urgical lung specimens. A histopathologic study of 44 cases of ung cancer in nickel refinery workers in Norway, 1948 to 1974, disclosed squamous ell carcinoma to be the predominant cell ype in 39 cases reported (table 8) (101). The ources from which the specimens were obained were not specified. The majority of hese workers (82%) were smokers. Nickel efining, like other industrial processes, re* ults in exposure to multiple substances, so hat an association of one cell type with a ingle agent is very difficult to determine vithou^^ironmental measurements. Chemicals iis(chloromethyl) ether. In the 1970s, sevral reports described an increased risk of mg cancer among employees exposed to hloroethers (102-106). Small cell carcioma was the predominant lung cancer cell ype found in 4 of the 5 studies (table 9). )nly one study reported sources of speci mens used for diagnosis (105); the histo pathologic classification was specified in 2 studies (105, 106). Lung cancer cases (8 or less) were reported in 3 studies in which the size of the exposed groups ranged from 8 to 136 (102-104). The high proportion of cases among the exposed workers reflects the ex cessive risk of lung cancer associated with BCME. Confirmation of a specific cell type association with exposure to BCME is dif ficult, however, considering the small numbers of cases and the limited informa tion available. The BCME-exposed workers reported by Lemen and associates (104) were enrolled in a sputum cytology sur veillance program. It is not clear whether the histopathologic diagnoses were based on specimens obtained in the course of the cytologic screening program or whether diagnostic material was obtained from other sources, such as surgical or autopsy specimens. Weiss and Figueroa (105) and Weiss and coworkers (106) studied 11 cases and 28 cases of lung cancer that occurred during the periods 1962 to 1972 and 1960 to 1977, respectively, among workers exposed to BCME. (Exposure to BCME included expo sure to chloromethyl methyl ether.) All workers in the first study (1962 to 1972) had been enrolled in a screening program in a chemical plant in Philadelphia, and were less than 59 yr of age when small cell carci noma was diagnosed. The sources of speci mens were: bronchial biopsy, 3; biopsy of metastatic lesions, 3; thoracic biopsy, 2; re sected lung biopsy, 2; autopsy, 1. The sec ond report included cases of lung cancer that occurred during the period 1960 to 1977 among the same group of employees exposed to BCME. Small cell carcinoma was found to predominate the lung cancer cell types identified among the 28 workers (table 9). The specific sources of tissue specimens were not reported in the later study. The 11 workers studied in the initial study were considerably younger than those included in the larger study, e.g., 64 versus 46% were 30 to 49 yr of age. Small cell car cinoma has been found to be highest in the group 40 to 49 yr of age, with a proportion ate decrease in the older age groups (table 2). The possible effect of age, as well as sources of tissue specimens, on the distri bution of lung cancer cell types among workers exposed to BCME needs further clarification. Vinyl chloride. An excess of respiratory cancer among workers engaged in the pro duction and polymerization of vinyl chlo ride has been reported in 4 studies (107110). In a cohort of 4,086 men employed at some time during the period 1942 to 1973 in a synthetic chemicals plant, 45 cases of lung cancer were identified (110). Histopatho logic material was available for 27 (60%) of the lung cancer cases among the chemical workers and a matched comparison group of 50 cases of lung cancer was selected from chronologically ordered pathology logs. Histopathologic material for all cases was reviewed by a panel of pathologists un aware of the employment histories of the study subjects. The proportional distribu tions of Jung cancer cell types were com pared between the 2 groups (table 9). A greater proportion of large cell carcinoma and adenocarcinoma was found in the group of chemical workers than in the com parison group. Many workers had been ex posed to a variety of substances, and