86 - Bacterial Infections of the Lungs and Bronchial Compressive Disorders

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 101 - Pathology of Carcinoma of the Lung

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Chapter 101

Pathology of Carcinoma of the Lung

Thomas W. Shields

DERIVATION OF TUMOR CELL TYPES

In the normal lung, stem cell activity, according to Otto and Wright (1997), involves three cell types: the basal cell of the bronchi and trachea, the Clara cell of the bronchioles, and the type II pneumocyte of the alveoli. These authors further note that stem cell activity of secretory cells remains unproved and that this is likewise true of the neuroendocrine cells. In tumor histogenesis, the role of one or more of these aforementioned cells remain undetermined. Many investigators have implicated one or more of these cell types, but no unified concept has evolved. At present, two main hypotheses of lung cancer pathogenesis exist. The first hypothesis is that of a pluripotent stem cell from which the various tumor phenotypes arise by differentiation. The second is the multiple primary hypothesis, in which the various phenotypes arise from different cells of origin. No universal acceptance of either hypothesis has occurred.

Brambilla (1997), in reviewing the basaloid carcinomas of the lung, has noted that basaloid carcinoma cells show the morphological, immunophenotypical, and ultrastructural features of totipotent reserve or basal cells, which have the propensity for further multi-directional differentiation among squamous, glandular, or even neuroendocrine pathways. This observation, if confirmed by others, would help to explain the heterogenicity of tumor cell types within a given tumor. Actually, heterogenicity is the rule rather than the exception in most lung tumors. Yesner (1977, 1983) reported the frequent finding of areas of non small cell tumor phenotypes in small cell lung cancers (SCLCs), as well as the presence of neuroendocrine differentiation in non small cell lung cancers (NSCLCs). Roggli and colleagues (1985) observed that only 34% of tumors studied in their investigation were homogenous for one cell type of cancer, and that 45% of tumors contained two major histologic cell types. Of the SCLCs reviewed, at least one-half contained an area of another major histologic type. What triggers the basal cell (indifferent/indeterminate basal or suprabasal intermediate cell, the small mucous granule cell) in the tracheobronchial epithelium to differentiate into one or more of the multiple tumor phenotypes is unknown. Minna (1993), however, has suggested that malignant transformation under various stimuli may result in different phenotypes depending on the type of mutation acquired on key genes that control proliferation, differentiation, and apoptosis.

PATHOLOGY

Gross Characteristics

Bronchial carcinoma occurs more frequently in the right lung than in the left lung, in a ratio of approximately 6 to 4. The upper lobes are involved more often than the lower lobes, and the middle lobe is involved the least frequently of all. In the upper lobes, the tumor is most likely to be located in the anterior segment, although the other segments are not spared as the site of origin.

The anatomic site of origin of the tumor may be classified as follows:

  • Central zone, including the main stem, lobar bronchi, and primary segmental bronchi of the lower lobe

  • Segmental or intermediate zone, including the third-, fourth-, and possibly the fifth-order segmental bronchi

  • Peripheral zone, which includes the remainder of the distal bronchi, bronchioles, and alveoli

In the radiographic localization of lung tumors, zones 1 and 2 may be considered the central area, and zone 3 is the peripheral area.

According to Meyer and Liebow (1965), approximately 50% to 60% of carcinomas of the lung originate in the peripheral area. Of those carcinomas that arise in the central and segmental zones (the central area), 20% to 40% arise in the former and 60% to 80% in the latter.

Grossly, the tumors in the central and segmental zones appear as firm, irregular masses of varying size. Intraluminal growth may occlude the bronchial lumen partially or

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completely, although obstruction also may be caused by circumferential narrowing of the lumen. Extrabronchial spread may extend for a variable distance into the adjacent lung parenchyma. The tumor is generally homogeneous, with a whitish gray cut surface. The endobronchial surface typically is ulcerated. Atelectasis or secondary inflammatory change, including secondary bronchiectasis, pneumonitis, or lung abscess distal to the site of the tumor, is frequently present.

The peripherally located tumors are firm and irregular and may or may not appear to be demarcated from the surrounding lung tissue. The cut surface is homogeneous. The smaller lesions are usually solid, although the larger ones may reveal central necrosis with cavitation. Umbilication or puckering of the overlying adjacent visceral pleura is often present. The blood supply of both the centrally and the peripherally located bronchial carcinomas is from the bronchial arteries.

Table 101-1. Modified Classification of Lung Carcinomaa

  1. Squamous cell carcinomab
  2. Small cell carcinoma
    1. Pure small cell carcinoma
    2. Small cell large cell carcinoma
    3. Combined small cell carcinoma (with areas of squamous or glandular differentiation)
  3. Adenocarcinoma
    1. Variant: bronchioloalveolar carcinoma
  4. Large cell carcinomac
  5. Adenosquamous carcinoma
aBasaloid tumors may be regarded as a distinct subtype of non small cell carcinoma.
b Presence of spindle cell tumor may be seen.
c Tumors may be of a giant cell or clear cell variety, but this does not alter the diagnosis.
Modified from Moori WJ: Common lung cancers. In Hasleton PS (ed): Spencer's Pathology of the Lung. 5th Ed. New York: McGraw-Hill, 1996, p. 1009.

Table 101-2. Comparison of Classifications of Neuroendocrine Tumors of the Lung

World Health Organization (1982) Gould et al (1983a) Travis et al (1998a) Wick (2000)
Carcinoid Carcinoid Carcinoid Grade I, well-differentiated neuroendocrine carcinoma
Atypical carcinoid Well-differentiated neuroendocrine Atypical carcinoid Grade II, moderately differentiated neuroendocrine carcinoma
Neuroendocrine carcinoma of intermediate cell type Large cell neuroendocrine carcinoma Grade III(a), poorly differentiated neuroendocrine carcinoma of the large cell typea
Small cell carcinoma, oat cell type Neuroendocrine carcinoma of small cell type Small cell neuroendocrine carcinoma Grade III(b), poorly differentiated neuroendocrine carcinoma of the small cell typea
Intermediate cell type, combined type  
a (a) and (b) were added by this author.

Histologic Classification

Many histologic classifications of lung tumors have been suggested. The modified classification suggested by Moori (1996) is shown in Table 101-1. This classification is less cumbersome than that proposed by the World Health Organization and International Association for the Study of Lung Cancer, published in 1999 by Travis and associates. In clinical practice it is common to separate these tumor types into either SCLC or NSCLC. Furthermore, the SCLCs belong to the spectrum of neuroendocrine tumors of the lung. Azzopardi (1959) and Bensch and associates (1968) were among the early investigators who established the recognition of the neuroendocrine features of these tumors.

Over the last 45 years, the initial classification has subsequently undergone numerous modifications, with better delineation and characterization of the various subtypes in the neuroendocrine tumor classification (Table 101-2). Arrigoni and colleagues (1972) identified the atypical carcinoid tumors. Gould and co-workers (1983a, 1983b), incorporating the increased knowledge concerning these tumors, suggested that the atypical carcinoid tumors be termed well-differentiated neuroendocrine carcinomas. They further suggested that the term neuroendocrine carcinoma of the intermediate cell type be applied to all types of poorly differentiated neuroendocrine tumors that were distinct from either the atypical carcinoids or the small cell type of neuroendocrine tumors. Travis and associates (1991) proposed a new category of these tumors, the large cell neuroendocrine tumors. The latter author and colleagues (1998a, 1998b) have further defined the criteria for the classification of the large cell neuroendocrine tumors. Wick (2000) suggests that a new terminology would be better for the neuroendocrine lung tumors:

  • Grade I, well-differentiated neuroendocrine tumor (carcinoid)

  • Grade II, moderately differentiated neuroendocrine tumor (atypical carcinoid)

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  • Grade III, poorly differentiated neuroendocrine tumor (a) of the large cell type and (b) of the small cell type

Whether this classification will be accepted remains to be seen.

Preinvasive Lesions

Squamous dysplasia/carcinoma in situ, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia are the three preinvasive lesions included in this category. The first two are related to squamous cell carcinoma and to bronchioloalveolar carcinoma/adenocarcinoma, respectively. The third, neuroendocrine cell hyperplasia, is believed to be the precursor lesion for carcinoids and will be discussed in Chapter 116. Despite earlier speculation that carcinoid tumorlets might represent early or in situ SCLC, Flieder and Vazquez (2000) note that there is no established relationship or association between these two lesions.

Squamous Cell Dysplasia/Carcinoma in Situ

Grossly, in situ carcinoma appears as an area characterized by a loss of the normal longitudinal folds of the mucosa of a major or even a segmental bronchus. The mucosal area involved may be thickened and erythematous. Microscopically, the in situ carcinoma reveals full-thickness cytologic atypia with an increased nuclear-to-cytoplasmic ratio. The nuclei are hyperchromatic, and mitoses may be present. These changes do not extend beyond the basement membrane. Often such changes are associated with frank squamous cell carcinoma, but, as observed by Auer and associates (1982), complete regression of an isolated in situ lesion may occur.

Atypical Adenomatous Hyperplasia

Atypical adenomatous hyperplasia (AAH) is a proliferation of bronchioloalveolar cells that is thought to be a precursor to adenocarcinoma. According to Ritter (1999), AAH resembles the nonmucinous variant of bronchioloalveolar carcinoma (BAC). Initially, these lesions were identified pathologically in lungs resected for adenocarcinoma. Rao and Fraire (1995) noted that these areas of hyperplasia are present in up to 20% of resected lung cancer specimens as ill-defined peripheral nodules, most often multiple in number. The size of the lesions, according to Weng and colleagues (1992), ranged from 1 to 10 mm, with the majority being 5 mm or less. With the advent of the use of helical computed tomography (CT) for lung cancer screening, many more small lesions less than 10 mm in size are being identified. Such lesions may be further analyzed with the use of high-resolution CT, as reported by Reeves and Kostis (2000a, 2000b). The resulting images contain a great deal of information, and the size and shape of the lesion can be precisely measured and recorded. The opacity of the AAH lesion is indeterminate, but at times may be ground glass in appearance.

Histologically, the lesion appears as a zone of alveolar wall thickening as the result of the alveoli being lined by a variable number of cuboidal or columnar cells (Fig. 101-1A,B). Kerr (1997) notes that many of the cells have a hobnail or pear shape reminiscent of Clara cells, whereas others show nuclear inclusions as seen in type II pneumocytes. There is variable nuclear pleomorphism, but most often it is mild in nature. There is a lack of any central fibrosis, and mucin production is absent. Kitamura and associates (1996) have classified these atypical adenomatous hyperplasias as low grade, high grade, and carcinomalike. The proliferative potential and p53 expression increase as the grade advances. Likewise, Kitamura and colleagues (1995) recorded that the nuclear area and lesion size increased as the

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dysplastic lesion progressed to a bronchioloalveolar carcinoma; also, an increase in carcinoembryonic antigen (CEA) levels was seen as these changes occurred.

Fig. 101-1. Atypical adenomatous hyperplasia (AAH). A. AAH is characterized by a discrete, less than 0.5 cm, peribronchiolar pneumocyte proliferation with mild alveolar septal thickening (hematoxylin and eosin, original magnification 2). B. The relatively noninflamed septa are lined by moderately atypical pneumocytes. The small size of the lesion and the absence of cellular crowding and papillary frond formation militate against a diagnosis of adenocarcinoma (hematoxylin and eosin, original magnification 20). From Vazquez MF, Flieder DB: Small peripheral glandular lesions detected by screening for lung cancer: a diagnostic dilemma for the pathologist. Radiol Clin North Am 38:579, 2000. With permission.

