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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Molecular pathogenesis

, MD, , MD, , MD, PhD, , MD, and , MD.

The rapidly developing technology of molecular biology has allowed the identification of genetic alterations in human lung cancer. However, the plethora of genetic abnormalities that have been detected has created some confusion as to their significance in the genesis and progression of lung cancer. This section will summarize areas of recent investigation of molecular events in human lung cancer, including oncogene activation and inactivation of tumor suppressor genes. Table 92-2 lists genes that have been implicated in lung carcinogenesis.

Table 92-2. Oncogenes and Tumor-Suppressor Genes Altered in Lung Cancer.

Table 92-2

Oncogenes and Tumor-Suppressor Genes Altered in Lung Cancer.

The gene families implicated in lung carcinogenesis include dominant oncogenes and tumor suppressor genes.3,36 Protooncogenes (normal homologues of the oncogenes) participate in critical cell functions, including signal transduction and transcription. Only a single mutant allele is required for malignant transformation. Primary modifications in the dominant oncogenes that confer gain of transforming function include point mutation, amplification, translocation, and rearrangement. A dynamic interplay exists within the cell between dominant oncogenes and tumor suppressor genes that constrain cell proliferation. Tumor suppressor genes appear to require homozygous loss of function by mutation, deletion, or a combination of these. Tumor suppressor genes appear to play a role in the governance of proliferation by regulating transcription and the cell cycle.


myc Family

One of the specific genetic changes first associated with lung cancer was the amplification of the c-myc oncogene, which was observed in a subgroup of SCLC cell lines.37 The SCLC cell lines having an amplified c-myc gene are morphologic and biochemical variants of SCLC (SCLC-V), with rapid doubling times and higher cloning efficiencies, tumorigenicities, and resistance to x-rays than other SCLC cell lines. After publication of reports that SCLC-V cell lines showed high levels of c-myc amplification and c-myc messenger ribonucleic acid (mRNA), the c-myc gene was transfected into the classic SCLC cell line H209. One of the transfectants expressing high levels of c-myc had an increase in doubling time and increased cloning efficiency, but the L-dopa decarboxylase levels and bombesin-like immunoreactivity were unchanged. Amplification of c-myc was observed in both classic and variant SCLC cell lines. However, c-myc mRNA levels were more elevated in the variant cell lines. Three classic lines had amplification of N-myc deoxyribonucleic acid (DNA), and one variant line had amplification of N-myc and myb.

Analysis of SCLC cell lines for c-myc amplification revealed additional EcoRI restriction fragments, suggesting myc -related genes. A third gene in the myc family, L-myc , was cloned and showed homology to c-myc and N-myc . Four SCLC cell lines had amplified L-myc genes. The N-myc gene is amplified and its expression increased in SCLC and non-small-cell lung cancers (NSCLC).38 Expression of N-myc in SCLC biopsy specimens was detected by in situ hybridization. Increased expression was associated with poor response to chemotherapy and short survival. N-myc gene sequences were amplified from 5- to 170-fold in SCLC cell lines. Both c-myc and N-myc were amplified in these cell lines, but only one member of the myc family was amplified in any one cell line. Amplification of N-myc has been reported in an adenocarcinoma of the lung. Others found amplification of one of the myc family genes in 10 of 12 SCLC cell lines, but again, only one member of the family was amplified in each cell line. All cell lines had deletions of chromosome 3.