it was concluded that polyvinyl chloride dust was the most likely etioiogic agent. Histopatho logic specimens were difficult to find among the chemical workers who died of lung cancer early in the study and who were older on the date of death. The lack of spe- TABLE 9 NUMBER AND RELATIVE FREQUENCIES {%) OF LUNG CANCER CELL TYPES IN STUDIES OF OCCUPATIONAL EXPOSURES TO CHEMICALS Bis (Chloromethyl) Ether Vinyl Chloride uthors, Date Published ime Period classification ource of Specimens ype of Exposure moking History Theiss and associates (102) 1973 1962-71 Not specified Not specified Chemical workers 75% smokers 25% unknown Sakabe (103) 1973 1955-70 Not specified Not specified Chemical workers 100% smokers Lemen and associates (104) 1976 1955-76 Not specified Not specified Chemical workers 80% smokers 20% unknown Weiss and associates (106) 1979 1960-77 WHO Waxweiler and associates (110) 1981 1942-73 VALCCSG Not specified Chemical workers 82% smokers 18% unknown Not specified Chemical workers Comparison Subjects Not specified ell type (n) (%) </) (%) in) (%) in) (%) (n> (%) <n) (%) quamous cell mall c denoc ma arge ceil ther- 0 5 63 0 0 3 37 0 1 20 1 20 0 3 60 0 4 80 0 1 20 0 14 19 68 5 18 27 14 6 22 6 22 7 26 8 30 0 15 30 15 30 14 28 5 10 12 For definition* of OOrl*tton*, m table 4. * Includes: not specified (102); simple, 1; Pancoest, 1; unknown, 1 (1(0); undifferentiated (106); not specified (110). R&S 117019 i: i i 204 CLINICAL COMMENTARY cificity associated with large cell carcinoma plus the substantial proportion of cases among the workers for whom histopatho logic specimens were unavailable make it difficult to interpret the significance of the findings in this study. A description of the lung cancer cell type distributions by sources of specimens and by age of study subjects, including those for whom histopathologic specimens were unavailable, might further clarify potential associations. Radioactive Substances Radon gas/radon daughters.J Among the respiratory carcinogens, radioactivity in general and uranium in particular have re ceived the most attention. A review of the early recognition of a pulmonary disease among miners in the Erz Mountains attrib utes Paracelsus, in 1531, as describing "mala metallorum" among miners on the German side of the mountains (Schneeberg) and Agricola, in 1556, as describing a pul monary disease among miners on the Bohe mian side (St. Joachimstahl) (112). The pul monary disease among the miners in Schneeberg was recognized as a malignant neoplasm by Harting and Hesse in 1879, and the disease among the miners in St. Joachimstahl was identified as being similar to that of the miners in Schneeberg by Ldwy in 1929 (112). The Schneeberg and St. Joachimstahl mines produced nickel, mag nesium, bismuth, and radium, and by the 1920s, it was suggested that radioactivity was the carcinogenic factor. Despite prior recognition of the risk, the incidence of lung cancer among uranium miners in the United States in the 1950s was 10 times greater than that of the general population (113). Examinations of the cell types of lung cancers among uranium workers indicated a preponderance of small cell carcinoma. A high relative frequency of small cell carcinoma in a matched, case-comparison study of 121 cases of lung cancer in U.S. uranium miners was reported by Saccomanno and associates (114). Exposures to in creasing amounts of radiation were found to result in a greater proportion of small cell carcinoma and a smaller proportion of squamous cell carcinoma. The study identi fied 116 "definite" and 15 "possible" lung cancer cases during the period 1949 to 1969. Five of the 15 "possible" cases were selected and included in the study to make a total of 121 lung cancer cases that were analyzed. 