Any lesion larger than 5 mm should be considered as a probable carcinomatous tumor. Vazquez and Flieder (2000) have stressed that the distinction between AAH and BAC is extremely difficult and subjective. Distinguishing between a benign lesion and a carcinoma by examination of a fine-needle aspiration of such lesions is not possible in the absence of finding a diagnostic malignant cell. If no malignant cell or cells are identified, a tentative diagnosis of atypical adenomatous hyperplasia may be made. However, the lesion should be reevaluated by high-resolution CT in 4 to 6 months to determine whether the lesion is stable or if growth has occurred. If growth is apparent, the degree and rate of growth can be established by the techniques described by Yankelevitz and associates (1999, 2000). Growth implies the presence of cancer, and further diagnostic evaluation or removal of the lesion is indicated.

As a consequence of an increased use of routine helical examination of the lungs and evaluation of any lesion identified by high-resolution CT, a subset of small lesions has been identified as being solitary pure ground-glass opacities. Any areas of fibrosis or scarring exclude the lesion from this category of indeterminate masses. The natural history of these pure ground-glass opacities has been heretofore unknown. In an attempt to evaluate the natural history and characteristics of these opacities, Kodama and associates (2002) investigated and reported 49 patients with solitary pure ground-glass opacity in the lung discovered by high-resolution CT. Thirty-nine patients had undergone surgical resection within 19 months of the initial identification of the lesion. Thirty-four patients had BAC, 4 had adenocarcinoma, and 1 patient had AAH. The average diameter of all lesions was 13.3 mm, but of the 4 patients with adenocarcinoma, the average diameter was 27 mm. Nineteen additional patients with pure ground-glass opacities (17 patients with solitary lesions, 1 patient with two lesions, and 1 with many lesions) were observed for a period of 2 years or longer. Reasons for observation varied, but eventually 10 of the patients agreed to have their lesion removed; 9 others elected continued observation. Overall, of the 19 patients, the lesion increased more than 5 mm in size in 5 patients, increased slightly in 6, and showed no change in 8. It is of interest that 6 of the patients who eventually elected to have a resection had a history of a previously resected cancer (5 in the lung and 1 in the kidney). Of the 10 lesions resected, the largest (25 mm) was an adenocarcinoma, 4 lesions were BAC, 1 was AAH, 3 showed the presence of a lymphoproliferative disorder, and 1 revealed the presence of pulmonary fibrosis. Of note is that 4 of the 5 patients with proven cancers had a prior history of a previously resected lung cancer.

From these data, although not statistically significant, it seems apparent that any pure ground-glass opacity that is greater than 10 mm in size, shows evidence of growth over a period of observation, or is identified in a patient with a history of lung cancer should be strongly considered for resection despite the observation that a prolonged period of observation may not be excessively detrimental. Watanabe and colleagues (2002) carried out limited resection in 17 patients with pure ground-glass attenuation on high-resolution CT. All were pure BAC lesions, and no recurrence or death has occurred on short-term follow-up (median follow-up time was 32 months).

Non Small Cell Tumors

Squamous Cell Carcinoma

Gross Features

The squamous cell tumors constitute approximately 20% to 35% of all lung carcinomas. In the early period of the last half of the 20th century, squamous cell carcinoma was the most common cell type of lung cancer throughout the world, but in the United States and Japan, this cell type is now less common than adenocarcinomas of the lung. However, squamous cell tumors remain the most common lung cancer in Europe and most other countries of the world. The cause of the changing incidence in the United States and Japan is obscure but is most likely the change in smoking habits and the demographics of smoking in these two countries.

The squamous cell carcinomas may occur in either the central or peripheral areas of the lung, although two-thirds are found in the central area. Squamous cell tumors grow relatively slowly and tend to metastasize late. The centrally located lesions tend to extend both intrabronchially as well as peribronchially; thus, frequently the lumen is constricted by extrinsic pressure but has a grossly normal-appearing mucosal pattern. The obstructing tumors are often associated with obstructive pneumonitis, distal pulmonary collapse, and consolidation. As the peripherally located squamous cell tumors enlarge, they tend to undergo central necrosis with resultant cavitation. This may occur in 10% to 20% of the peripheral lesions.

Small, superficial squamous cell tumors of the bronchial mucosa, although not a separate variety, deserve mention. These tumors are radiographically occult and may occur in both the larger main-stem and lobar bronchi as well as in the more distal divisions of the bronchial tree. The more proximal lesions may be identified by bronchoscopic examination as abnormal areas in the otherwise normal-appearing bronchial mucosa. Some of these tumors are only carcinoma in situ, but many are invasive lesions, most of which do not extend beyond the bronchial wall. The length, the gross area of involvement, and the depth of extension determine whether these are aggressive lesions (see Lymphatic Metastasis, later in this chapter).

Microscopic Features

The well-differentiated squamous cell tumors have polygonal or prickle-type cells, stratification, and intercellular

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bridge formation (Fig. 101-2). Individual cells keratinize or tend to form epithelial pearls, or both; the nuclei may be uniform, pleomorphic, or giant. The moderately differentiated tumors have polygonal or prickle-type cells, stratification, intercellular bridge formation, and some keratinization. Rarely, squamous cells can take on a spindle shape, which makes the tumor look sarcomatous histologically. The poorly differentiated tumors are composed predominantly of anaplastic cells, with little but still distinct evidence of intercellular bridge formation or individual cell keratinization, or both. A tumor without these latter features should not be placed in this category. Some squamous cell carcinomas may be composed of small cells resembling basal cells. These tumors may be confused with small cell carcinoma, but these tumors have been placed in a separate non small cell category called basaloid cancers by Brambilla and associates (1992). These tumors are described in Chapter 119.

Fig. 101-2. Photomicrograph of squamous cell carcinoma of the lung.

Electron Microscopic Features

Tumor cells frequently have degenerated and bizarre mitochondria and have more free ribosomes, fewer profiles of granular endoplasmic reticulum, and more lipid than normal cells. The Golgi apparatus is usually poorly developed. Squamous cell carcinomas are composed mainly of polygonal cells with distinct cell membranes and numerous desmosomes between adjacent cells. Tonofilaments, keratohyalin granules, and some keratin pearls are dominant features. No neuroendocrine granules or mucin is seen as a rule.

Immunohistochemical Features

Squamous cell carcinomas are readily stained by polyclonal antibodies to epidermal-type cytokeratin, as noted by Blobel (1984) and Gould (1992) and their associates. Schaafsma and Ramaekers (1994) identified keratins 4, 8, 13, 14, 15, 16, 17, and 18 of Moll and colleagues' (1982) catalog as being present. Many of these keratins are found in other lung tumors; however, keratin 14 is found in all squamous cell tumors but not in pulmonary adenocarcinomas or in any of the neuroendocrine tumors. Leu-7 antigen is also strongly associated with a squamous phenotype. Also, these tumor cells are stained with antibodies to epithelial membrane antigen, CEA, and desmosomal plaque proteins, but these are not unique to squamous cell differentiations.

Other molecular markers have been identified in varying percentages and in varying quantities in squamous cell tumors by numerous investigators, including D'Amico and associates (1999, 2000, 2001) at Duke University. These include those related to cell growth stimulation (EGF and erb-B2), cell cycle regulation (Rb and Ki-67), interference with apoptosis (p53 and bcl-2), tumor angiogenesis (factor VIII), invasive cell adhesion (STN and CD44), and adhesion factors (Eph-A2 and E-cadherin). Other markers, as well as those listed, will be discussed in more detail subsequently in the section on molecular and biologic markers later in this chapter.

Lastly, Berendsen and colleagues (1989) observed that neuroendocrine differentiation status could be identified by monoclonal antibody based immunohistologic procedures in a small percentage of squamous cell carcinoma cells.

Exophytic Endobronchial Squamous Cell Carcinoma

Sherwin (1992) and Dulmet-Brender (1986) and their co-workers described exophytic endobronchial squamous carcinoma as an uncommon type of squamous lung cancer with a papillomatous, polypoid, or verrucous growth pattern. This tumor has a gray-white granular to papillary appearance. It tends to fill and obstruct the bronchus. Microscopically, these tumors have a verrucous, papillary, or polypoid growth pattern with an underlying fibrovascular stalk. The epithelial cells are malignant squamous cells with intercellular junctions (prickle cells) and possible keratinization. A lymphoplasmacytic reaction may be present in the underlying connective tissue. The squamous cells usually show superficial, focal invasion into the bronchial wall, but some may be only in situ carcinoma. The electron microscopic and immunohistochemical findings in these tumors are similar to those of the typical squamous cell carcinomas.

Adenocarcinoma

Gross Features

Adenocarcinomas account for approximately 30% to 50% of all carcinomas of the lung. In 1977 Vincent and associates reported an increasing incidence of adenocarcinoma; they identified more adenocarcinomas than squamous cell tumors in 1,682 lung tumors studied. This observation was confirmed by numerous investigators, including Yesner and Carter (1982), who reported that in an

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all-male population of veterans in a two-decade period, a 7% increase in adenocarcinomas of the lung, an associated decrease of 4% in squamous cell tumors, and a 3% decrease in small cell carcinomas occurred. Amemiya and Oho (1982) noted a similar preponderance of adenocarcinoma in Japan. Travis and colleagues (1995) reported that the incidence of adenocarcinoma is 40%, that of squamous cell carcinoma 30%, that of large cell carcinoma 10%, and that of small cell lung cancer 20%, thus establishing adenocarcinoma as the most common histologic cell type of lung cancer at this time.

Adenocarcinomas are divided into five major subtypes according to their growth pattern:

  • Acinar, glandular

  • Papillary

  • Bronchioloalveolar carcinoma

  • Solid adenocarcinoma with mucin formation

  • Adenocarcinoma with mixed cell types.

Several variants, such as mucinous cystadenocarcinoma and signet ring adenocarcinoma, have been described. However, not all investigators agree that the aforementioned subtypes are of necessary importance. Moori (1996) and co-workers believe that only the bronchioloalveolar variant needs to be considered separately among the five subtypes. Miyoshi and associates (2003) have described a subtype of micropapillary pattern in small (early) adenocarcinomas. Histologically in this subset, there are no central fibroblastic cores that are normally seen in the usual early papillary tumors. The long-term survival of p stage 1 lesions without the presence of a central core versus that of the papillary lesions with a central fibrovascular core is 93% versus 79% at 5 years and 89% versus 69% at 10 years, respectively; both percentages are statistically significant.

The usual glandular variety of adenocarcinoma arises in the peripheral area of the lung, although one-fourth or even more may occur in the central area. Many of the tumors are found to arise in areas of chronic interstitial fibrosis and in conjunction with a lung scar. The so-called scar carcinoma was presumed to arise from or in the scar tissue. The studies of Barsky and co-workers (1986) and Madri and Carter (1984), however, suggested that the scars were secondary to the desmoplastic properties of the carcinoma, and it is now believed that these tumors do not represent an adenocarcinoma arising in a scar. Clinically, these so-called scar carcinomas behave as typical adenocarcinomas. It is of interest that the presence of a fibrotic focus (scar) in small peripheral adenocarcinomas is of prognostic significance. Noguchi (1995) and Eto (1996) and their associates, among others, noted that the prognosis was poorer when central fibrosis was present than when it was absent.

Recently, Suzuki and coinvestigators (2000) have shown that the size of the central fibrosis is also a significant prognostic factor. When the central fibrosis was less than 5 mm the prognosis was excellent, but as the size increased up to 15 mm the long-term survival was less. Furthermore, the worst prognosis was seen when the size of the fibrosis exceeded this 15-mm limit. In contrast to the poor prognosis of the increasing size of central fibrosis, the presence and increasing size of a ground-glass opacity on high-resolution CT of adenocarcinomas 3 cm in size or smaller portend a better prognosis. The incidence of lymph node involvement is lessened or even absent when a greater percentage of the tumor has a ground-glass appearance. Matsuguma and co-workers (2002), in a series of 96 patients with these small tumors, found that lymph node metastases were absent when a proportion greater than 50% of a lesion (26 patients) had a ground-glass opacity on high-resolution CT. When the percentage of the proportion was less than 50% (70 patients), 18.7% were found to have lymph node involvement. Lymphatic and vascular invasion showed a similar correlation.

