A n n a l s o f C l i n i c a l a n d L a b o r a t o r y S c i e n c e , Vol. 4, No. 1 Copyright © 1974, Institute for C lin ic a l S c ie n c e

The Histologicial Classification o f Malignant Lung Tum ors

BO YD O. W IL SO N , M .D . A N D H E C T O R A. B A T T IF O R A , M .D .

Departments of Pathology, Northwestern Memorial Hospital, and Northwestern University Medical School,

Chicago, IL 60611

ABSTRACT

The gross and microscopic features of malignant lung tumors are discussed within the framework of the WHO International classification. Recent informa­tion contributed by electron microscopy is included where pertinent.

In tro d u ctio nThe problem of classification of malig­

nant tumors of the lung is, at present, only partially resolved. The lack of a uniform classification becomes apparent when an attempt is made to compare various series as to incidence, behavior, etc. of the various types of malignant tumors. Not only do the categories vary, but the criteria by which a tumor is assigned to a particular category also may vary from study to study. Not in­frequently, the criteria for classification are not even mentioned, or it is merely stated that the slides were reviewed and classified by one or more pathologists. Therefore, scientists are faced with not only the prob­lem of what are at times rather vague and subjective criteria but also the problem of intra- and inter-observer variation. This lat­ter problem has been subjected to analysis in only a few studies.23’24

In an attempt to alleviate this situation, the World Health Organization created, in 1953, an International Reference Center for

Please address correspondence to Boyd O. Wil­son, M.D., Department of Pathology, Northwestern Memorial Hospital, Wesley Pavilion, 250 East Superior Street, Chicago, IL 60611.

the Histological Definition and Classifica­tion of Lung Tumors. This center was lo­cated in Oslo and headed by Professor Leiv Kreyberg. At the same time, a tentative histological classification was adopted which was very similar to that used by Professor Kreyberg for a number of years. In 1967, the WHO published a slightly revised classification. Several studies have been published which found the WHO classification practical and useful. If future studies adhere to this classification or at least specify explicitly to what extent they deviate from it, the situation will be much improved.

The WHO international classification of lung tumors is shown in table I. This report will deal with groups I through XI of this classification.

C lassification

G r o u p I. E p id e r m o id C a r c in o m a s

Epidermoid, or squamous cell carcinoma, is the most common type of primary ma­lignant epithelial tumor of the lung, com­prising approximately 50 percent of all cases. It has a decided male preponderance

HISTO LO GICAL C LA SSIFIC A TIO N O F M A LIG N A N T LUN G TU M O BS

T A B L E IT h e WHO I n t e r n a t i o n a l C l a s s i f ic a t i o n o p L u n g T u m o b s

I. EPID ER M O ID CARCINOM AS

II. SM A LL C E L L ANAPLASTIC CARCINOM AS

1. Fusiform cell type2. Polygonal cell type3. Lymphocyte-like (“ oat-cell” ) type4. Others

III. ADENOCARCINOM AS

1. Bronchogenica. acinar "1

—with or without mucin formationb. papillaryJ

2. Bronchiolo-alveolar

IV. LA RG E C E L L CARCINOM AS

1. Solid tumors with mucin-like content2 . Solid tumor without mucin-like content3. Giant cell carcinomas4. “ Clear” cell carcinomas

V. CO M BIN ED EPID ER M O ID AND ADENOCARCINOM AS

VI. CARCINOID TUM ORS

VII. BRO N CH IAL GLAND TUM ORS

1. Cylindromas2. Mucoepidermoid tumors3. Others

VIII. PA PILLA R Y TUM ORS OF T H E SU R FA C E E P IT H ELIU M

1. Epidermoid2. Epidermoid with goblet cells3. Others

IX . “ M IX E D ” TU M O RS AND CARCINOSARCOM AS

1. “ Mixed” tumors2. Carcinosarcomas of embryonal type (“blastomas” )3. Other carcinosarcomas

X . SARCOMAS

X I. U N C LA SSIFIED

X II. M ESOTH ELIOM AS1. Localized2. Diffuse

X III . M ELANOM AS

which varies from 75 percent to 96 percent in several reported series. This male pre­ponderance can be explained in part by two etiologic factors: cigarette smoking and occupational exposure to carcinogenic substances, such as uranium ore and as­bestos.