3 "Ores bearing uranium include its decay products which form a series of radionuclides. One of these radionuclides is the inert gas radon, which diffuses into mine atmospheres where it decays (half life of 3.8 days) into radioisotopes of polonium, bismuth and lead which collectively have a half life of about 30 minutes. These radio nuclides ("daughters" of radon) attach them selves to the nearest solid which is usually an air borne dust particle ... a large proportion of the radon daughters is deposited in the tracheobron chial tree including some which as "free ions" are unattached to particulates in air." p. XXI (111). TABLE to MEAN AGE ANO MEAN CIGARETTE-PACK-YEARS FOR URANIUM MINERS BY ESTIMATED WORKING LEVEL MONTHS (WLM) OF EXPOSURE AND THEIR WORKING COMPARISON SUBJECTS (NONURANIUM MINERS)* 701-1,200 WLM <n = 27) Compar ison Subjects 1,201-2,500 WLM (n = 24) Compar ison Subjects 2,501-9,700 WLM <n = 30) Compar ison Subjects Mean age Mean cigarette- pack-years 55.5 36.7 58.1 44.7 53.3 34.3 62.3 45.8 53.2 30.7 65.2 57.2 * Adapted from Saecooiknno and associates (114). TABLE 11 NUMBER AND RELATIVE FREQUENCIES <%) OF LUNG CANCER CELL TYPES AMONG URANIUM MINERS AND AGE- AND CIGARETTE-MATCHED COMPARISON SUBJECTS* Uranium Miners, 40-200 WLMt Comparison Subjects Uranium Miners, 201-700 WLM Comparison Subjects Cell Type Squamous cell carcinoma Small cell carcinoma Adenocarcinoma Large cell carcinoma Other Total (n) (V.) <r>) (V.) (n) (V.) <) 6 42.9 9 64.3 9 34.6 15 5 35.7 3 21.4 11 42.3 4 2 14.3 1 7.1 4 15.4 3 1 7.1 1 7.1 1 3.8 4 1 3.8 14 100.0 14 100.0 26 100.0 25 (%) 57.7 15.4 11.5 15.4 100.0 ' Adapted (ram Saccomsnno and associates (114). ! Working level months. Criteria for selection of the 5 "possible" cases were not specified, and these cases were not identified in the analyses. A com parison group of lung cancer cases among nonuranium-exposed miners was chosen and an attempt was made to match on age and smoking status. Considerable difficulty was encountered in attempting to match the cases with the comparison group of non uranium-exposed miners on the basis of age and smoking history. Two thirds of the uranium miners were in the high exposure group: 701 to 9,700 working level months (WLM).4 Within the two highest exposure groups, 1,201 to 2,500 WLM and 2,501 to 9,700 WLM, mean ages between cases and comparison subjects differed by 9 and 12 yr, respectively, and mean cigarette-packyears differed by 11.5 and 26.5 pack-years (table 10). Because these 2 highest exposure groups constituted 44.6% (n = 54) of the uranium miner cases, large differences in age and smoking diminish the value of this comparison. The matching technique did not accomplish complete age-matching but it did establish more valid comparisons for the low exposure categories in which the proportion of small cell carcinoma is greater among the miners in the 40 to 200 and 201 to 700 WLM categories than among the comparison subjects (table 11). 4 A working level month = 1.3 x 10' million electron-volts of potential alpha energy from ra don daughters per liter of air in the mine in which a man works 40 h/wk for 4.S wk. The investigators reported that "blind" readings of tissue slides of lung cancer were not possible because the miners' lungs showed fibrosis and pigmentation. Any possible bias resulting from this problem was not estimated. In a later report on U.S. uranium miners (115), many of whom were in the early study of Saccomanno and asso ciates (114), there were marked differences in the proportion of all cell types within dif ferent age groups (table 12). The propor tion of squamous cell carcinoma shows a consistent increase in successively older age groups, i.e., from 18.5% of lung cancer in miners 40 to 49 yr of age to 50.0% in miners 70 to 79 yr of age. Small cell carcinoma, however, constituted 76.6% of lung cancer in miners younger than 49 yr of age, and the proportion then declines with age, con stituting only 10% in miners 70 to 79 yr of age. Small cell carcinoma constitutes more than half (57%) of all lung cancers in uranium miners 50 to 69 yr of age, but when the grouping is younger than 55 yr of age versus 55 yr of age and older, small cell car cinoma constitutes 74.5 versus 48.3% of all the cell types. The proportionate increase of squamous cell carcinoma and decrease of small cell carcinoma within successively older age groups of uranium miners is similar to Kreyberg's study (52) (see table 2), thus emphasizing the importance of hav ing a carefully age-matched comparison group. A summary