The growth rate of the adenocarcinomas is intermediate between that of the squamous cell and the undifferentiated large cell types. The peripheral adenocarcinomas are being found in increasing numbers as small nodules 5 to 15 mm in size by helical CT scans of the lungs in asymptomatic high-risk patients, as seen in the screening studies reported by Kaneko (1996, 2000) and Sone (1998) and their colleagues in Japan, as well as by Henschke and Yankelevitz (2000) and Henschke and associates (1999) in America. When undetected, the peripheral adenocarcinomas may enlarge significantly and yet remain asymptomatic. Of interest is that in contrast to the peripheral squamous cell tumors, necrosis with cavitation is rarely observed in the large peripheral adenocarcinomas. The adenocarcinomas tend to spread early by way of the vascular system. Lymphatic metastases are also common early in the course of the disease, and small lesions appear to have a greater propensity to do so than similarly sized squamous cell tumors. Sagawa and associates (1990) reported an incidence of mediastinal node metastasis of 20% in patients with adenocarcinomas 3 cm or smaller in size as compared with a 10% incidence in similarly sized small squamous cell lesions.

Microscopic Features

The well-differentiated tumors are composed of cuboidal to columnar epithelial cells with fairly uniform round nuclei, have adequate pink or vacuolated cytoplasm, are arranged in distinct acinar or glandular patterns, and are supported by a fibrous stroma. The cells may show papillary intraluminal growth and may contain mucicarmine-positive vacuoles or secretions.

The moderately differentiated tumors are composed of nests, cords, or isolated cells, occasionally arranged in an acinar or glandular pattern (Fig. 101-3). The cytoplasm is supported by a fibrous or desmoplastic stroma. Mucicarmine-positive vacuoles may be present in this histologic subtype as well.

The poorly differentiated tumors are composed predominantly of anaplastic cells of variable size and shape with minimal but distinct evidence of acinar formation. Mucicarmine-positive

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vacuoles may be present. It has been suggested that tumors without distinct acinar formation should not be placed in the category of adenocarcinomas.

Fig. 101-3. Photomicrograph of adenocarcinoma of the lung.

Electron Microscopic Features

Adenocarcinomas are composed of cuboidal or columnar cells. Aggregates of chromatin are dispersed inside the nuclei. Well-developed apparatuses are often missing or poorly formed in many of the tumor cells. Intracellular or intercellular lumina are present. Mucin production is evident, and Clara cell or type II pneumocyte differentiation may be identified. The tumor cells show the presence of straight microvilli. Desmosomes and terminal bars may be identified.

Immunohistochemical Features

According to Lee and associates (1985, 1987) and summarized by Gould and Warren (1989), adenocarcinomas of the lung are readily immunostained with monoclonal antibodies that recognize either a membrane-associated glycoprotein molecule or the specific sugar sequence found in lacto-N-fucopentose III. Of particular interest is that these reactions, according to Gould and Warren (1995), are either absent or weakly expressed in diffuse mesotheliomas and thus may be a differentiating feature when, histologically, a mesothelioma may present as a glandular and papillary structure.

Adenocarcinomas also immunostain for epithelial keratins CK7, 8, 18, and 19. According to van de Molengraft and associates (1993), CK7 antibody (OV-TL 12/30) is a marker for glandular differentiation in lung cancer. CK14, found in all squamous cell tumors, is not present. Asada and colleagues (1993) have noted further that in most adenocarcinomas (26 of 29 tumors in their study), dipeptidyl aminopeptidase IV activity is expressed. Other markers may be identified, including CEA, found in approximately 75% of adenocarcinomas. Epithelial membrane antigen, leu-7, and vimentin are found in a minority of tumors. Surfactant apoproteins (PE-10 immunoreactivity or Clara cell protein) may be demonstrated in approximately 50% of tumors, according to Mizutani and colleagues (1988). The latter investigators did not identify PE-10 activity by pulmonary tumors of other cell types; however, Nicholson and associates (1995) have described the presence of PE-10 reactivity in both small cell carcinomas and atypical carcinoids.

Lastly, neuroendocrine differentiation features can be identified by monoclonal antibody staining techniques. Hiroshima and colleagues (2002) reported that neuroendocrine differentiation was identified in 23% (21 tumors) of 90 resected adenocarcinomas 3 cm or less in size. Only a third of these (7 tumors, 7.8% of the total number of specimens) had by the criteria of the authors sufficient neuroendocrine differentiation to presage a poorer prognosis than that of patients with tumors with no (76.7%) or nonsufficient neuroendocrine features (15.6%). The 5-year survival rates were 57% for the first group and approximately 93% for the latter two groups, respectively. As with squamous cell carcinomas, other molecular markers may be identified, as documented by D'Amico and colleagues (2000) as well as numerous other investigators.

Bronchioloalveolar Carcinoma

Bronchioloalveolar carcinoma represents highly differentiated adenocarcinoma, but many pathologists have considered it a separate and distinct tumor. Nonetheless, Moori (1996), as previously noted, believes these tumors represent a unique subset of adenocarcinoma. These tumors constitute 1.5% to 7.0% of all bronchial carcinomas, with an average incidence of 2.5%. However, Barsky and colleagues (1994a) have noted an increasing incidence of these tumors; in 1955 the bronchioloalveolar carcinomas accounted for only 5% of the resected lung cancer specimens, whereas in 1990 these tumors made up 25% of the resected lung cancers.

Grossly, these tumors may occur in one of three forms: solitary, multinodular, and diffuse or pneumonic type. The first is the most common and accounts for slightly less than one-half to almost two-thirds of the tumors of this subclassification. In the series reported by Hill (1984), the percentage of a solitary mass or nodule was 43%, and in the series reported by Harpole (1988), Daly (1991), and Ebright (2002) and their colleagues, the percentages were 59%, 69%, and 64%, respectively. Approximately 66% of the solitary tumors in Daly and associates' (1991) series were 3 cm or less in diameter. Only a small number of these, however, fit the criterion of a solitary pulmonary nodule (i.e., a well-demarcated lesion less than 3 cm in diameter completely surrounded by pulmonary parenchyma).

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In the aforementioned series of 184 bronchioloalveolar carcinomas, only an 11.2% incidence of solitary pulmonary nodules was recorded. The vast majority of the small lesions were ill-defined infiltrates. The larger diffuse tumors may appear as a mass, an infiltrate, or even consolidation of an entire lobe. The multinodular, unilateral, or bilateral lesions make up just less than 10% of the total. Direct extension beyond the lung is uncommon, and lymph node metastasis is likewise infrequent. Daly and associates (1991) recorded only a 7.5% incidence of lymph node metastasis in tumors of this type. Ebright and co-workers (2002) reported a similar incidence (7.2%) in the series from the Memorial Sloan-Kettering Cancer Center.

Singh and associates (1981) described the criteria for the diagnosis of BAC as follows: (a) absence of primary adenocarcinoma elsewhere in the body, (b) absence of a central bronchial adenocarcinoma, (c) a peripheral location, (d) growth using the alveolar septa as supporting structures (lepidic growth), and (e) a characteristic histologic appearance different from other lung tumors. In addition, aerogenous spread of the tumor within the lung is believed to be important.

Microscopically, the alveolar spaces are lined by malignant cuboidal or nonciliated columnar epithelium in layers or in papillary formation (Fig. 101-4). The alveolar spaces may be filled, or even distended, with this proliferating epithelium. Occasionally, single cells or clusters containing large multinucleated giant cells may appear lying free. The nuclei are hypochromatic, but mitoses are not common. The cytoplasm is acidophilic and abundant, or the cells may be mucous cells with extensive amounts of mucus filling the alveolar spaces. The lung architecture is most often preserved, although a few show diffuse malignant invasion. Scar formation is seen in approximately one-half of the tumors. Also, in approximately one-half of tumors, mucin-producing cells are observed as the dominant cell type. Clayton (1986) initially separated bronchioloalveolar carcinomas into two cell types: mucinous and nonmucinous (i.e., Clara cells and type II pneumocytes). Rarely, the tumor may consist of a mixture of the mucinous and nonmucinous subtypes.

Fig. 101-4. Photomicrograph of bronchioloalveolar cell carcinoma.

Clayton (1988) subsequently has divided the bronchioloalveolar carcinomas into three subgroups. Histologically, the first group is tumors composed of high columnar, mucin-producing cells with little nuclear atypia; in Clayton's series, this group made up approximately one-fourth of all bronchioloalveolar tumors. This subtype tends to spread aerogenously, forming satellite tumors. The second subgroup is made up of tumors composed of cuboidal or low columnar cells with a high degree of atypia and producing little or no mucin; psammoma bodies may be present. The third subgroup is formed by those tumors that have a central area of necrosis and that are often termed sclerosing bronchioloalveolar tumors. Barsky and associates (1994a) reported the incidences of the three subtypes as nonmucinous in 48% of cases, mucinous in 42%, and sclerotic in 10%. Of possible prognostic significance was that areas of dedifferentiation of BAC into solid areas of moderately or poorly differentiated adenocarcinoma were seen in 10%, 27%, and 42% of the nonmucinous, mucinous, and sclerotic types, respectively.

Clayton (1986) had earlier shown by electron microscopy that the bronchioloalveolar carcinomas may be composed of Clara type cells, type 2 granular pneumocytes, or mucous cells. Barsky and colleagues (1994b) also identified these three phenotypes in the bronchioloalveolar tumors and have suggested that these findings, as well as the multifocality of these cancers, are evidence of a multiclonal origin of these tumors. This conclusion was supported to some extent by the study of p53 mutations in primary and secondary lung cancers by Mitsudomi and associates (1997). However, Holst and co-workers (1998), in a study of eight multifocal cases of bronchioloalveolar carcinoma using topographic genotyping to define the spectrum of point mutational changes in K-ras-2 and p53 oncogenes, showed that although no commonality existed between the two gene mutations, the primary tumor and the satellite and intrathoracic metastases showed the same point mutations of either oncogene when present. These authors concluded that their findings support a monoclonal origin of multifocal bronchioloalveolar carcinoma, the multifocal disease being the result of intraalveolar, lymphatic, and aerosol spread.

Immunohistochemical studies by Lee and colleagues (1987) have shown that antibodies used to detect exocrine features that depend on sugar or glycolipid epitopes immunostain alveolar carcinomas regardless of mucin production. These tumor cells also immunostain for high- and low-molecular-weight keratin, epithelial membrane antigen, CEA, and Leu-7.

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Significance of Bronchioloalveolar Carcinoma

With the increased identification of small peripheral nodes less than 2 cm in size by helical CT and subsequent high-resolution CT, the separation of atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, and frank adenocarcinoma has become very important because the management and prognosis of each of these lesions are markedly different. The differentiation of AAH and BAC has been discussed previously in this chapter. Thus, the current focus will be on the separation of BAC from frank adenocarcinoma.

Noguchi and associates (1995) have separated these two subtypes into six categories by using a relatively simple histologic classification:

  • Type A, localized bronchioloalveolar carcinoma with replacement growth of alveolar-lining epithelial cells

  • Type B, localized bronchioloalveolar carcinoma with foci of structural collapse of alveoli

  • Type C, type A with foci of active fibroblastic proliferation

  • Type D, poorly differentiated adenocarcinoma

  • Type E, tubular adenocarcinoma

  • Type F, papillary adenocarcinoma with compressive growth pattern.

Types A and B have no associated lymph node metastases and have the most favorable prognosis. These latter observations were confirmed by Wu and co-workers (2001). Furthermore, in a report by Brethnach and associates (2001) reviewing 33 patients with stage I bronchioloalveolar carcinoma and 105 patients with stage I adenocarcinoma (see Chapter 105 for staging criteria) the 5-year survival rate was 83% for the former and 63% for the latter patients, respectively, the difference being statistically significant.