Analysis of fresh tumor specimens showed that the amplification and rearrangement of myc genes were heterogeneous.39 N-myc or L-myc amplification was noted in 4 of 17 SCLC. In 3 of 12 NSCLC, c-myc amplification was seen. In some cases, amplification was seen in the primary tumor but not in the metastases. In two cases, amplification was seen only in the cell lines but not in the original tumors from which they were derived. Expression of the myc family genes was demonstrated in SCLC cell lines and nude mouse xenografts by using in situ hybridization techniques. The significance of the increased expression of the myc family genes remains uncertain. Amplification of c-myc was first described in SCLC cell lines with a variant morphology. This variant morphology is also called small-cell/large-cell carcinoma and is thought to indicate an unfavorable prognosis. Cell lines with the variant morphology are more resistant to chemotherapy and radiation therapy than either the SCLC or NSCLC types. However, review of pathology specimens of patients with extensive-disease SCLC showed that the variant cell type was rare, occurring in only 4.4% of 550 specimens.40 There were no significant differences in response rates to chemotherapy between prognosis for patients with the classic morphology and those with the variant morphology. Amplification of the c-myc gene was more frequent in cell lines from SCLC patients with tumor relapse than in those from patients who were untreated. Amplification of c-myc was associated with shorter survival in patients who relapsed.

The role of increased expression of the myc family genes in the genesis of lung cancer requires further definition. It is likely that increased myc expression leads to progression of SCLC. Increased myc expression is unlikely to be a primary event, however, because it is detected in a minority of tumors. Its association with the variant cell type and the significance of this cell type require additional clarification. Expression of myc may be increased by any of several mechanisms and is not always associated with gene amplification.

ras Family

The ras family of oncogenes (homologous to the rat sarcoma virus) has three primary members (H-ras, K-ras, and N-ras) that are among the most common activated oncogenes found in human cancer. The ras genes code for a protein (p21) that is located on the inner surface of the plasma membrane, has GTPase activity, and may participate in signal transduction. The ras oncogenes are activated by point nucleotide mutations that alter the amino acid sequence of p21.

ras in Carcinogen-Induced Tumors

Studies in mice with carcinogen-induced lung cancers implicate genes of the ras family in the process of carcinogenesis. Mouse lung tumors induced by tetranitromethane contained mutated K-ras genes. Mice harboring the mutated H-ras transgene developed tumors exclusively in the lungs within weeks after birth. Lung tumors can be induced in mice with the tobacco-specific nitrosamines NNK or nitrosodimethylamine. Ninety percent of these tumors have transforming genes in the NIH 3T3 assay; the gene was K-ras in all lung tumors. The mutations were generally GC to AT transitions, indicating that DNA methylation is the most likely pathway to induction of neoplasia by these carcinogens.

Human Studies

The K-ras oncogene is activated by point mutation in lung cancer cell lines.41 Calu-1 has a mutation in codon 12 (glycine to cysteine), and PR310 has a mutation in codon 61 (glutamine to histidine). Reduced fragment-length polymorphism analysis for a codon-12 mutation (glycine to arginine) found no mutations in 24 primary NSCLC lung cancers. Other mutations have been detected in codon 12 with the use of a highly sensitive technique based on amplification with the polymerase chain reaction (PCR) and detection with a panel of oligonucleotide probes. In most studies, K-ras mutations were confined to adenocarcinomas of the lung and occurred in 30% of tumors. Mutations were not observed in adenocarcinomas from nonsmokers. K-ras mutation appears to be an independent prognostic factor that indicates a poor prognosis and is unrelated to conventional staging criteria such as tumor size or lymph node metastases. In all patients studied, mutations occurred in a single allele.

ras mutations can influence the differentiation of tumor cells. For example, infection of SCLC cell lines with the Harvey murine sarcoma virus alters the phenotype of variant but not classic cells. Following infection, the variant SCLC cell line developed features of a large cell undifferentiated lung carcinoma, including increased carcinoembryonic antigen and keratin expression.

Studies done so far favor the interpretation that ras activation contributes to progression in lung cancer. Activation of ras apparently occurs in about one-third of adenocarcinomas arising in patients with a history of heavy smoking. However, premalignant lung lesions have not been studied to determine if such mutations exist at the precancerous stage, as is the case for adenocarcinoma of the colon.