of the histopathologic types of carcinoma of the lung in uranium CLINICAL COMMENTARY TABLE 12 NUMBER AND RELATIVE FREQUENCIES (%) OF LUNG CANCER CELL TYPES IN 111 WHITE, UNDERGROUND URANIUM WORKERS, 1950 TO 1971, BY AGE*_________________ Age Groups In Years Total 30-39 40-40 50-59 60-69 70-79 Less than 55 55 and over Cell type in) <%> <n) (%) (h) (V.) (n) (V.) (") (/.) <) <%) (") (%) (h) <V.) Squamous cell carcinoma Small cell carcinoma Adenocarcinoma Othert Total 28 25.2 0 5 18.5 12 22.6 8 36.4 3 50.0 10 19.6 18 30.0 67 60.4 3 100.0 20 74.1 31 58.5 12 54.5 1 16.7 38 74.5 29 48.3 7 6.3 0 9 8.1 0 0 5 9.4 0 2 33.3 1 2.0 6 10.0 2 7.4 5 9.4 2 9.1 0 2 4.0 7 11.7 111 100.0 3 100.0 27 100.0 53 100.0 22 100.0 6 100.0 51 100.0 60 100.0 * Adapted from Archer and associates (115) (WHO classification In 71%; autopsy, 73%). 11ncludes; Large cell, 1; combined epidermoid and adenocarcinoma, 3; carcinoid, 1; double primaries: small cell and epidermoid, 1; epidermoid end smell cell, 2; small cell and adenocarcinoma, 1. 205 workers, 1950 to 1971, describes the main sources from which tissue specimens were acquired (table 13) (115). It also relates the patterns of cell types diagnosed by a threemember panel of pathologists as well as the pattern diagnosed by a hospital pathologist in instances where tissue specimens were un available to the panel. Two thirds (n = 75) of the diagnoses were made by the panel and one third (n = 36) were obtained from a report by a hospital pathologist. The sources from ^Hch specimens were obtained permittej^Piuping into two main methods of diagnosis, i.e., autopsy series (n=81, 73%) and biopsy series (n = 30,27%). A dear dis tinction between bronchial and surgical bi opsies was not presented. Small cell carci noma was predominant (60%) and it was more pronounced in the autopsy series (67% of cell types) than in the biopsy series (43% of cel) types). These proportional dif ferences may be a reflection of the sources from which the tissue specimens were ob tained. The proportion of small cell carci noma diagnosed by the panel in the autopsy series was 74.6%, whereas the proportion of small cell carcinoma diagnosed by the hospital pathologist was 45.5%. In the biopsy series, the proportion of small cell carcinoma diagnosed by the panel was TABLE 13 NUMBER AND RELATIVE FREQUENCIES OF LUNG CANCER TYPES IN 111 WHITE, UNDERGROUND URANIUM WORKERS BY METHOD OF DIAGNOSIS AND TYPE OF PATHOLOGY REVIEW* Type of Pathology Review Method of Diagnosis, .ung Cancer Cell Types autopsy specimens Squamous cell Small cell Adenocarcinoma Othert Total biopsy specimens Squamous cell Small cell Adenocarcinoma Othert Total ombined Autopsy & iopsy Specimens Squamous cell Smal^^ Aden^^pnoma Other^^ Totsl Three Pathologists (including author) ----------------------------- (n) (%) 9 15.3 44 74.6 3 5.1 3 5.1 59 100.0 5 31.3 9 56.3 0 2 123 16 100.0 14 18.7 53 70.7 3 4.0 5 6.7 75 1003 One Pathologist (independent of study) ---------------------------------- <n) (%) Combined Reviews --------------------------- </>) (%) 7 313 16 19.8 10 453 54 66.7 2 9.1 5 63 3 13.6 6 7.4 22 100.0 81 100.0 7 50.0 12 40.0 4 28.6 13 43.3 2 14.3 2 6.7 1 7.1 3 10.0 14 100.0 30 100.0 14 38.9 28 25.2 14 38.9 67 60.4 4 11.1 7 6.3 4 11.1 9 8.1 36 100.0 111 100.0 * Adapted from Archer and associate* (115). 11ncludes: Largs cell, 1: combined epidermoid and adenocarcinoma, 3; carcinoid, 1; doubts prtmarlaa: amall call and Marmotd, 1; apldannoid and amall call, 2; amall call and adenocarcinoma. 1. 56.3% and by the hospital pathologist, 28.6%. The higher proportion of small cell carcinoma reported by the panel compared with that reported by the hospital patholo gist may be a reflection of differences in techniques, expertise, or cases examined. It is unfortunate that observer variability was not reported in the studies of the urani um miners, particularly in view of the 25% disagreement reported in earlier studies among pathologists diagnosing small cell carcinoma (75, 76). The effect of age on distributions of cell types of lung cancer re quires careful attention in studies of envi ronmental exposures inasmuch as small cell carcinoma seems to have