Undifferentiated Large Cell Carcinoma

Gross Features

Because of the lack of uniformity in the criteria for the histologic diagnosis of these lesions, their actual incidence is unknown, but is probably between the 4.5% recorded by Shinton (1963) and the 15.0% recorded by Yesner and associates (1965). Travis and associates (1995) reported the incidence to be 9%. These tumors may occur in either the central or the peripheral zone, although the latter site is somewhat more common. They spread earlier and have a relatively poorer prognosis than the more differentiated non small cell types. The peripherally located tumors may cavitate, but the incidence is less than that seen in peripheral squamous cell tumors (6% versus 15% to 20%, respectively).

Microscopic Features

These heterogeneous tumors, which cannot be classified readily either as squamous cell carcinomas or as adenocarcinomas, are considered anaplastic tumors that show no apparent evidence of squamous or glandular differentiation (Fig. 101-5). Tumors composed of stratifying cells without evidence of intercellular bridge formation or keratin production are included in this group. Individual cells have enlarged, irregular vesicular or hyperchromatic nuclei that may have prominent nucleoli. The cells have abundant cytoplasm and may show a high mitotic rate.

Fig. 101-5. Photomicrograph of undifferentiated large cell carcinoma of the lung.

Electron Microscopic and Immunohistochemical Features

Undifferentiated large cell carcinomas show marked variation in cell shape. Cell membranes are often indistinct. Large nuclei with abundant cytoplasm and numerous organelles are present. Occasionally, tonofilaments are identified, but no distinctive features are present to permit categoric determination of cell type. Warren and associates (1985) noted that dense-core granules and predominantly neuroendocrine differentiation appear in 40% of the so-called large cell tumors; such tumors are now classified as large cell neuroendocrine carcinomas.

Piehl (1988) suggested that approximately 50% of undifferentiated large cell carcinomas could be regarded as poorly differentiated adenocarcinomas given their expression of exocrine phenotype antigens. Also, Gould and colleagues (1992) reported that most of these large cell undifferentiated carcinomas express cytokeratin polypeptides of the simple epithelial type shown by adenocarcinomas and neuroendocrine neoplasms, and only a small number display cytokeratin of the epidermal type that is characteristic of squamous cell carcinoma.

Giant Cell Tumors

The so-called giant cell tumor is considered a variety of the undifferentiated large cell carcinoma. A varying combination

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of cell types may occur in this lesion: pleomorphic, anaplastic multinucleated cells, and spindle cells. The clinical course of these lesions is rapidly fatal. Fortunately, this variety is uncommon and constitutes less than 1% of all lung tumors.

Clear Cell Carcinoma

Clear cell carcinoma is considered a subtype of large cell anaplastic lung cancer, although it can also be a variant of either a squamous cell tumor or an adenocarcinoma. Histologically, these tumors are composed of malignant cells in nests, sheets, or clusters with large vesicular nuclei and abundant clear cytoplasm, which may or may not contain glycogen. Edwards and Carlyle (1985) reviewed six cases of clear cell lung carcinoma. On further analysis of the tissue by both light and electron microscopy, they found glandular differentiation in three cases and squamous differentiation in two. They concluded that clear cell carcinoma should not be considered a separate entity. Katzenstein and colleagues (1980) reviewed 348 cases of lung cancer and found 15 tumors with clear cells. Ten of these tumors showed foci of epidermoid differentiation, and 4 had glandular differentiation. Only one lesion qualified as a true clear cell carcinoma.

In summary, these two reports question the validity of having a separate category of clear cell anaplastic carcinoma, given that these tumors really appear to be poorly differentiated squamous cell carcinomas or adenocarcinomas. Even when one is attempting to classify a lesion as a clear cell carcinoma, other pathologic diagnostic possibilities must be considered (Table 101-3). Gaffey and co-workers (1998) note that immunohistochemical and electron microscopic features are necessary to establish the proper diagnosis. The features of the benign clear cell tumor (sugar tumor) are discussed in detail in Chapter 118, especially its unique reactivity to HMB45, a melanogenesis-related marker.

Table 101-3. Clear Cell Tumors of the Lung

Benign clear cell tumor (sugar tumor)
Clear cell acinic cell carcinoma
Clear cell large cell anaplastic carcinoma
Clear cell change in squamous cell carcinoma or adenocarcinoma
Clear cell carcinoid tumor
Metastatic renal cell carcinoma
Tumors showing focal clear cell change
Granular cell tumor
Bronchioloalveolar carcinoma
Oncocytoma
Mucoepidermoid carcinoma
Various miscellaneous primary and metastatic tumors
Modified from Leong AS-Y, Meredith DJ: Clear cell tumors of the lung. In Corrin B (ed): Pathology of Lung Tumors. New York: Churchill Livingstone, 1998, p. 172.

Adenosquamous Carcinoma

Adenosquamous carcinomas are defined as tumors composed of an admixture of squamous cell carcinoma and adenocarcinoma. At least 5% of the tumor should be composed of the minority cell type, according to the criteria of Takamori (1991) and Shimizu (1996) and their co-workers, although the World Health Organization (1982) gives no reference to the actual ratio. The Japan Lung Cancer Society (1987) stated that at least 20% of the tumor should be formed by the less dominant variety; this group also notes that the tumors should be categorized as 20% to 40%, 40% to 60%, and 60% to 80% of either one of the cell types.

The overall incidence of adenosquamous carcinoma is between 0.4% and 4.0%; in the surgical series reported by Takamori (1991) and Shimizu (1996) and their associates, the incidence was 2.6% and 3.4%, respectively. These tumors are more often peripheral rather than central in location. Although Ishida and co-workers (1992) reported an almost equal occurrence in men and women, Shimizu and associates (1996), in a much larger series (44 patients versus 11 patients), reported a marked preponderance in men (35:9). Three-fourths of these tumors were greater than 3 cm in size, with a range of 1.5 to 6.0 cm. Microscopically, either component may be well, moderately, or poorly differentiated. The squamous cell component was the dominant tumor in the majority of cases in Shimizu and associates' (1996) report.

Ichinose and associates (1993) reported that the DNA ploidy patterns of both components showed, despite the different phenotypes, that in 67% of the specimens examined, similar biological characteristics were present. These findings support the theory of Steele and Nettesheim (1981) that these tumors arise from instability of differentiation. Immunohistochemically, the pan keratin stained both the squamous and glandular components. The high-molecular-weight keratin stained mostly the squamous component and not the glandular one. The low-molecular-weight keratin stained the glandular component slightly more often than the squamous component, but in most cases, it did not stain either component to any great extent. The CEA and epithelial membrane antigen stained both elements of most tumors with relatively high frequency.

Blood vessel invasion is common, and lymph node metastasis occurs in over 50% of patients. The latter was present in 61% of the specimens in Takamori and associates' (1991) series. The incidence of lymphatic metastasis appears to be greater in patients with a higher percentage of adenocarcinoma present in the tumor. The cell type of the metastatic disease can vary, as shown in Table 101-4. Overall, the prognosis is poorer than that of either a squamous cell carcinoma or adenocarcinoma of a similar stage. Likewise, a greater number of patients have a higher stage of disease when initially identified. The studies of the aforementioned authors, as well as the observations of Fitzgibbons and Kern (1985) and Naunheim (1987) and Riquet (2001)

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and their colleagues, support these conclusions. It should be noted, however, that Sridhar and associates (1990) found that no significant difference existed in the survival rates of patients with adenosquamous carcinomas and those patients with other non small cell cancers.

Table 101-4. Comparison of Histologic Types Between the Primary Adenosquamous Lesions of the Lung and Lymph Node Metastasis

Primary Lesion No. of Cases Lymph Node Metastasis Lymph NodeMetastasis Absent
Ad Ad-Sq Sq
Ad > Sq 8 3 2 1 2
Ad = Sq 5 4 0 0 1
Ad < Sq 29 3 9 2 15
Total 42 10 11 3 18
Ad, adenocarcinoma; Ad-Sq, adenosquamous carcinoma; Sq, squamous cell carcinoma.
From Shimizu J, et al: A clinicopathologic study of resected cases of adenosquamous carcinoma of the lung. Chest 109:989, 1996. With permission.

Small Cell Lung Cancers: Grade III Poorly Differentiated Neuroendocrine Carcinomas Type (b)

Small cell lung cancers are aggressive, highly malignant lesions. Only a few patients with these tumors are considered surgical candidates. The origin of these lesions, as previously noted, is debated and as yet unsettled. Yesner (1977, 1986) believes these tumors arise from the same stem cells that give rise to the NSCLCs, whereas other authors think they arise from basally located neuroendocrine cells (endodermal Kulchitsky's cells) or their precursors.

The cells of these tumors have the features of neuroendocrine cells, including common expression of amine precursor uptake and decarboxylation cell properties. Many investigators, including Gould and colleagues (1983a, 1983b), Travis (1994), and Gould and Warren (1995), categorize these tumors as one of the neuroendocrine tumors of the lung. However, in this chapter the SCLCs are considered separately from the other tumors in this category. According to Moori (1996) and others, the World Health Organization classification is not appropriate because both the typical oat cell tumors and the intermediate small cell tumors behave essentially in a similar manner clinically. Hirsch and colleagues (1988) and, more recently, Moori (1996) have suggested that the tumors' reported pathologic differences may only be artifacts caused by variations in processing of these tumors for histologic examination. As shown in Table 101-5, Hirsch and associates (1988) have classified these tumors as pure small cell carcinoma, mixed small cell large cell carcinoma, and combined small cell carcinoma with areas of squamous or glandular differentiation. Each of these types makes up approximately 90%, 4% to 6%, and 6% to 4% of cases, respectively.

Table 101-5. Classification of Small Cell Lung Carcinoma

Pure small cell carcinoma
Mixed small cell large cell carcinoma
Combined small cell carcinoma admixed with either squamous cell carcinoma or adenocarcinoma
Adapted from Hirsch FR, et al: Histopathologic classification of small cell lung cancer. Changing concepts and terminology. Cancer 62:973, 1988.

Gross Features

The various types of small cell tumors constitute approximately 15% to 35% of all bronchial carcinomas. Approximately four-fifths of these arise in the central area, and the remainder arise in the peripheral area of the lung. The mucosa overlying the tumor in the bronchus is frequently uninvolved, although the normal furrowing of the mucosa may be obliterated. Tumors arising in either region involve the hilar and mediastinal lymph nodes early. Central necrosis with cavitation within the tumor or changes in the parenchyma of the lung distal to the tumor occur less frequently than do such changes in squamous cell carcinomas.

Microscopic Features

Pure Small Cell Carcinomas

The histologic features may be either those of the typical or intermediate cell type. The first type is characterized by clusters, nests, or sheets of small, round, oval, or spindle-shaped cells with small, dark, round nuclei, with delicate chromatin and without prominent nucleoli (Fig. 101-6). Cytoplasm is scanty and the cells are supported by a vascular fibrous stroma. The second type, the intermediate small cell carcinoma, is composed of clusters or sheets of slightly larger size than the typical small cell and is fusiform or polygonal in shape. The cytoplasm, although still scanty, is more distinct. The central nuclei tend to have peripheral aggregations of clumped chromatin material. This form of pure small cell tumor is occasionally misclassified as undifferentiated large cell carcinoma.

Mixed Small Cell Large Cell Carcinomas

Histologically, mixed small cell large cell tumors present varying combinations of areas of pure small cells, often of the fusiform or polygonal type, and large cells in an organized, trabecular, or palisading pattern. The latter cells have a low nuclear cytoplasmic ratio, and mitotic figures are frequently seen.

Fig. 101-6. Photomicrograph of undifferentiated small cell carcinoma of the lung.