Antisense technology has been used to study the effects of eliminating expression of a mutant K-ras oncogene in NSCLC cells.42 A selective decrease in mutant oncogene expressions was achieved, associated with decreased growth of cancer cells as heterografts in nude mice. This technique provides an opportunity to determine the effects of selective inhibition of oncogenic protein expression on the malignant phenotype. This study and subsequent confirmatory ones showed that reversal of a single genetic abnormality was sufficient to prevent human cancer cells from forming tumors. Thus, it may not be necessary to reverse all the genetic lesions in a cancer cell to achieve a therapeutic effect. These observations raise the intriguing possibility of specific gene therapy for cancer. Gene sequences could be delivered to tumor cells via viral vectors that specifically inhibit expression of the oncogenes activated in the cancer cell. Such constructs would be relatively nontoxic because, as in the example above, they could target a single gene whose function may be assumed by other redundant genes of the same family. A retroviral vector expressing antisense K-ras has successfully suppressed growth of orthotopic human lung cancer cells in nude mice.43

Growth Factors and Autocrine-Paracrine Growth Control

Tumor cells that produce a growth factor and express its receptor may show self-stimulatory or autocrine growth. Cells that are regulated by an autocrine loop have several features. They secrete a biologically active growth factor and demonstrate increased proliferation in response to that factor. Antibodies that bind specifically to the growth factor will inhibit cell growth. Growth factors may act to stimulate growth in adjacent cells in a paracrine manner. Interaction of ligand and receptor in the cytoplasm of the cell may form an internal autocrine loop.

Autocrine growth factors have been implicated in the stimulation of SCLC cell growth. The majority of SCLC cell lines produce bombesin, a 14-amino acid peptide that is identical to a carboxy-terminal heptapeptide sequence of a mammalian analog, gastrin-releasing peptide. SCLC cell lines express a single class of high-affinity, saturable binding receptors for bombesin. Bombesin is also a potent stimulator of clonal growth for human NSCLC. Bombesin receptors have not been demonstrated on NSCLC.

Oncogene products related to growth factor receptors of the tyrosine kinase family are implicated in retrovirus-induced neoplasia. For example, v-erbB, the transforming gene of avian erythroblastosis virus, codes for a truncated version of the epidermal growth factor receptor (EGFR). Activation of the overexpressed normal receptor gene appears to be sufficient for transformation of NIH/3T3 cells. NSCLC cells express high levels of functional EGFR, but SCLC cells rarely do. NSCLC cells also show amplification of the EGFR gene. This suggests that growth factors and their receptors may play an important role in the development and/or maintenance of the malignant phenotype. Studies have suggested that transforming growth factor (TGF)-α and insulin-like growth factor (IGF)-I participate in autocrine growth stimulation.


erbB2 is a member of the EGFR family. This family includes four genes with a receptor-like structure, including an external ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The neu/erbB2 oncogene was first identified in an ethylnitrosourea-induced rat neuroblastoma. The rat oncogene is activated by a point mutation, but the mechanisms in human cells appear to be amplification and overexpression. The gene has homology to the EGFR gene, and its 185 kDa product is a tyrosine kinase. The structure of this protein is receptor-like, and several ligands have been identified.

The erbB2 gene is activated in NSCLC. In one study, erbB2 was amplified in only 10% of 60 paired samples of NSCLC and normal lung.44 However, adenocarcinomas showed high levels of erbB2 mRNA. In contrast, SCLC cells did not express erbB2. A study of freshly excised surgical specimens confirmed and extended these findings. Six of 16 NSCLC specimens showed higher levels of erbB2 RNA expression than did paired normal lung samples. Expression of erbB2 was increased in both early and advanced stages. Fresh SCLC showed minimal or no expression of erbB2 RNA. In a study that used immunohistochemical techniques, the erbB2 gene product p185 was expressed at higher levels in the tumor than in the bronchiolar epithelium. The investigators found that erbB2 expression in adenocarcinomas is independently correlated with diminished survival.45