Epidermoid carcinomas commonly orig­

inate from large bronchi, either mainstem, lobular or major segmental bronchi. Their occurrence in a peripheral location is pos­sible but infrequent. These tumors may occasionally grow predominantly as a bulky intrabronchial mass. More com­monly, they cause gradual narrowing and eventually complete obstruction of the

6 W ILSON AND BATTIFORA

'£

F ig u r e 1. Photomicro­graph of a spindle cell variant of epidermoid carcinoma of bronchial origin. Hematoxylin and eosin. (X 2 0 0 )

bronchus. Owing to their location and mode of growth, epidermoid carcinomas are amenable to diagnosis by bronchial biopsy or the cytologic examination of sputum.

Metastasis commonly occurs first in the hilar and then in the mediastinal and supraclavicular lymph nodes. Since they are more accessible, the supraclavicular nodes are sometimes biopsied as an ad­junct to diagnosis. The occurrence of more distant metastases seems to correlate with the degree of differentiation, frequently occurring later in the better differentiated tumors.

By light microscopy the typical features are stratification of cells, whorl formation, intracellular bridges and keratinization. Areas of necrosis are not infrequent and, indeed, this process may on rare occasions be so extensive that the tumor presents as a cavitary lesion on X-ray.

Less well-differentiated epidermoid car­cinomas, in which keratinization and intra­cellular bridges are inconspicuous, may maintain a semblance of stratification and assume a transitional pattern. In some such cases, cuboidal or columnar cells may line the periphery of clumps of tumor cells,

giving the appearance of a basilar layer. In these less well-differentiated tumors, it is sometimes helpful to examine the bronchial mucosa adjacent to the tumor for evidence of intraepithelial malignant change.

Epidermoid carcinomas may rarely have areas where the majority of the cells as­sume a spindle shape (figure 1). This change may be so pronounced that the tumor appears sarcomatous. This histologic variation probably accounts for many of the tumors that have been classified as carcinosarcomas in the past.

By electron microscopy tonofibrils in bundles and abundant, well-developed des- mosomes are the most significant organelles (figure 2). These two structures are inti­mately associated at the intercellular bridges which are numerous. These or­ganelles become noticeably scarce as the tumor de-differentiates.

G r o u p II. S m a l l C e l l A n a p l a s t i c

C a r c i n o m a s

The WHO classification recognizes four sub-groups under this heading: (1 ) fusi­form cell type, (2) polygonal cell type,(3) lymphocyte-like ( “oat-cell” ) type and(4) other. Of these the oat-cell carcinoma

HISTOLOGICAL CLA SSIFICA TIO N OF M A LIGN ANT LUNG TUM ORS 7

F ig u r e 2 . Electron mi­crograph of part of a cell from a spindle cell variant of epidermoid carcinoma. Tonoflbrils, desmosomes and intercellular bridges are evident. ( X 15,100)

is by far the most widely recognized and will be discussed as a prototype of the group. The other categories serve to ac­commodate what appears at present to rep­resent significant histologic variations from this pattern.

Oat-cell carcinoma comprises approxi­mately 20 percent of all malignant epithel­ial lung tumors. It also has a decided male preponderance, probably for much the same reasons as are proposed for epider­moid carcinoma. Kreyberg13 has divided carcinomas of the lung into two groups: group I composed of epidermoid and oat­cell carcinoma and group II consisting of adenocarcinomas and some much rarer types of tumors, i.e., carcinoids. Group I has a much higher percentage of males and shows an increasing risk of developing lung cancer with increasing numbers of cigar­ettes smoked. Group II shows much less of a male preponderance and many more non- smokers or light smokers.

The majority (approximately 70 per­cent) of oat-cell carcinomas arise from

main bronchi. In contrast to epidermoid carcinomas, they do not typically form bulky intrabronchial masses but tend to spread along submucosal lymphatics caus­ing an irregular thickening of the mucosa. Not uncommonly, the primary focus is rel­atively small but has produced extensive metastases, i.e., to mediastinal lymph nodes. It was probably this characteristic, in addi­tion to the histologic appearance of the tumor, that accounted for the early desig­nation of this tumor as mediastinal sar­coma. The epithelial origin of oat-cell car­cinoma was first recognized in 1926 by Barnard.2 Subsequently, it was considered an anaplastic (possibly epidermoid) carci­noma. Origin from “reserve cells” of bron­chial epithelium was also postulated.

The true nature of this tumor was estab­lished in several stages. Azzopardi1 and others made the first step by delineating its unique histologic appearance by light microscopy. After the histologic character­istics became well established, oat-cell car­cinomas began to be associated with cer­

8 W ILSON AND BA TTIFO RA

tain clinical features, such as a generally poor prognosis and occasional endocrine activity.