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Combined Small Cell Carcinoma Admixed with Either Squamous Cell Carcinoma or Adenocarcinoma

In these tumors, areas of either typical squamous cell carcinoma or adenocarcinoma are readily identified within the small cell carcinoma. Adelstein and colleagues (1986) noted that 10% of their patients with SCLC had a major type of NSCLC present. Baker (1987) and Shepherd (1989) and their associates, as well as others, have observed that the incidence of the presence of areas of non small cell carcinoma in small cell tumors is increased after chemotherapy. In fact, at times only non small cell cancer cells can be identified in a tumor that was a pure small cell cancer on the original biopsy specimen.

Electron Microscopic Features

Undifferentiated small cell carcinoma reveals cellular pleomorphism, but the shape of the cell is usually round to ovoid in transection. Some cells adjacent to the basement membrane possess pseudopodlike processes extending between adjacent cells. Cell membranes are often indistinct. The nuclei are large, often with eccentric nucleoli, and are surrounded by a narrow zone of cytoplasm. Bensch and co-workers (1968) identified neurosecretory granules in the undifferentiated small cell tumors, which many authors, including Warren and associates (1985), subsequently have confirmed. According to Moori and colleagues (1986), the neuroendocrine granules can almost always be found in the cells of the pure small cell tumors as well as in the cells of the mixed small cell large cell tumors.

Biological Behavior

The small cell tumors have been studied extensively in cell cultures, and such cultures can be established in 75% of small cell cancers. The cultures can be separated into two cell lines: the classic cell line and the variant line. The former is characterized by tight spherical aggregates and has a doubling time of 50 hours and low colony-forming efficiency, whereas the latter grows in looser aggregates of floating cell lines and has a faster doubling time and a greater colony-forming efficiency. The classic line corresponds to the pure small cell carcinoma, expresses the usual production of the various biological substances, and contains many dense granules. The variant lines have few granules, produce fewer biologically active substances, such as adrenocorticotropic hormone, and resemble the combined cell types clinically. The production of peptides is characteristic of small cell carcinoma. Classic small cell lines produce L-dopa decarboxylase, adrenocorticotropic hormone, bombesin or its mammalian analogue gastrin-releasing peptide (GRP), neuron-specific enolase, and creatine kinase. The variant lines do not produce L-dopa decarboxylase or bombesin, and the level of neuron-specific enolase is usually significantly lower.

Immunohistochemical Features

The SCLC cells react positively to neuron-specific enolase, creatine kinase, synaptophysin, chromogranin, and occasionally to serotonin. Positivity is often shown to epidermal growth factor (EGF), cytokeratins 8 and 18 of Moll's catalog, and Leu-7.

Large Cell Neuroendocrine Carcinomas: Grade III Poorly Differentiated Neuroendocrine Carcinoma, Type (a)

Travis and co-workers (1991) identified a fourth subset of neuroendocrine tumors of the lung: the large cell neuroendocrine carcinomas. Garcia-Yuste and colleagues (2000) recorded that one-third of these tumors are located centrally and two-thirds are located peripherally in the lungs.

Histologic Features

Microscopically, the cells of these tumors have an organoid, trabecular, or palisading pattern. The tumor cells are large, with a low nuclear cytoplasmic ratio and eosinophilic cytoplasm. Saldiva and associates (1997) describe the nuclei as showing peripheral clumping of chromatin and a prominent nucleolus. Hasleton (1996) reported similar findings, but Travis and colleagues (1998a, 1998b) have reported the nucleoli to often be absent or faint at best. Mitotic activity is high, and often extensive necrosis is

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present. Travis and associates (1998a) have used these two features to aid in the differentiation of the large cell tumors from the atypical carcinoids (Table 101-6). Lastly, foci of adenomatous or squamous differentiation may be present.

Table 101-6. Modified Diagnostic Criteria for Neuroendocrine Lung Tumors

Tumor Mitotic Activitya Necrosisa Retinoblastoma Protein Expressionb
Typical carcinoid <2 per 10 HPF Absent Few strongly positive cells
Atypical carcinoid >2, <10 per 10 HPF Punctate Many strongly positive cells
Large cell neuroendocrine >11 per 10 HPFc Extensive No positive staining
Small cell neuroendocrine >11 per 10 HPFd Extensive No positive staining
a Adapted from data from Travis WD, et al: Survival analysis of 200 pulmonary neuroendocrine tumors with classification of criteria for atypical carcinoid and its separation from typical carcinoids. Am J Surg Pathol 22:934, 1998a.
b Adapted from the data of Cagle PT, et al: Differential retinoblastoma protein expression in neuroendocrine tumors of the lung. Potential diagnostic implications. Am J Pathol 150:393, 1997.
c Median number of 70 per 10 HPF.
d Median number of 80 per 10 HPF.
HPF, high-power field.

Electron Microscopic and Immunohistochemical Features

Travis and colleagues (1991) described the electron microscopic and immunohistochemical features of these tumors. Electron microscopy revealed that these tumor cells contain neurosecretory granules and occasionally a suggestion of granular differentiation or intercellular junctions suggestive of squamous differentiation. Immunohistochemically, these tumor cells stain for neuron-specific enolase, CEA, and keratin and stain variably for chromogranin, Leu-7, synaptophysin, and adrenocorticotropic hormone. Wick and associates (1992) have confirmed these findings. Takei and colleagues (2002) have suggested the use of three neuroendocrine markers to identify a neuroendocrine tumor: neural cell adhesion molecule, chromogranin A, and synaptophysin. Focal staining by at least one of these three neuroendocrine markers was deemed to represent positivity for the presence of neuroendocrine phenotype.

Clinical Features

The clinical course, response to treatment, and prognosis of large cell neuroendocrine tumors of the lung are yet to be determined. Only small numbers of cases have been reported, but the majority view suggests that these patients on the whole respond poorly to treatment and have a poor prognosis. The report of Dresler and colleagues (1997) of 40 cases cites a 13% 5-year survival despite early-stage disease in many patients, which supports the aforementioned statement; however, this latter report has been criticized by Travis and associates (1998a) because they believe the diagnostic criteria were not strict enough to ensure a true representation of this tumor's clinical behavior. In the more recent report by Garcia-Yuste and co-investigators (2000), a 5-year survival of 20.8% was recorded in 22 patients who had undergone surgical resection of this tumor, followed by either adjuvant chemotherapy or radiation therapy in 12 of the patients. However, this survival rate was not statistically different than that obtained in 31 highly selected patients with typical small cell cancers (most were stage I cancers) managed by surgical resection followed by postoperative adjuvant chemoradiation therapy. Iyoda and associates (2002) likewise have found these neuroendocrine large cell tumors to be very aggressive. Despite 5- and 10-year disease-free survival rates of 25.6% and 18.6%, respectively, for the neuroendocrine large cell tumors as compared with 5- and 10-year survival rates of 16.6% and 12.4%, respectively, for SCLCs, there was no statistically significant difference in survival between the two groups. Although Takei and colleagues (2002) reported an overall higher survival rate in 87 patients with large cell neuroendocrine carcinoma of the lung (a 5-year survival of 57%) than recorded in the aforementioned series, again there was no significant difference in survival between the large cell neuroendocrine tumors and the 31 patients with SCLC in their study.

METASTASIS OF BRONCHIAL CARCINOMA

Carcinoma of the lung has three modes of spread. Its dissemination occurs by direct extension and by lymphatic and hematogenous metastases.

Direct Extension

A lung tumor may extend directly into the adjacent pulmonary parenchyma, across the fissure, along the bronchus of origin, and also into adjacent structures in the thorax.

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Commonly, tumors situated in the central area extend directly along the bronchus.

Cotton (1959) studied this bronchial extension and noted five important factors in this type of spread:

  • Direct extension continuous with the tumor in the bronchial wall and the adjacent peribronchial tissues

  • Direct extension into bronchi other than the bronchus of origin, particularly by tumors arising close to a segmental or a major lobar bronchial orifice

  • Invasion of the submucosal lymphatics in the bronchial wall

  • Extension of the tumor proximally along the lumen of the bronchus by papillary or polypoid process without further attachment to the bronchial wall

  • The presence of epithelial metaplasia, particularly if the epithelial change shows atypical proliferative features.

Cotton (1959) found that spread into the bronchial wall beyond the palpable mass occurred in 12% of patients with lung cancer, and the maximum distance of the spread was three-fourths of an inch (1.9 cm). This extent of spread essentially agrees with findings reported by Griess and colleagues (1945), who found that the proximal extension of tumor in the bronchial wall could be removed satisfactorily if the line of resection included 1.5 cm of grossly normal bronchus. Polypoid extension of the tumor into the lumen of the bronchus without bronchial wall involvement was observed as far as 2.5 to 3.2 cm. Submucosal lymphatic spread was noted in only 6% of the tumors, and these specimens had extensive lymph node involvement. Cotton (1959) found epithelial metaplasia beyond the tumor in 31 of 100 specimens, but it was extensive in only 8 specimens. In these 8, it extended as far as 5 cm. All the aforementioned factors are important considerations in the surgical treatment of carcinoma of the lung.

Most important, however, is that direct extension occurs into adjacent structures within the thorax. The sites commonly involved are the pleura, pulmonary vessels, chest wall, superior sulcus area and its adjacent neurogenic and bony structures, diaphragm, pericardium, and heart and great vessels. Although direct extension from the tumor may involve the superior vena cava, contiguous nerves (i.e., the recurrent laryngeal and phrenic nerves), and esophagus, these structures more frequently are invaded by secondary extension from metastatic disease within the mediastinal lymph nodes.

Occult Pleural Dissemination

Pleural lavage in the absence of gross pleural seeding with cytologic examination of the cells collected both before and after resection of a lung cancer may identify occult pleural spread. Eagan and associates (1984) were among the first to note that tumor cells could be present in the pleural cavity in the absence of effusion or gross disease. Buhr and colleagues (1989, 1990, 1997) noted that lavage specimens in 132 patients (38.6%) with early localized lung carcinomas were positive for tumor cells. Kondo (1989, 1993), Okumura (1991), and Arnau Obrer (1996) and their associates recorded similar findings, although the incidence of tumor cells was lower in these studies: 9%, 14%, and 26.7%, respectively. Additional reports by Higashiyama (1997), Hillerdal (1998), Okada (1999), and Dresler (1999) and their co-workers recorded similar data, as noted in the review of Jiao and Krasna (2002). In most of these studies the presence of tumor cells in the lavage specimens portended a poorer prognosis for the patient, particularly in those with early disease, with the exception of the reports by Arnau Obrer and associates (1996), in which no survival data were presented, and by Hillerdal and colleagues (1998), in which no relevance to survival was noted.

The source of the tumor cells in the pleural space is yet to be determined. Exfoliation of tumor cells, lymphatic invasion within the lung, and vascular invasion have been suggested by the various aforementioned investigators. Once the cells are free within the pleural space, they may gain access into the general circulation via the parietal pleural lymphatics, as noted in Chapter 54.

Lymphatic Metastasis

Lymphatic metastasis is common in patients with carcinoma of the lung. Ochsner and DeBakey (1942) reported regional node metastases in 72.2% of 3,047 lung cancer patients studied. Cell type, as noted, affects the rate of incidence; it occurs in undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenosquamous cell carcinoma, adenocarcinoma, and squamous cell carcinoma, in order of decreasing frequency. According to Martini and Ginsberg (1990), approximately one-half of patients with NSCLC have mediastinal lymph node involvement at the time of presentation. This, of course, is not reflected in the surgical series reported in the literature.