Transforming Growth Factor-α

TGF-α is a single polypeptide of 50 amino acids that is derived from a 160-amino acid transmembrane precursor by proteolytic cleavage. TGF-α is structurally and functionally related to the epidermal growth factor (EGF) and binds to the EGFR. A possible autocrine/paracrine growth mechanism was investigated in vitro with cloned NSCLC cell lines. None of the cell lines expressed EGF by Northern analysis. All cell lines expressed TGF-α mRNA. Because TGF-α binds to the EGFR, the investigators studied the biologic response to and production of TGF-α by these cell lines. Exogenously added TGF-α increased [3H] thymidine uptake in each of four cell lines and increased colony formation in soft agar and medium containing serum for three of the four cell lines. All cell lines expressed some TGF-α mRNA, although to differing degrees. Cell lysates and spent media competed for EGFR binding with EGF, thus showing a TGF-α-like activity. There was heterogeneity in the mechanism of autocrine growth stimulation among the four cell lines.

The growth of H322a and H226b cells was specifically inhibited by the anti-TGF-α monoclonal antibody AB-3 at low cell density, suggesting that the antibody blocks an autocrine growth loop. This inhibition was dose dependent and did not occur following addition of the isotype-identical monoclonal antibody MOPC21. However, the AB-3 antibody did not alter the growth of H460a and H596b cells, even though these cells express EGFR and secrete TGF-α. Suramin, which blocks binding of ligand to receptor in other autocrine systems, inhibited the growth of both cell lines. Addition of TGF-α specifically reversed inhibition by suramin. Addition of the platelet-derived growth factor (PDGF) did not reverse suramin inhibition. This suggests that autocrine activation of these cell lines occurred in the intracellular compartment between unprocessed receptor and unsecreted ligand. TGF-α appears to be an important autocrine growth factor for NSCLC cells of both squamous and adenocarcinoma histologic types.

Tumor Suppressor Genes

The inactivation of certain genes may contribute to tumor growth. In one scenario, both copies of the gene must be eliminated or inactivated to eradicate the growth suppressive function of the gene.36 Because both copies must be eliminated, the tumor suppressor gene is called recessive. This model was developed to explain the inheritance pattern of retinoblastoma. Patients with a familial predisposition have a germline inactivation of one copy of the retinoblastoma (Rb) gene. The tumor develops when the wild-type allele is either inactivated or deleted. Development of the sporadic form of retinoblastoma requires two somatic mutations. This model has spawned multiple studies searching for consistent chromosomal deletions in human tumors.

One of the earliest known and most consistent chromosomal deletions in lung cancer occurs in chromosome 3 (p14–p23) in SCLC.46 Allelic loss in this region was documented with polymorphic DNA probes and was seen to occurr at a high frequency. Loss of heterozygosity for alleles on chromosomes 3, 11, 13, and 17 occurs in NSCLC as well.47 The fragile histidine triad (FHIT) gene, which is located at the 3p14.2 fragile site, is frequently abnormal in many lung cancers, and its protein product is often not expressed.48–50 This suggests it may be functioning as a tumor suppressor gene. Restoration of expression of FHIT in human lung cancer cells lacking protein expression triggered apoptosis and suppression of tumor growth in a xenograft mouse model, confirming the tumor suppressor function of this gene.51

The high frequency of chromosomal deletions in both SCLC and NSCLC suggested that loss of specific gene function may be a critical step in the development of lung cancer. Two additional candidate tumor suppressor genes in lung cancer are the nuclear phosphoproteins p53 and Rb.

Loss of heterozygosity on chromosome 13q suggests that the R .locus, located at 13q14, is deleted. Studies show that up to 60% of SCLC and 75% of carcinoid cell lines do not express Rb mRNA. Of 13 SCLC cell lines reviewed in one study, only 3 expressed more than a trace amount of Rb mRNA. The role of Rb in NSCLC appears variable. In one study, 90% of NSCLC cell lines expressed Rb. In contrast, other studies have shown a significantly higher involvement of altered Rb function. For example, another study found that Rb protein was absent in 10 of 36 immunostained primary NSCLC tumors.