The final step in delineating the origin of this tumor was an ultrastructural study by Bensch3 which demonstrated the pres­ence of neurosecretory-type granules in oat-cell carcinomas similar to those seen in bronchial carcinoids. He had previously identified Kultschitzky-like (argentaffin) cells in normal bronchial epithelium and postulated that oat-cell carcinoma and bronchial carcinoid might be, respectively, the malignant and locally malignant form of tumors derived from these cells. A re­cent study by Hattori et al11 has shown good correlation between the number of neurosecretory-type granules and the level of serotonin in the serum and in the tumor.

Oat-cell carcinomas are typically com­posed of small, ovoid cells, most of which are slightly larger than lymphocytes and have scant cytoplasm and hyperchromatic nuclei. These cells are distributed in irreg­ular sheets and cords, mitoses are frequent and areas of necrosis may be present. Some of these tumors may show areas where the cells are arranged in ductules or rosette formations. In such areas, mucin-like ma­terial may be identified by means of special stains. Small foci of epidermoid differentia­tion may also be present. None of these features invalidates the diagnosis of oat-cell carcinoma. These tumor cells are fragile and areas showing crush artifact are com­monly seen in biopsy material.

The salient ultrastructural features of oat-cell carcinoma are angulated nuclei with coarsely clumped chromatin, scant cytoplasm with few organelles, and vari­able numbers of neurosecretory-like gran­ules. These granules have electron-dense homogeneous round cores, are bound by a single membrane and vary in size from 50 to 240 microns. They are often aggre­gated in pseudopod-like processes of the cell.

G r o u p III. A d e n o c a r c in o m a s

Adenocarcinomas make up approximately 20 percent of malignant epithelial lung tu­mors. They do not show a marked pre­dilection for either sex, but most series have a slight male predominance. Many adenocarcinomas arise in a more peripheral location and a significant number are asso­ciated with scars.

The WHO classification recognizes two principal categories of adenocarcinoma:(1 ) bronchogenic and (2 ) bronchiolo- alveolar. The bronchogenic category is further subdivided into (a ) acinar and (b ) papillary types, both of which may or may not form mucin. The bronchogenic adeno­carcinomas, as the name implies, originate from a bronchus, either from the surface epithelium or rarely from bronchial glands. By light microscopy, the better differenti­ated tumors are composed of columnar or cuboidal cells that resemble bronchial epi­thelial cells and are in continuity with a bronchus where transition to normal ap­pearing epithelium may be demonstrable. Some mucus secreting cells are almost al­ways present and they may be numerous. Less well-differentiated tumors have a less obvious glandular pattern, but some of these cells usually contain intracytoplasmic mucin. It remains a debatable point as to whether or not a small amount of intracyto­plasmic mucin is sufficient justification for classifying an otherwise undifferentiated tumor as adenocarcinoma.

By electron microscopy, features com­mon to tumors of glandular derivation are observed in pulmonary adenocarcinoma. There are usually rich networks of rough endoplasmic reticuium and vacuoles con­taining secretory products including mucin. Typically there is a well developed juxta- nuclear Golgi apparatus. The apical surface often displays microvilli. In a well-differen­tiated cell there is often polarization of cytoplasmic organelles so that a “secretory pole” is recognizable. Neighboring cells

HISTO LO GICAL C LA SSIFIC A TIO N O F M A LIG N A N T LUN G TUM ORS 9

exhibit terminal bars at the level of the secretory pole. Desmosomes are present but tonofibrils are not.

Bronchiolo-alveolar carcinomas typically originate in the peripheral portions of the lung beyond a grossly recognizable bron­chus and tend to grow on the walls of pre-existing alveoli. A papillary pattern is often present and the alveoli are lined by cylindrical cells which may show evidence of mucin production. A clear-cut separation from other adenocarcinomas may at times be difficult and a primary tumor in other sites, such as the gastrointestinal tract or ovary, must always be excluded.

Several recent reports on the electron mi­croscopy of bronchiolo-alveolar carcinoma appear to have at least partially resolved the controversy concerning the cell of or­igin.6’15’17 The cells comprising these tu­mors typically have numerous microvilli over their free borders. Although granular endoplasmic reticulum and Golgi com­plexes are prominent as in adenocarci­nomas, secretory vacuoles are usually ab­sent. The most distinctive feature, however, is the presence in variable numbers of lamellated cytosomes thought to contain surfactant. The tumor cells thus bear a strong resemblance to the granular or type2 pneumocytes. It has been suggested by several investigators that these are the cells of origin.