a high proportion in young age groups, whereas squamous carcinoma has a high proportion in older age groups (table 2). Saccomanno and asso ciates (114) attempted to address this ques tion in their study of uranium miners; how ever, as noted previously, age-matching was difficult and the possible effect of age on the distribution of cell types of lung cancer in these workers is not dear. Saccomanno and associates (116) have recently observed that the proportion of small cell carcinoma among uranium miners decreased from 59% in 1960 to 22% in 1980 and that the proportion of adenocarcinoma increased with increasing WLM. The excess for each of the cell types of lung cancer observed in the 121 uranium miners and their comparison subjects was recently estimated (117). Because uranium miners were observed to have 5.4 times the number of lung cancers expected, the total number of lung cancers in each cell type category was multiplied by 5.4 and the re sulting distribution was compared with the distribution of cell types observed in the comparison group of 121 nonuranium miners. This technique of applying a rela tive increase to the observed distribution does nothing to clarify the histopathologic patterns of lung cancer in uranium miners. A study of lung cancer cell types evalu ated in 115 uranium miners in Czechoslo- R&S 117021 t I I 206 CLINICAL COMMENTARY vakia, 1948 to 1974, revealed that the ma jority were small cell carcinoma (53-9*Po) and squamous cell carcinoma (34.8%) (118). An unspecified proportion of the specimens were unclassifiable, thus the representative ness of the series is unknown. Factors that may have affecied the quality of the evalua tions, e.g., quality of the tissue slides, were not described. One pathologist, not informed of the working history of the deceased and using the VALCCSG classification, reviewed all the specimens. The investigators, esti mating ratios of observed to expected cell type proportions, reported that the propor tions of both squamous cell and small cell carcinomas were increased by the level of cumulated radiation exposure. Adenocarci noma was found not to be elevated in fre quency, but the number was small (n=4). Important aspects of a histopathologic study of lung cancer, such as sources of specimens, ages of patients, and validity and reliability of histopathologic diagnoses, were not included in the report. A case series of 16 Navajo uranium miners in whom lung cancer was diagnosed, 1965 to 1979, reported the following cell types: small cell carcinoma, 5; undifferentiated dSfeinoma, 5; squamous cell carcinoma, 3; alveolar carcinoma or adenocarcinoma, 2; unknown, 1 (119). The average age at death was 46.1 yr and the mean value of cumula tive radon exposure was 1,140 WLM. The significance of the distribution of lung can cer cell types in this case series is unclear be cause of the large proportion (38%) of un differentiated or unknown cell types that, in the conclusions of the original report, were grouped with small cell carcinomas. Among fluorspar miners with lung cancer in Newfoundland, Canada, 29 were diag nosed by sputum cytologic examination (miners refused surgical intervention) (120). Of these 29 cases, 26 (90%) were squamous cell carcinoma. This preponderance of squamous cell carcinoma is probably a re flection of the central location of this type of lung tumor. The low proportion of small cell carcinoma (7%) among this group of radon-exposed workers is unexplained. A cohort of uranium workers in Ontario, Canada, has also been studied (121). The lack of a standard histopathologic classifi cation among the pathologists was noted as a problem, and inclusion of terms such as anaplastic, undifferentiated, or poorly dif ferentiated in all 3 of the 4 major cell types reported may be a reflection of this lack of standardization. In addition to classifica tion problems, the use of general labels for reporting cell type distributions prohibits determination of a histopathologic pattern within this group of workers with lung cancer. Atomic bomb survivors. A total of 204 cases of lung cancer (male, 136; female, 68) was identified in an autopsy series. 