The p53 gene encodes a 375-amino acid phosphoprotein that can form complexes with host proteins such as large T antigen and E1B. Missense mutations that result in loss of suppressor function are common in the p53 gene. The p53 gene appears multifunctional, with major domains that can transactivate, bind proteins, bind sequence-specific DNA, and oligomerize with p53. Abnormalities in one or more of these functions could contribute to abrogation of the tumor suppressor function of p53. Certain mutations also have a dominant transforming capability. The wild-type p53 gene may suppress genes that contribute to uncontrolled cell growth and proliferation or activate genes that suppress uncontrolled cell growth. Thus, either absence or inactivation of wild-type p53 may contribute to transformation. However, some studies indicate that the presence of the mutant p53 may be necessary for full expression of the transforming potential of the gene.

Mutations of p53 are common in a wide spectrum of tumors.52 These mutations occur in both NSCLC and SCLC cell lines and in fresh tumors. The precise role of these mutations in oncogenesis and the mechanisms involved are subjects of active investigation. Mutations in p53 positively correlate with lifetime cigarette consumption.53 Radon exposure, which increases lung cancer risk, is also associated with p53 mutations, although the type of mutations differ from those seen in tobacco-associated lung cancer.54 Insertion of a wild-type p53 in lung cancer cell lines with a mutant or deleted p53 can suppress their growth, even though the cells have multiple genetic lesions.55 This may occur because of the multiple pathways, including cell cycle and apoptosis, regulated by p53. The p53 protein may be overexpressed in lung cancer cells, although this is not always associated with the presence of a mutant p53 gene. However, overexpression of the p53 protein has correlated positively with a poor prognosis.47,56 Deletions in 17p, p53 mutations, and 3p deletions have been detected in preneoplastic lesions of the lung, such as severe dysplasia. Mutations in p53 and ras appear to be independent events.Other candidate tumor suppressor genes include the APC and MCC genes, first identified in colon cancers.

To assess the role of the p53 gene in the development of human cancer, wild-type p53 cDNA in either sense or antisense orientation was introduced into human NSCLC cell lines.57 Elevated levels of antisense p53 RNA in transfected cells reduced the levels of wild-type and mutated p53 proteins. Although parental H322a and H226b cells formed tumors in nu/nu mice after a long latency period, their antisense transfectants, with reduced levels of p53 proteins, formed large tumors in 15 days. Functional inactivation of mutated and wild-type p53 by antisense RNA was therefore a direct experimental demonstration of p53 tumor suppressor function and suggested that at least some p53 mutations also have residual cell growth and tumor suppressor functions that may be dose dependent. Although mutations in the p53 tumor suppressor gene are common in human lung cancers, the wild-type form of p53 is dominant over the mutant, and, thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumors.

The therapeutic efficacy of direct administration of a retroviral vector expressing wild-type p53 in an orthotopic human lung cancer model has been shown.58 Thirty days after tumor cell inoculation, 63% to 80% of the control mice showed macroscopic tumors of the right mainstem bronchus. The wild-type p53 retroviral vector suppressed H226Br tumor formation in 62% to 100% of mice, and the effect depended on the amount of virus given. These results suggest that direct administration of a retroviral vector expressing wild-type p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression.

Development of an adenoviral vector for delivery of wild-type p53 has been reported.59 A high level of expression of exogenous p53 was achieved in p53-deleted human lung cancer cells that were infected with the adenovirus-p53 vector. Expression lasted for 15 days, which was sufficient for mediating apoptosis of the lung cancer cells. The growth of normal human bronchial epithelial cells taking up the vector was not affected. The efficacy of the adenovirus-p53 vector in inhibiting tumorigenicity was shown in the mouse model of orthotopic human lung cancer and was similar to that seen with the retrovirus-p53 construct.43