On the other hand, some bronchiolo- alveolar carcinomas have ultrastructural features resembling those of adenocarci­noma.8’19 It is thus possible that some tu­mors classified as alveolar type are gland­ular in origin, while others are of true alveolar origin. Whether establishing this histogenetic difference will have any bear­ing on prognosis is not yet known.

G r o u p IV. L a r g e C e l l C a r c in o m a s

The WHO classification currently recog­nizes four subgroups of large cell carci­noma: (1 ) solid tumors with mucin-like

content, (2 ) solid tumors without mucin­like content, (3 ) giant cell carcinomas, and(4) “clear” cell carcinomas. Together they constitute approximately 10 percent of all carcinomas of the lung. The most widely recognized of these is the third type, giant cell carcinoma. This entity was first de­scribed by Nash and Stout in 1958.16

Histologically, giant cell carcinomas are composed of large, extremely pleomorphic cells. Bizarre, multinucleated tumor cells are a prominent feature. Phagocytosis is sometimes exhibited by the tumor cells. It is extremely important in making the diag­nosis of giant cell carcinoma to exclude the possibility of a primary adrenal tumor.

Although these tumors lack distinctive features by electron microscopy, with the possible exception of the multinucleated cells, they have typically been found to possess abundant rough endoplasmic retic­ulum, Golgi zones, and secretory vacuoles. It is thus possible that at least some of these represent a poorly differentiated form of adenocarcinoma, but this relatively un­common tumor’s histogenesis remains con­troversial.

G r o u p V. C o m b i n e d E p id e r m o id a n d A d e n o c a r c in o m a s

If one adheres to strict diagnostic criteria, this type of tumor is rare, representing less than one percent of all malignant epithelial tumors of the lung. Prerequisite for the diagnosis are areas with well-developed epidermoid and glandular features. Elec­tron microscopy simply confirms the pres­ence of organelles characteristic of each cell type.

G r o u p VI. C a r c in o id T u m o r s

Carcinoid tumors were originally classi­fied as bronchial adenomas along with adenoid cystic carcinomas. Carcinoid tu­mors comprised about 90 percent of this group. For some time, carcinoids were re­garded as benign, largely because of their

1 0 W ILSON AND BA TTIFO RA

F ig u r e 3. Electron mi­crograph showing part of the cytoplasm from a bronchial carcinoid. Characteristic membrane- bound neurosecretory granules are seen. Similar granules are found in most oat-cell carcinomas. (X 55,400)

favorable prognosis compared to the more common types of carcinoma of the lung. As larger numbers of these tumors were collected, controversy arose over their true nature. They are now generally regarded as malignant.6’10 Though typically slow grow­ing, they are capable of local destruction and metastasis. Carcinoid tumors charac­teristically occur as polypoid submucosal growths projecting into the lumen of a major bronchus. The more aggressive ones may have only a small intrabronchial com­ponent with the majority of the tumor pro­truding into the pulmonary parenchyma. Carcinoids may occur in the more periph­eral branches of the bronchial tree in which case they are usually quite small. The pa­thology, symptomatology and clinical course of the bronchial carcinoids share many common features with intestinal car­cinoids, including the secretion of sero­tonin.

Histologically, these tumors are com­posed of uniform cells with pale eosin­ophilic cytoplasm and rounded nuclei ar­ranged in trabecular, acinar or alveolar formations. Special stains may reveal mu­cus production or argentaffin cytoplasmic granules. Some tumors, especially those

located more peripherally, may be com­posed of spindle-shaped cells similar to those seen in oat-cell carcinoma.

By electron microscopy the most charac­teristic feature is the presence of neuro­secretory granules previously described in the section on oat-cell carcinomas (figure 3).

G r o u p VII. B r o n c h i a l G l a n d T u m o r s

Bronchial gland tumors are divided by the WHO classification into (1) cylindro­mas, (2) mucoepidermoid tumors and (3) others. Cylindromas, or adenoid cystic car­cinomas, arise from the mucus glands ad­jacent to large bronchi. This type of tumor more frequently occurs in the major and minor salivary glands.

Its mode of presentation and growth is similar to that of bronchial carcinoids but it usually behaves in a more aggressive manner. If not widely excised, it is likely to recur and may metastasize to regional lymph nodes or distant organs.