1961 to 1970, of survivors of the atomic bomb blasts in Hiroshima and Nagasaki (122). In males, the predominant cell type was squa mous cell carcinoma (33.8%), and in fe males, it was adenocarcinoma (52.9%). The proportion of small cell carcinoma in males (22.8%) was about twice that in females (11.8%). Three cell types demonstrated a higher proportion in the 200 rad exposure group than in the < 1 rad exposure group: squamous cell carcinoma, small cell carci noma, and adenocarcinoma. The difference between the 2 exposure groups was signifi cant only for small cell carcinoma. Expo sure data by cell type was not reported for 22.5% of the 204 cases of lung cancer; therefore, the representativeness of the ex posure is uncertain. The proportion of lung cancer cases autopsied in the > 200 rad ex posure group (10%) was twice the propor tion of lung cancer cases autopsied in the < 1 rad exposure group (5%). The larger proportion of lung cancer cases autopsied in the & 200 rad exposure group may be of importance considering the high relative frequency of small cell carcinoma identified in the autopsy series. A review of this study noted that the excess number of cases, rela tive to expectation based on the < 1 rad ex posure group, are too small to exclude equal increases in cell types other than small cell carcinoma (123). Summary and Conclusions Historically, pathologists and epidemiolo gists have been limited by available technol ogy and classification systems in studies of the association of histopathologic cell types of lung cancer with environmental expo sures. Prior to the 1960s, techniques used in the procurement and preparation of tissue specimens limited their quality and, hence, the accuracy of histopathologic diagnoses. It is only 15 yr since the WHO published the first international standard for histopatho logic classification of lung tumors, which eliminated much of the ambiguity in earlier descriptions of cell types. Furthermore, in formation on environmental exposures available to epidemiologists has been se verely limited in character (e.g., intensity, duration and type). An increase in all major cell types of lung cancer, with no significant excess of a single cell type, has been associated with cigarette smoking. Different lung cancer cell types have been reported to predominate in studies of arsenic exposures. This predominance of numerous cell types may be a reflection of differences in the type and content of ar senic ores, differing histologic techniques, various sources of tissue specimens, and varying study designs. Two cell types, aden ocarcinoma or small cell carcinoma, de pending upon whether the source of the tis sue specimens was autopsy or biopsy, were prominent in a single study of beryllium exposure. Squamous cell carcinoma was the pre dominant cell type reported in a case series of workers exposed to chromates and in a case series of nickel workers. The availabil ity of comparable tissue diagnoses for non- exposed groups, identification of sources of specimens, and environmental monitoring data would greatly enhance these studies. Small cell carcinoma was the predomi nant cell type reported in 3 of the 4 pub lished case series of workers exposed to BCME. The 2 U.S. studies included cases associated with screening programs for re spiratory disease, and in one of them, age may have affected the distribution of lung cancer cell types. As noted earlier, the dis tribution of lung cancer cell types is af fected by the source of tissue specimens. The high proportion of small cell carcinoma reported in studies of uranium workers is impressive. In one study of uranium miners, the proportion of small cell carcinomas dif fered by sources of tissue (autopsy versus biopsy) and by type of tissue review (panel versus hospital pathologist). This provokes the question as to what extent, if any. the distribution of lung cancer cell types in uranium miners may have been affected by these factors. The effects of age at time of diagnosis and of observer variability on lung cancer cell type distribution are un clear in studies of cell types of lung cancer in persons exposed to radioactive