In many patients, the initial lymphatic metastases are either to the lobar or hilar nodes of the ipsilateral lung, but in some, as has been noted in Chapter 6, the mediastinal lymph nodes may be the initial site. The sites of potential involvement from each lobe are described in detail in the aforementioned chapter. The most important intrapulmonary area is the lymphatic sump of each lung, as defined by Borrie (1952). With progression of the lymphatic spread of the tumor, the various lymph node groups of the mediastinum become involved. However, lymph node involvement is not systematically progressive from the tumor to the most adjacent node group and then successively to the next higher lymph node level or levels. Instead, any given lymph node level (segmental, bronchial, hilar, or mediastinal) associated with the lymphatic drainage pattern of each lobe (described in Chapter 6) may be bypassed in the lymphatic metastasis of the tumor. Lymphatic spread to the mediastinal nodes, however, is most often regional [i.e., upper

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lobe tumors metastasize to the superior mediastinal node levels (stations 1 to 6), and the lower lobe tumors metastasize to the inferior lymph node groups (stations 7 to 9)]. Nonregional metastases do occur (i.e., upper lobe tumors to inferior mediastinal nodes, and lower lobe tumors to superior mediastinal nodes). Watanabe (1996) observed that in 182 patients with mediastinal node metastases resected at operation (77 with a single level of metastasis and 105 with multilevel metastasis), most of the metastases were noted in the regional lymph nodes. The upper lobe lesions primarily involved the upper superior mediastinal node levels (levels 4, 3, and 2 on the right and levels 6, 5, 4, 3, and 2 on the left). The lower lobe tumors mostly involved the levels in the inferior mediastinum (7, 8, and 9 on both the right and left sides). It was also noted that tumors in the right and left lower lobes involved the nonregional superior mediastinal nodes, and tumors of the right upper lobe involved the nonregional inferior nodes more frequently than tumors of the left upper lobe involved the nonregional inferior mediastinal nodes. An exception to this latter statement is that when metastatic lymph node involvement occurs with a tumor arising in the lingular (inferior) segment of the left upper lobe, the metastatic disease is located in a station 7 node in 50% of instances, as noted by Asamura and associates (1999).

In patients with small peripheral primary NSCLC less than 3 cm in size, Naruke (2000) and Asamura and colleagues (1996) have recorded that the most commonly involved mediastinal lymph node station or stations for each pulmonary lobe are relatively constant. These lymph nodes have been termed the sentinel lymph nodes. These sentinel lymph node stations are listed in Table 101-7. When metastatic disease is absent in the respective station or stations, the possibility of having other mediastinal lymph node stations involved is quite low. However, such involvement does occur on occasion. Watanabe and co-workers (1990), as well as other investigators, have described solitary involvement of other lymph node stations, especially station 7 (subcarinal nodes) in patients with primary tumors of the right upper lobe and those with tumors in the lingular division of the left upper lobe.

Table 101-7. Location of Sentinel Mediastinal Lymph Nodes in Patients with Small Peripheral Non Small Cell Lung Carcinomas

Site of Primary Tumor Sentinel Node(s)
Right upper lobe 4, 3
Right middle lobe 3, 7
Right lower lobe 7
Left upper lobe 5, 6
Left lower lobe 7
From the data of Asamura H, et al: Lymph node involvement, recurrence, and prognosis in resected small peripheral, non-small cell lung carcinomas. Are these carcinomas candidates for video-assisted lobectomy? J Thorac Cardiovasc Surg 111:1125, 1996.

Of interest relative to the designation of the aforementioned sentinel mediastinal lymph node in small tumors (<2 cm in size) is the report of Ichinose and coinvestigators (2001), who documented the stations of lymph node involvement in 406 N2 patients (126 with T1 tumors, 229 with T2 tumors, and 47 with T3 tumors). These investigators found a very similar, although not identical, distribution of metastases from the various pulmonary lobes when only a single lymph node station was involved; these stations likewise remained the most commonly involved station when two or more N2 stations contained metastatic disease (Table 101-8).

These aforementioned sentinel lymph nodes should not be confused with the sentinel lymph node described by Liptay and associates (2000). This latter node is the initial bronchopulmonary, hilar, or mediastinal lymph node that is identified by radioisotope uptake after injection of the radioisotope substance into the primary tumor at the time of

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operation. The significance of this sentinel lymph node being positive or negative for metastatic involvement is yet to be determined.

Table 101-8. Most Commonly Involved N2 Stations in 402 Patients with Resected N2 Disease

  Right Upper Lobe Middle and Right Lower Lobe Left Upper Lobe Left Lower Lobe
Single Station Two or More Single Station Two or More Single Station Two or More Single Station Two or More
Lymph node station
   1 9% 54%
   2     7%
   3 54%a 89%a 16% 68%
   4 23% 64%   46% 12% 51% 17% 48%
   5         61%a 78%a 10% 59%
   6         19% 51%
   7     62%a 86%a     57%a 72%a
No. of patients 59 56 61 57 59 51 30 29
No. of stations involved 59 171 61 178 59 138 30 77
a Most commonly involved station.
Adapted from the data of Ichinose Y, et al: Completely resected stage IIIa non small cell lung cancer: the significance of primary tumor location and N2 station. J Thorac Cardiovasc Surg 122:803, 2001.

A variable number of patients (approximately 25% to 29% of patients who undergo resection of lung tumors with involved mediastinal lymph nodes) have no metastatic involvement of either the hilar or lobar nodes. Such metastatic mediastinal disease is referred to as skip metastases by Libshitz and colleagues (1986), Martini and Flehinger (1987), and Martini (1983) and Ishida (1990b) and their associates. The probable pathways of these skip metastases have been described by many of the early investigators of the lymphatic drainage of the lungs, as well as more recently by Riquet (1993) and colleagues (1989) (see Chapter 6). Clinically, skip metastases are seen more commonly in patients with peripheral adenocarcinomas located in either upper lobe. Watanabe and associates (1990) reported a higher frequency of metastatic involvement of lower inferior mediastinal lymph nodes in patients with right upper lobe lesions than was recorded in most earlier studies. These authors noted that in 11% of the patients with right upper lobe primary lesions, metastasis to the inferior mediastinal nodes (i.e., subcarinal nodes) was the only mediastinal lymph node involvement present. This finding supports the recommendation of the Lung Cancer Study Group reported by Thomas and colleagues (1988) that the subcarinal lymph nodes be evaluated in all patients regardless of the primary site of the tumor.

The spread of tumors from the various lobes of the lung to the tracheobronchial and other mediastinal lymph nodes is usually ipsilateral. Contralateral spread, however, does occur. From the right side, such contralateral spread is unusual. Nohl-Oser (1989) (see Chapter 6) reported this spread in only 4% of patients with right upper lobe tumors and 5% of those with right lower lobe tumors. On the left side, however, patients with upper lobe lesions had a 9.3% incidence of contralateral spread, and those with lower lobe tumors had a 28% incidence. Greschuchna and Maassen (1973) also reported a high incidence of bilateral or contralateral spread (a total of 21% in 540 patients with nodal metastases from bronchial carcinoma routinely investigated by mediastinoscopy). In an update of his continuing experience, Maassen (1985) noted that 30% of his patients had locally advanced stage III disease, and that the incidence of positive mediastinal nodes was 71% in this group. The high incidence of advanced disease obviously influenced the high rate of contralateral spread originally reported. Hata and colleagues (1990) reported that contralateral spread from the left lung to the right side of the mediastinum was affected by the cell type of the primary lung tumor. Contralateral spread was more common with adenocarcinoma than with squamous cell carcinoma (Table 101-9), and, in fact, contralateral spread rarely is seen in early clinical stage I squamous cell tumors.

Table 101-9. Influence of Cell Type and Contralateral Lymph Node Metastasis (Left Lung)

Primary Site Cell Type (%)
Squamous Cell Adenocarcinoma Total
Left upper lobe 12 37.5 18.2
Left lower lobe 20 50 28.6
Total 14.3 41.7 21.3
From Hata E, et al: Rationale for extended lymphadenectomy for lung cancer. Theor Surg 5:19, 1990. With permission.

The size of the primary non small cell carcinoma also affects the incidence of mediastinal lymph node metastasis. Miller and associates (2002) from the Mayo Clinic noted an incidence of mediastinal node metastases of 7% in 101 patients with tumors 10 mm or less in size. Yankelevitz and Henschke (2000) have even reported the detection of mediastinal lymph node metastases in several patients with lung cancers (adenocarcinomas) only 4 mm in size. On the other hand, however, Ishida and associates (1990a) reported no positive mediastinal nodes in any tumor less than 1 cm in diameter, a 12% incidence in tumors ranging from 1.1 to 2.0 cm, and a 25% incidence of involvement in tumors 2.1 to 3.0 cm in diameter in a series of 221 patients with tumors 3 cm or less in diameter. Sagawa and colleagues (1990) reported similar data in tumors 3 cm or less in size: 8.9% and 24.5%, respectively, for lesions 2 cm or less versus tumors 2.1 to 3.0 cm. The overall incidence of 19% of mediastinal lymph node involvement in patients with T1 tumors in the two aforementioned series is similar to the 17% incidence reported by Vallieres and Waters (1987). In the latter series, such metastases were most common in patients with large cell carcinomas (33%), less so in patients with adenocarcinoma (17%), and infrequent in patients with squamous cell tumors (10%). Watanabe (1996) reported that in 1,053 patients with resected and nonresected lung cancers (875 were peripheral in location and 178 were hilar in location), the incidence of N1, N2, and N3 metastatic disease was 14%, 27%, and 4%, respectively. The incidence of N2 disease increased as the tumor size increased, as in the aforementioned series. Patients with tumors of less than 10 mm had an incidence of less than 2%; when the tumor size was 11 to 20 mm, the incidence was 15%; when the size was 21 to 30 mm, the incidence was 24%; and when the size was greater than 30 mm, more than 30% of the patients had N2 disease (Fig. 101-7). Comparable data are not available for tumors of larger size, but in most surgical series, such as those of Martini and Flehinger (1987) and Naruke (1978, 1988), Watanabe (1990), and Ishida (1990b) and their colleagues, mediastinal lymph node involvement is three or more times more common with lesions greater than 3 cm in diameter than with smaller primary lesions.

In patients with radiographically occult tumors that are localized only by bronchoscopy, Nagamoto and associates (1989) reported a zero incidence of lymph node metastasis if the tumor was only a carcinoma in situ or if the longitudinal length of an invasive lesion was less than 20 mm. If the length of involvement was greater, as was noted in a total of 25 patients, a 24% incidence of hilar/lobar lymph node invasion

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was observed, as was a 4% incidence of mediastinal node invasion. In each of these cases, the tumor had extended beyond the bronchial wall.

Fig. 101-7. Incidence of lymph node metastasis in relation to tumor diameter. From Watanabe Y: Results of surgery for N2 non small cell lung cancer. J Thorac Cardiovasc Surg 2:85, 1996. With permission.

Lymph nodes beyond the thorax may become involved with metastatic disease. Supraclavicular and, infrequently, other cervical lymph node metastasis occurs in approximately 16% of all lung cancer patients, although Naruke (1993) recorded an incidence of 31.4% in 1,065 autopsy specimens at the National Cancer Center Hospital in Tokyo. The incidence of involvement of the scalene (supraclavicular) lymph nodes is affected by the location, in the right or left lung, of the primary tumor, according to Kiricuta and colleagues (1994). In assessing 266 patients for irradiation, these authors found that in 105 patients with tumors in the left lung, scalene node involvement was present in 13.3% (9.5% of the nodes were ipsilateral and 3.8% were contralateral in location). In 161 patients with tumors in the right lung, the incidence was 10.3% (8.5% were ipsilateral and 1.8% were contralateral, respectively). The overall incidence was slightly greater than 11%. Lee and Ginsberg (1996) also noted that the extent and location of intrathoracic mediastinal lymph node involvement affected the incidence of scalene lymph node disease. In a small series of patients with right-sided tumors undergoing mediastinoscopy, they found that 15.4% of patients with N2 disease had occult scalene node metastases, whereas those with intrathoracic N3 disease (contralateral mediastinal lymph node metastases) had an incidence of 68.4%. No patient with only either N0 or N1 disease had scalene node involvement.