Previous studies had shown that expression of wild-type p53 in human lung cancer cells can mediate apoptosis, but not all cell lines tested showed this. H358a cells, which have a homozygous p53 deletion, showed a reduction in their rate of proliferation after transduction with wild-type p53, but the cells did not undergo apoptosis. It is possible that if the level of DNA damage in the cell could be elevated acutely at the time the wild-type p53 gene was expressed, apoptosis would occur. Adenovirus-p53 and cisplatin given in a sequential combination were evaluated for the induction of synergistic tumor regression in vivo.60 Following 3-day direct intratumoral injection of adenovirus-p53, H358a tumors subcutaneously transplanted in nu/nu mice showed a modest slowing of growth; these tumors regressed, however, if cisplatin was administered intraperitoneally for 3 days. Histologic examination revealed necrosis of tumor tissue in the area where adenovirus-p53 was injected in mice treated with cisplatin. In situ staining showed extensive areas of apoptosis. In contrast, tumors treated with cisplatin alone or adenovirus-p53 alone showed no apoptosis.

Recently, clinical trials have begun to assess the feasibility of restoring defective tumor suppressor gene function in cancer patients with the use of gene transfer technology. In the first human clinical trial, 9 patients with NSCLC received a retroviral vector containing the wild-type p53 gene under the control of a β-actin promoter.61 All patients had failed other treatments and had tumors documented as having a p53 mutation. Because transduction via retrovirus was known to yield low titers of the transduced gene, the vector was injected into the tumor on 5 consecutive days, using either a bronchoscope or, in the case of chest wall lesions, a percutaneous needle. Regression of the injected lesion was seen in 3 patients, whereas stabilization of disease was seen in 3 others. In 1 patient, who died of a progressive kidney metastasis, there was no evidence of viable tumor at the treated site on autopsy 4 months following injection. One patient had progressive primary disease, and 2 were inevaluable (1 was intolerant of the general anesthetic and did not complete treatment, and 1 died within 3 weeks of treatment). PCR and/or in situ hybridization studies of posttreatment biopsy specimens from 8 patients prior to evaluation of treatment effects showed that tumor cells had indeed integrated vector DNA sequences in up to 20% of cells in certain areas of tumor. An important finding was that TUNEL staining (which detects DNA nicking) of posttreatment biopsy samples showed that apoptosis had increased following treatment compared with the pretreatment baseline. No side effects attributable to the p53-vector sequences occurred in any patient, although bronchoscopy-related complications occurred in 3 patients. The authors found no evidence of retroviral sequences in DNA extracted from lymphocytes, sputum samples, or various nontumor tissues obtained at autopsy on 3 patients. These results thus showed for the first time that defective tumor suppressor gene function could be restored in the tumor of a cancer patient and that this mediates tumor regression.

These promising results have been supported by a more recent two-arm study in which a wild-type p53 gene was given to 52 patients with NSCLC via an adenovirus vector.58 Patients received adenovirus-p53 (Ad-p53), either alone or preceded by cisplatin, 80 mg/m2 over 2 hours, 3 days before p53 injection (cisplatin was chosen because of preclinical studies that had shown a synergistic effect with p53 gene replacement). Either bronchoscopically or under computed tomography (CT) guidance, p53 treatment was given as a single intratumoral injection once per month for up to 6 months. Most patients had received previous chemotherapy, in some cases with cisplatin, and all had progressive tumor growth with conventional therapy prior to entry into the study.

As with the study that used the retroviral vector, both clinical and laboratory evidence of p53 expression were seen. Ad-p53 alone (26 evaluable patients) mediated 2 partial responses and stabilization of disease in 16 patients. Progression-free survival (PFS) was increased with a higher dose of Ad-p53. Ad-p53 + CDDP cisplatin (23 evaluable patients) mediated a partial response in 2 patients previously treated with CDDP. One additional patient achieved a partial response but did not have the required follow-up documentation to confirm the response. PFS was prolonged with Ad-p53 + CDDP compared with Ad-p53 alone. A majority of patients also had evidence of vector DNA upon PCR of posttreatment biopsies. Although antiadenovirus antibodies were detected in all patients after one treatment, subsequent treatments were not accompanied by anaphylaxis or other toxicities except transient fever. Perhaps surprisingly, despite high levels of serum antiadenovirus antibody, p53 transgene expression occurred in the tumor cells, and clinical responses were maintained.