substances. A predominance of adenocarcinoma was R&S reported in 3 of the 4 studies specific to lung cancer in males exposed to asbestos. Diag noses were based on autopsy material in 2 of these studies and, in the third study, the source of tissue specimen was "pathologic material." It is likely that an association of a single cell type of lung cancer with asbes tos exposure is chiefly artifactual. Greater * rtoo proportions of large cell carcinoma and adenocarcinoma were found among chemi cal workers exposed to polyvinyl chloride dust in a synthetic chemicals plant than in a comparison group. The significance of these findings is not clear. Most studies associating environmental exposures with histopathologic patterns of lung cancer cell types have attempted to identify a predominance of a single cell type in order to facilitate identification of causal exposures. Evidence available for a variety of known respiratory carcinogens (tobacco smoke, asbestos, arsenic,, beryllium, chro mate, nickel, BCME, vinyl chloride, radon gas/radon daughters, and radiation from atomic blast) has been reviewed. Limita tions as described herein, prohibit definitive conclusions and, to date, no study has un equivocally demonstrated that a specific lung cancer cell type in humans is uniquely associated with a specific physical or chemi cal exposure. Conversely, several investiga-, tors have concluded that an increased rela tive frequency of two or more lung cancer cell types occurs after certain specific expo sures. It is possible that one or more lung cancer cell types may be associated with specific environmental exposures. How ever, in order to differentiate apparent from real associations, studies must con sider the correlated factors discussed above. CUNiqAL COMMENTARY 207 * which may influence proportional distribu tions of lung cancer cell types. The challenge for researchers of this topic design and conduct studies that will distributions of lung cancer cell types^Whe general population as well as cell type distributions in populations ex posed to specific agents. It is necessary to establish the distribution of lung cancer cell types in the general population in order to identify any differences that may occur in other populations as a result of exposure to specific substances. The dilemma for re searchers is how to account for the numer ous factors, as outlined herein, that may impinge upon the precision and reliability of a study of lung cancer cell types in popu lations. The dilemma may be resolved somewhat by the following procedures: (/) use carefully obtained and prepared speci mens for diagnosis; (2) ensure that qualified persons, using a standard classification, examine specimens in a way that will dimin ish bias, such as that associated with a priori knowledge of exposure and observer varia tion; (3) consider the effect of age of study subjects and sources of specimens on histo pathologic distributions; (4) specify expo sure^) clearly; (5) select appropriate com parison subjects; (6) establish a complete follow-up of all study subjects. Janet C. Ives' Patricia A. Buttler* S. Dagu Greenberg Ttaffliversity of Texas Health Science Center at Houston School of Public Health, and Department of Pathology Baylor College of Medicine Houston, Texas 5 The writers are indebted to the reviewers who contributed substantially to the critical review and synthesis of the extensive pathology, epide miology, and occupational medicine literature related to the topic. In the area of pathology, Drs. P. Kotin, M. Kuschner, G. Saccomanno, and R. Yesner provided invaluable suggestions and critical comments. Review and discussions with Drs. D. T. Carr, M. M. Key, and J. Samet were particularly valuable with regard to occupa tional exposures, occupational and pulmonary medicine, and the relevance of this review. We are equally indebted to our colleagues in epide miology, Drs. A. H. Holguin, F. E. Lundin, Jr., L. W. Pickle, B. J. Selwyn, R. A. Stallones, and Ms. S. M. Wood for their thoughtful and incisive comments. 4 Requests for reprints should be addressed to Dr. Patricia A. 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