Lymph nodes in the paraaortic region below the diaphragm are involved in approximately 8% of patients. Riquet and colleagues (1988, 1990) demonstrated direct connection to these lymph nodes from the lungs in a small percentage of patients.

Axillary lymph nodes are rarely involved. Although over 50 years ago Ochsner and DeBakey (1942) reported an incidence of 6.6% in a collective review, Riquet and associates (1998) reported an incidence of less than 1%. In 1,233 patients resected for cure, these latter authors observed the presence of axillary lymph node involvement at the time of operation in one patient with chest wall involvement (1 in 147 patients with such disease, an incidence of 0.6%) and in eight other patients during subsequent follow-up. The overall incidence was 0.7% in this select group of patients. The commonly held concept that chest wall involvement is a major factor in the occurrence of axillary node metastases is not supported by Riquet and colleagues' (1998) findings.

A second hypothesis is that of retrograde spread from involved supraclavicular lymph nodes, as suggested by Marcantonio and Libshitz (1995) from their observations of computed tomographic findings in 17 patients (the total patient base was not stated). These latter authors also noted in support of their hypothesis that M. M. Lindell, in a personal communication, had recorded a 2% incidence of retrograde lymphatic flow from the supraclavicular nodes to the axillary nodes in 200 bipedal lymphangiograms. However, Riquet and associates (1998) refute this hypothesis from their own observations and suggest that the most likely route of spread is hematogenous in nature. This certainly is true for the rare occurrence of inguinal lymph node involvement [0.08% in Riquet and associates' (1998) series].

Hematogenous Spread

Blood-borne metastases are common in patients with bronchial carcinoma. Direct invasion of the smaller branches of the pulmonary veins occurs in many of the patients with these tumors. At times, a major vein may be filled with tumor, which may extend even as far as the left atrium. Invasion of the pulmonary artery also occurs.

Detectable blood vessel invasion on histologic examination of the tumor has been documented in most surgical series to portend an unfavorable prognosis, although in reviewing data from the Veterans Administration Surgical Oncology Group's lung studies, I (1983) did not find that parenchymal blood vessel invasion had prognostic significance. Interestingly, however, parenchymal lymphatic vessel invasion, even in the absence of lymph node metastases, suggested a poor prognosis.

The finding of tumor cells in the circulation has not been well-correlated with prognosis. The fate of these circulating cells is undetermined in the individual patient, but these cells are certainly responsible for the development of metastatic deposits in distal organs at one time or another in the host tumor relationship.

The size of the lesion, as well as its histology as noted, affects the initial incidence of distant metastatic spread. Hematogenous metastasis is rare in lesions less than 10 mm in diameter and, in fact, Ishida and associates (1990a) recorded no occurrences of this type of spread in their experience in patients with small (<10 mm) NSCLCs. They did note, however, a 4% and 5% incidence of hematogenous metastasis, respectively, in lesions 1.1 to 2.0 cm and 2.1 to 3.0 cm in diameter. In larger lesions, both occult and clinically manifest distant metastases are more common. Accurate data, however, are not readily available.

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The organs and structures most commonly involved by hematogenous spread at the time of diagnosis are the brain, skeletal system, liver, adrenal glands, kidneys, lungs, spleen, and pancreas, according to the study of Quint and colleagues (1996). The incidence of brain metastasis varies with the cell type, the extent of disease at time of presentation, and duration of the patient's survival after appropriate treatment of the primary lesion. Salbeck and associates (1990) reported that in a total of 271 patients with lung cancer who underwent computed tomographic scans of the brain during initial staging, metastatic disease was present in 11% of the asymptomatic patients and in 33% of the patients with symptoms of possible brain involvement. Asymptomatic patients with SCLC had an incidence of 11.9%, whereas asymptomatic patients with NSCLC had an incidence of 17.5%. However, the incidence was zero in all stage I and II NSCLC patients, and all occult metastases were identified in stage III patients: squamous cell carcinoma, 4.9%; adenocarcinoma, 12.1%; and large cell undifferentiated carcinoma, 38.5%. In symptomatic patients the incidences were 37.5%, 66.7%, and 40.0%, respectively. In symptomatic patients with SCLC, the incidence was 21.1%. The overall incidence was highest in patients with large cell carcinoma, followed in the order of decreasing frequency by those with adenocarcinoma, small cell carcinoma, and squamous cell carcinomas. No brain metastases were recorded in patients with mixed cell histology. Furthermore, it is to be noted that in almost all surgical series, such as those of Martini (1983), Feld (1984), Pairolero (1984), and Ichinose (1989) and their associates, the brain is the most common site of initial failure caused by metastatic disease.

Skeletal metastases are usually osteolytic; they occur most commonly in the ribs, spine, femur, humerus, and pelvis. Metastatic deposits distal to the knee or elbow are rare. Although, as Clain (1965) noted, the incidence of bony metastasis from carcinoma of the lung is less than that from four other primary sites (i.e., prostate gland, breast, kidney, and thyroid gland), the lung is second only to the breast as the most common primary site of metastases to bone.

Metastatic deposits may occur in the skin and subcutaneous tissue, myocardium, thyroid gland, small intestine, spleen, and ovary. Although deposits in these locations are uncommon, the lung is the most common primary site responsible for secondary metastases in the heart. After carcinoma of the breast and melanoma, the lung is the next most common primary site for metastases to the skin and subcutaneous tissue. Rosen (1980) reported that cutaneous metastases occur in 2.8% to 7.5% of lung cancer patients. As noted by Coslett and Katlic (1990), such metastases may be the initial manifestation in a small number of patients.

OCCULT MICROMETASTATIC DISEASE

Since the late 1980s, there has been increasing interest in the documentation and significance of the occurrence of occult micrometastatic disease in patients with resectable, early NSCLC. Occult micrometastatic disease may be defined as the presence of one or more malignant cells, up to clumps of malignant cells less than 2 mm in size. These tumor deposits, as a rule, cannot be identified by standard light microscopic techniques (hematoxylin and eosin stain) but can be detected by either genetic (molecular) or immunohistochemical techniques. Occult micrometastatic deposits have been identified in blood and bone marrow, as well as in bronchopulmonary, hilar, and mediastinal lymph nodes that were considered to be free of metastatic involvement by standard histologic examination.

The Identification of Occult Micrometastases

Genetic Techniques

Generally one of two genetic techniques, either (a) single-strand conformation polymorphism (which can be performed by either mutant allele-specific amplification or oligonucleotide hybridization) or (b) reverse transcriptase polymerase chain reaction (RT-PCR), has been used. The latter has been the more commonly preferred technique. Betz and colleagues (1995) have used surfactant protein gene expression, and Salerno and associates (1998) reported the use of RT-PCR to detect messenger RNA (mRNA) transcriptase for MUC1 (a cell surface glycoprotein present in lung tissue but absent in normal lymph nodes). Unfortunately, MUC1 has subsequently been found on various normal cells by Brugger (1999) and Dent (1999) and their co-workers, and it is no longer believed to be a suitable tumor marker. Keratin gene fractions (CK19 mRNA) have also been identified by the RT-PCR technique. Ahrendt and coinvestigators (2002) have reported the use of direct sequencing by allele-specific ligation for K-ras mutations and oligonucleotide hybridization of TP53 in NSCLC specimens. D'Cunha and colleagues (2002) have used RT-PCR for the identification of CEA mRNA as a marker for occult micrometastases and for quantitation of the micrometastatic tumor burden in the mediastinal lymph nodes in patients with stage I NSCLC.

Immunohistochemical Techniques

Immunohistochemical identification of occult micrometastatic disease is not as sensitive as the RT-PCR technique but is quite satisfactory in demonstrating occult micrometastatic disease in bone marrow and lymphatic tissue, according to most investigators. Passlick (1994, 1996, 1999) and Izbicki (1996) and their associates reported the use of antiepithelial monoclonal antibody BerEp4. Passlick (2001) noted that Momburg (1987) and Latza (1990) and their colleagues presented evidence that monoclonal antibody BerEp4 is directed against two glycopolypeptides of 34 and 49 kDa present on the surface and in the cytoplasm of all epithelial cells except the superficial layers of squamous epithelium, hepatocytes, and parietal cells. The antibody does not react with mesenchymal tissue, including

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lymphoid tissue. Passlick (2001) found that it stained 81 of 82 primary lung tumors (45 adenocarcinomas and 37 squamous cell carcinomas).

Dobashi and colleagues (1997) and Gu and associates (2002) have used the monoclonal antibody anti-p53 for the identification of micrometastatic disease. A major drawback of the use of p53 is that it can only be used when the primary tumor is stained positively, and this only occurs in approximately 50% of primary non small cell lung tumors.

Ohta and associates (2000, 2001), among many others including Pantel (1996), Cote (1998), and Chen (1993) and their co-workers, have used various monoclonal anticytokeratin antibodies to identify cytokeratin polypeptides to label micrometastatic lung cancer cells. Ohgami and associates (1997) have used CK2, a monoclonal antikeratin antibody, to recognize cytokeratin 18 in lymph nodes and bone marrow, which is not normally present in either of these two sites.

Micrometastasis in Blood

The detection and quantification of circulating cancer cells in the peripheral blood has been carried out in patients with lung cancer by several groups of investigators using the RT-PCR techniques to identify products of cancer cells that are not normally found in the blood. Castaldo (1997) and Kurusu (1999) and their associates have used RT-PCR of carcinoembryonic antigen messenger RNA in patients with NSCLC, whereas Bessho and colleagues (2000) have used the neuromedian B receptor (NMB-R) gene (one of the bombesinlike peptide receptors) in patients with SCLC. The initial data in all three studies show some correlation of the degree of positivity to the stage of the primary lesion, and indicate that positive patients appear to have a shorter survival time than do the negative patients. Yamashita and associates (2002) have updated the study of Kurusu (1999). This latter report further confirmed the initial findings and also reported that the finding of a postoperative persistent presence of CEA mRNA is an even more important prognosticator of a poor outcome than is its preoperative presence. In all these studies, false-positive findings in the control populations were infrequent. Unfortunately, the follow-up in the positive patients is short or lacking altogether, so that any effect on long-term survival of the presence of circulating cancer cells is impossible to quantify at this time.

In addition to these aforementioned studies, Peck and co-workers (1998) utilized RT-PCR for the detection and quantification of circulating cancer cells by the use of cytokeratin 19 (CK19) mRNA. In this study, there were 86 lung cancer patients and 62 control patients without malignant disease. The positive detection rate was 40% in patients with adenocarcinoma, 41% in patients with squamous cell tumors, and 27% for patients with SCLC. Only one (1.6%) patient in the control group had a positive result. These authors also noted that serial measurement of the relative number of circulating cells correlated with the tumor burden and treatment response. The effect of the presence of these micrometastatic cells in the blood on survival was not given. Unfortunately, several investigators have shown that RT-PCR expression of CK19 mRNA could detect nontissue-specific constitutive low-level (illegitimate) expression of CK19 mRNA in peripheral blood mononuclear cells in a significant number of healthy controls. Krismann and associates (1995) found in their study a 50% positive result in lung cancer patients but also a 20% positive result in the healthy control group. Fleischhacker and co-workers (2001) also found that positive results for the presence of CK19 mRNA in the bloodstream were shown in the control sera of all patients in their study of RT-PCR-based amplification systems. Thus, even though Peck and co-workers (1998) had only one positive control, it must be concluded that additional experience with the procedure of RT-PCR expression of CK19 mRNA must be obtained before any final decision is made as to its usefulness in the evaluation of the lung cancer patient.

Micrometastasis in Bone Marrow in Non Small Cell Lung Cancer

Bone marrow specimens can be aspirated from either iliac crest preoperatively or at the time of operation, as reported by Osaki and colleagues (2002), or from a rib segment at the time of thoracotomy (either pre- or postresection). The latter approach is preferred, and recently Mattioli and associates (2001) have suggested from their studies that iliac crest aspirations are inadequate and should not be used.