Even though these studies corrected only one of the many genetic abnormalities present in NSCLC, the evidence suggests an antitumor effect based directly on p53-mediated apoptosis, as shown in the retroviral p53 trial. The two trials provided no evidence for the contrary view that tumor stabilization and regression resulted from a nonspecific immune reaction. In the adenovirus-p53 study, vector DNA was detected by PCR for the majority of patients, but fewer patients showed evidence of gene expression. Detection of gene expression following transfer of wild-type p53 in vivo is difficult because successful transfer and expression of wild-type p53 in a tumor may destroy evidence of gene expression if apoptosis is induced and the cells die. However, in those patients where serial gene expression could be quantitated by immunohistochemistry, it was clear that expression of the transgene occurred despite the presence of high titers of antiadenovirus antibody. It is possible that serum antibodies have little effect because of poor penetration into solid tumors as a result of high interstitial fluid pressure. It is not known whether suppression of the antiadenovirus immune response would further enhance the levels of transgene expression in the tumor. In any case, repeated intratumoral injections of adenoviral-p53 appear safe despite increases in antiadenovirus antibodies.

A common theme with many of the genetic lesions occurring in cancers is their relationship to regulation of progression through the cell cycle. Premature entry of cells into the next phase of the cell cycle may prevent completion of important molecular events such as DNA repair and may lead to genetic instability. The cell cycle may pause at both the G1 and G2 checkpoints. Phosphorylation of the Rb protein will release the transcription factor E2F and mediate transition across the G1 check point. Inactivation of Rb by mutation or deletion could therefore cause a state of activation. A gene encoding an inhibitor (called variously p21, WAF1, Cip1, or Sdi1) of the proteins that mediate cell cycle progression (cyclins) is one of the downstream effectors of p53 and mediates G1 arrest. Another inhibitor of the cyclin system is p16. This gene is frequently inactivated in many cancers including lung cancer.

Several other genes (such as hSRBC, SEMA3B) are newly identified tumor suppressor gene candidates.62 Other tumor suppressor genes less frequently involved include PTEN, hOGG1 (DNA repair), BAP1 (ubiquination). Many tumor suppressor genes in lung cancer (APC, CDH13, RAR, FHIT, RASSF1A, TIMP3, p16, MGMT, SEMA3B, DAPK) appear to be inactivated by promoter hypermethylation.63 Allelic losses on chromosome arm 3p are the most frequent and earliest genetic abnormality detected in human lung cancers, indicating the presence of one or more lung cancer tumor suppressor genes in this region. In particular, a 600kb lung cancer homozygous deletion region at 3p21.3 shows frequent allele loss in tumors and smoking-damaged lung epithelium. A group of candidate tumor suppressor genes in this small 600kb 3p21.3 region have been identified. Several (CACNA2D2, BLU, RASSF1A isoform, and SEMA3B) had their expression extinguished due to tumor-acquired promoter DNA methylation. With the use of a variety of expression vectors, it was found that several of the candidate 3p21.3 tumor suppressor genes, FUS1, 101F6, NPRL2, and SEMA3B, effectively inhibited tumor cell growth by induction of apoptosis in vitro and in vivo, whereas others, RASSF1A and CACNA2D2, efficiently inhibited anchorage-independent growth in vitro and xenograft growth in vivo without inducing apoptosis (RASSF1A) or inducing apoptosis only in p53 wild-type tumors (CACNA2D2), strongly suggesting that several of these contiguous 3p21.3 genes function as lung cancer tumor suppressors.64

Molecular Abnormalities in Premalignancy

Loss of specific chromosomal regions on a single allele (loss of heterozygosity [LOH]) has been detected frequently in lung cancer and bronchial epithelium exposed to tobacco carcinogens. The earliest and most frequent regions of allelic loss occur at 3p21, 3p22–24, 3p25, and 9p21.65 It is noteworthy that many of these changes are seen in histologically normal bronchial epithelium from smokers but not nonsmokers.66 However, these changes appear to become more frequent and extensive in terms of chromosome loss with advancing abnormality of premalignancy. In some cases, these molecular changes appear to be clonally independent. Methylated sequences of tumor suppresseor gene promoters can be detected in tumors, smoking-damaged normal lung (preneoplastic changes), sputum, and blood. These represent attractive surrogate biomarkers for early detection and monitoring chemoprevention, smoking cessation and response to therapy.