Microscopically, these tumors are com­posed of nests of small cells with scant cytoplasm and hyperchromatic nuclei. Within these clumps of cells are round to ovoid acellular spaces which typically con­

HISTO LO GICAL CLA SSIFICA TIO N O F M A LIG N A N T LU N G TUM ORS 1 1

tain hyalinized or mucinous material. It is the unique appearance of these acellular spaces that led Billroth4 to describe these tumors as cylindromas.

Electron microscopy has so far not been of help in solving the problem of the his­togenesis of this tumor.21

Mucoepidermoid tumors are rarely en­countered as primary pulmonary neo­plasms, being much more commonly of salivary gland origin. They may be present as polypoid intrabronchial growths and sometimes show infiltration. They are char­acterized by masses of epidermoid cells among which are scattered collections of extracellular mucus as well as epithelial cells containing intracytoplasmic mucus. Variable numbers of indeterminate cells which cannot be definitely classified as epidermoid or glandular may also be present.

It may at times be difficult to separate these tumors from group V ( combined epi­dermoid and adenocarcinomas). This dif­ferentiation is important because of the more favorable prognosis of mucoepider­moid tumors. The principal distinction is that in combined epidermoid and adeno­carcinomas there are separate areas of un­equivocal epidermoid and adenocarcinoma, a feature not shared by the typical muco­epidermoid carcinoma.9

Electron microscopy only confirms the presence of both types of cells and is usually not otherwise contributory.

G r o u p VIII. P a p i l l a r y T u m o r s o f t h e S u r f a c e E p i t h e l i u m

These are divided into (1 ) epidermoid, (2 ) epidermoid with goblet cells and (3) others. This group of tumors has been singled out, not because of unique histo­logic characteristics, but because they have a much better prognosis than the broncho­genic carcinomas. They are frequently lo­cated near the carina of the trachea and may be radiosensitive.

G r o u p IX. “ M ix e d ” T u m o r s a n d

C a r c in o s a r c o m a s

This group is divided into: (1 ) “mixed” tumors, (2 ) carcinosarcomas of embryonal type ( “blastomas” ), and (3) other carcino­sarcomas. As a group, these tumors are rare and consequently rather poorly understood. Many of them occur in children and young adults, and the prognosis, although usually better than for bronchogenic carcinoma, is difficult to predict.

“Mixed” tumors are similar to their coun­terparts in salivary gland. Carcinosarcomas of embryonal type are situated peripherally in the lung and are circumscribed though not necessarily encapsulated. They often contain areas of hemorrhage and necrosis. Histologically they consist of tubules re­sembling fetal bronchioles embedded in immature connective tissue. Spencer has called these tumors blastomas and thinks they are the pulmonary counterpart of Wilms’ tumor of the kidney.20

G r o u p X. S a r c o m a s

Although there have been rare reports of most types of sarcomas occurring as pri­mary lung tumors, only leiomyosarcomas and lymphomas are sufficiently frequent to warrant discussion here. Leiomyosarcomas of the lung do not differ significantly, either grossly or microscopically, from those aris­ing elsewhere. They may be either central or peripheral in location. Those that in­volve major bronchi often present as poly­poid endobronchial growths. In this regard, they must be differentiated from polypoid epidermoid carcinomas exhibiting a spin- died or pseudosarcomatous type of pattern. Metastatic leiomyosarcoma must be ruled out, especially in adult women where the uterus may contain an occult primary.

Primary malignant lymphomas are rare having an estimated incidence of 0.45 per­cent of bronchial carcinomas. Of the slightly more than 100 cases reported, 80 percent have been lymphosarcomas. Most

1 2 W ILSON AND BA TTIFO R A

of the remainder were reticulum cell sar­comas with Hodgkin’s disease being ex­tremely rare.

Papaioannow and Watson18 defined pul­monary lymphomas as primary if the tumor is confined to one lung, with or without involvement of hilar lymph nodes, but without mediastinal spread. Jenkins and Salm12 considered this definition too nar­row and felt it should be broadened to in­clude bilateral pulmonary involvement.

These tumors tend to grow slowly, me­tastasize late and have a more favorable prognosis than lymphosarcomas in general with the exception of some gastrointestinal lymphosarcomas which may also be cured by radiotherapy, surgery or both.

G r o u p XI. U n c l a s s if i e d

This category is included for those pri­mary lung tumors that cannot be placed in any of the type categories described.

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