Under optimal conditions, a single tumor cell among 100,000 to 1 million normal cells can be identified by either of the aforementioned diagnostic techniques. Cote and colleagues (1995, 1998) detected occult micrometastatic disease in the bone marrow in 40% (24% of the patients with stage I or II disease and 46% with stage III disease) of patients with completely resected NSCLC. Pantel and colleagues (1996) detected a 59.7% incidence of bone marrow involvement in patients in whom no intrathoracic lymph node disease was present on standard light microscopy. In a Cox regression analysis, the presence of the micrometastatic cells in the bone marrow was a significant and independent predictor for earlier clinical relapse as compared with the patients in whom the bone marrow was negative for occult micrometastatic disease. Ohgami and co-workers (1997) reported an incidence of 27% in patients with stage I disease and likewise noted an earlier recurrence time in these patients compared with those patients without bone marrow involvement.

Passlick (2001), using immunohistochemical techniques with CK2 antikeratin antibody to identify cytokeratin 18, found that 33 (51.6%) of 62 patients with stage I pN0 disease on standard histologic examination had micrometastatic

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tumor cells in the bone marrow. At a median observation time of 66 months, patients displaying two or more CK18-positive cells per 4 106 mononuclear cells in the bone marrow had a significant overall survival disadvantage over those with only one or no tumor cells present. It is of note that in patients with occult bone marrow metastasis, osseous relapse was only infrequently seen, and the initial relapse occurred in the usual sites noted in patients with recurrent disease in the general population of resected patients. It is believed that the occult micrometastatic tumor cells found in the bone marrow are in a resting phase and are primarily only an indicator of undetectable metastatic disease at other sites.

Recently, Poncelet and co-workers (2001) reported an incidence of bone marrow micrometastasis of less than 20% and that the presence of occult micrometastasis in the bone marrow had no influence on either overall or disease-free survival. Likewise, Osaki and associates (2002), although they found an incidence of bone marrow micrometastasis of 27% in 115 patients with stage I disease, also could not detect any effect of its presence on the patients' disease-free or long-term survival. The discrepancy among these various studies regarding the significance or lack thereof of the presence of bone marrow micrometastasis on patients' survival is yet to be resolved.

Occult Micrometastatic Disease in Negative Intrathoracic Lymph Nodes

Izbicki and colleagues (1996), using an immunohistochemical technique with antiepithelial monoclonal antibody BerEp-4, reported that in 93 resected patients, they detected 20 patients (27.4%) of 73 who were initially staged as having N0 disease and 9 patients (45%) of 20 who were thought to have only N1 disease to have occult micrometastatic N2 disease. The spread of such disease was erratic, and skip metastases were common. Of major interest was the observation that the mean relapse-free survival was significantly decreased with the presence of occult micrometastatic N2 disease as compared with those without such disease. Dobashi (1997) and Maruyama (1997) and their associates reported similar findings, as have Ohta (2000, 2001), Passlick (2001), Wu (2001), and Osaki (2002) and their co-workers. Ohta and associates (2000, 2001) made the observation that the deleterious effect of the presence of the micrometastases in the otherwise normal lymph nodes was only evident when there was an associated elevation (overexpression) of the vascular endothelial growth factor (VEGF) in the primary tumor; this has not been reported by other investigators. Ohta and co-workers (2001) discovered micrometastatic disease in 24.3% of 181 patients with stage I disease. Micrometastases were found in patients with adenocarcinomas as small as 0.5 cm, but in patients with squamous cell tumors, no lymph node micrometastases were found with any primary tumor smaller than 2 cm in size. This latter observation needs to be confirmed.

Osaki and associates (2002), in the study of 115 patients mentioned previously, found an incidence of micrometastatic lymph node disease in 19.4% of stage Ia patients and in 37.7% of stage Ib patients. There was a significant decrease in survival between the positive group and the negative group: a 52.4% 5-year survival versus a 78.7% 5-year survival, respectively. Of interest, the significant survival difference was confined to the stage Ib patients.

Recently, Gu and colleagues (2002) investigated the presence of micrometastatic lymph node disease in 49 patients by two of the reported immunohistochemical techniques: (a) biclonal antikeratin antibody AE1/AE3 and (b) monoclonal antibody anti-p53 protein. One-half of these patients had primary tumors that were positive for p53. There were 18 stage Ia patients and 31 stage Ib patients. AE1/AE3-positive lymph nodes were found in 17 of the 49 patients, and 10 of the 25 patients whose tumors were positive for p53 had involved lymph nodes; 5 of the latter were also AE1/AE3 positive. Thus, a total of 22 patients had micrometastatic lymph node disease, an incidence of 44.9% (9 patients were restaged as N1 disease, and 13 as N2 disease). The overall 5-year survival rates were 81.5% and 31.8% for the negative and positive groups, respectively. The patients with stage Ia disease who were negative for the presence of micrometastatic lymph node metastases and those who were shown to be positive for such involvement by the aforementioned immunohistochemical techniques had 5-year survival rates of 90% and 50%, respectively, whereas the similar stage Ib patients had 5-year survival rates of 76% and 21.4%, respectively. Whether the use of more than one marker for the identification of micrometastatic disease in lymph nodes is worthwhile is unknown, but it may be better than the examination of both the negative lymph nodes and the bone marrow for the presence of micrometastasis in the same patient, as will be noted subsequently.

Not all investigators have been able to confirm the adverse prognostic effect of the presence of occult lymph node micrometastatic tumor or, in fact, even the high incidence of such disease as reported by most authors. Both Nicholson (1997) and Goldstein (2000) and their associates are among these latter investigators. Moreover, Ahrendt and colleagues (2002) found a 28% incidence of occult lymph node micrometastases in otherwise negative nodes in patients with stage I disease but did not find any difference in survival between these patients and those without occult micrometastases. Also, Kawano and associates (2002) reported the finding of lymph node micrometastatic disease in 26.5% of 49 patients with stage I left lung cancers; however, they could not show any difference in survival in these patients as compared with the other 36 patients without such involvement. The reason for this is unknown, but the latter authors tentatively ascribed this result to their extensive bilateral lymph node dissection carried out in the patients with stage I left lung tumors. Thus, a note of caution regarding the significance of nodal micrometastasis must be sounded until further studies are recorded. As in patients with bone marrow micrometastases, relapse in the patient

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with lymph node micrometastasis is similar to that which is observed in patients without such involvement, the majority of the relapses being at distant extrathoracic sites with only a minimal number of intrathoracic recurrences.

The relationship between bone marrow and mediastinal lymph node occult micrometastases is as yet undetermined. Of interest is the study of Osaki and associates (2002). In this report, the same 115 patients were evaluated for both lymph node micrometastases (the primary antibody used was biclonal AE1/AE3 for type I and II cytokeratins) and bone marrow micrometastases (the antibody used was CK2 for identification of CK18). They found that both stage I patients who were negative for micrometastatic lymph node involvement and those with positive micrometastatic lymph node disease had the same incidence (28%) of micrometastatic cancer cells in the bone marrow. No relationship (survival or otherwise) was found between the presence of the micrometastatic disease in the bone marrow and that in the lymph nodes. Furthermore, they noted that cancer cells in the bone marrow had no effect on survival, whereas the AE1/AE3-negative lymph node patients had a 78.7% 5-year survival but the AE1/AE3-positive lymph node patients had only a 52.4% 5-year survival. It is obvious that different mechanisms play a role in the development of lymph node and bone marrow micrometastases. These mechanisms are yet to be elucidated.

Lastly, in addition to the aforementioned immunohistochemical studies, D'Cunha and coinvestigators (2002) have reported the use of real-time polymerase chain reaction for estimation of lymph node micrometastatic tumor burden in stage I NSCLC. These investigators used CEA (a 200-kDa cell surface glycoprotein involved in cellular adhesion) messenger RNA to establish the quantitation of the micrometastatic tumor burden. Of the 53 tumors (29 stage Ia and 24 stage Ib) analyzed by quantitative real-time PCR, 48 (90.5%) were CEA mRNA positive. Fifty-nine (25.4%) of 232 lymph node specimens were quantitative CEA mRNA positive, and were distributed among 30 (56.6%) of the 53 patients with stage I NSCLC. Disease-free survival and overall survival were not noted, but this technique may add further to our knowledge of micrometastatic disease.

MOLECULAR AND BIOLOGIC MARKERS

Carcinoma of the lung is accompanied by acquired genetic mutations and alterations in the levels of, or even absence of, various normal cellular markers in the tumor cells. The presence of genetic abnormalities and the quantification of changes in the values of the numerous markers are identified by an appropriate immunohistochemical technique in most studies, although the RT-PCR technique and other genetic techniques have been used in some studies. The markers may be grouped into at least six major categories: growth regulation, cell cycle regulation, angiogenesis, cellular adhesion, basement membrane invasion, and others (Table 101-10). These factors have been studied singly or in groups to evaluate and stratify the risk of recurrence and the prognosis of lung cancer patients, to substage stage I NSCLC, to predict the presence and significance of mediastinal lymph node occult micrometastases in stage I and II disease, to assess the possibility of isolated cerebral metastasis, and to predict the prognosis of patients with known mediastinal node metastasis.

Table 101-10. Important Molecular and Biologic Markers in Non Small Cell Lung Cancera

Growth regulation
   erb-B2 (p185-c erb-B2, HER-2/neu)
   EGFR (epithelial growth factor receptor)
Cell cycle regulation/apoptosis
   p53 (tumor suppressor gene)
   bcl-2 (related to delay of apoptosis)
   Rb (retinoblastoma gene)
   Ki-67 (tumor proliferating cell nuclear antigen)
   PCNA (proliferating cell nuclear antigen)
   Telomerase  
Angiogenesis
   Factor VIII  
   VEGF (vascular endothelial growth factor)
Cellular adhesion
   Eph A2  
   STN (sialyl-Tn)
   E cadherin  
   CD44 (cluster designation 44)
   AMFR (autocrine motility factor receptor)
   ICM-1 (intercellular adhesion molecule-1)
   Plakoglobin  
Basement membrane invasion
   UPA (urokinase plasminogen activator)
   UPAR (UPA receptor)
   PAT-l (plasminogen activator inhibitor-1)
Other
   CEA (carcinoembryonic antigen)
   K-ras  
   MRP-1 (motility related protein-1)
aSelected references are listed in Reading References.

An interesting example of the evaluation of the presence of various tumor markers in stage I NSCLC patients was conducted by D'Amcio and colleagues (2000). The expression of nine molecular markers (p53, Rb, bcl-2, EGFR, erb-B2, STN, CD44, Ki-67, and factor VIII) was evaluated in 408 NSCLC patients. The authors found that among men, the only molecular marker associated with decreased cancer-specific survival was erb-B2, whereas in women, four markers (p53, Rb, CD44, and factor VIII) were so associated. In patients with squamous cell carcinomas, the only marker associated with decrease in survival was erb-B2. In patients with adenocarcinoma, there were three factors: p53, CD44, and factor VIII. Many other excellent studies have been reported, but the number of studies is too extensive to include them in this discussion of the pathology of lung cancer. The reader is referred to the Reading References section at the end of this chapter for selected references in this area.

Despite the plethora of studies, this field of investigation is in its infancy. Additional data to confirm or to negate the value of such information in the understanding of the

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agressiveness or nonaggressiveness of the various histologic types of lung cancer are obviously necessary. As pointed out in an editorial by D'Amico (2002), molecular biologic staging will most likely be more successful and effective by the use of a panel of markers in NSCLC patients.

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General Thoracic Surgery. Two Volume Set. 6th Edition
General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]
ISBN: 0781779820
EAN: 2147483647
Year: 2004
Pages: 203

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