Second Primary Cancers

Patients who have had a primary epithelial cancer of the upper aerodigestive tract (head and neck, esophagus, or lungs) have a higher risk of developing a simultaneous or subsequent second primary cancer. It is hypothesized that the epithelial surface of the upper aerodigestive tract may share a common carcinogen exposure and increased risk of cancer development. It is thought that epithelial cancers can arise independently as separate primary cancers following prolonged carcinogen exposure. This effect is called field cancerization. Such field effects have also been proposed for breast and colorectal cancers. This hypothesis is testable, in that it predicts that if a common carcinogen is involved, second primary cancers would arise from similar but independent events.

A molecular marker to determine the independent origin of cancers must have several characteristics to be informative. The marker should be associated with the development of the cancer. Alterations in the marker such as mutations should occur early in the development of the cancer. Finally, these mutations should be clonally preserved. The p53 gene fulfills these criteria for the three most common primary and second primary cancers of the aerodigestive tract: head and neck, lung, and esophagus. Many studies have shown that inactivation of p53 by mutation or deletion results in cell transformation. Mutations in the p53 gene occur early in the development of upper aerodigestive tract cancers and are detected frequently in fresh tumor specimens.54 Mutations in the p53 gene occur in premalignant lesions from aerodigestive tract cancers. Mutations of the p53 gene have been frequently detected in early stage cancers of the head and neck, as well as those of the lung and esophagus, and the incidence of these mutations does not increase with advancing stage of disease as would be expected if p53 mutations were associated with cancer progression. Mutations of the p53 gene show clonal fidelity for recurrent cancers and metastases. Differences in p53 mutations between the primary cancer and second primary cancers would provide evidence of independent origin for these multifocal tumors.

The tumors of 31 patients with primary cancers of the head and neck and associated second primary cancers were studied with single-strand conformation polymorphism analysis and DNA sequencing.67 The overall frequencies of p53 mutations among primary tumors and second primary cancers were 42% (13 of 31) and 37% (13 of 35), respectively. Mutations were found in 19 of 52 head and neck squamous cell carcinomas (36%), in 4 of 7 squamous cell carcinomas of the lung (57%), in 2 of 5 adenocarcinomas of the lung, and in 1 of 2 squamous cell carcinomas of the esophagus. Twelve samples had p53 mutations on exon 5, 9 on exon 7, and 11 on exon 8. Six samples had mutations in more than one exon.

Of 31 patients, 21 (68%) had p53 mutations in one or more specimens. In all 21 cases, the genetic lesions were discordant such that the presence or location of the mutation in the primary tumor was different from those of the second and third primary cancers. In the 5 patients with p53 mutations in both the initial primary cancer and second primary cancer, the mutations occurred in different regions of the p53 gene. In the other 16 patients, a p53 mutation was found in one primary tumor but not in the other. In 8 of these 16 cases, a mutation was found in the first primary but not the subsequent primary cancer, and in the other 8 cases, a p53 mutation was not detected in the initial primary but was detected in subsequent primary cancers.

The discordant p53 mutations in second primary cancers arising in patients with primary epithelial cancer of the upper aerodigestive tract suggest that these cancers arise as in-dependent events. These observations provide the first indication of a molecular basis for field cancerization effects in cancers of the upper aerodigestive tract.

Several series have noted the increased risk of the development of a second primary tumor in patients who have had lung cancer. In one series of patients with stage I NSCLC, second primary tumors developed in 34% of patients, and second primary lung cancers developed in 11.7%.68 The longer the time interval from treatment of the first primary lung tumor, the higher the chance of developing a second primary tumor.69 In a review by the LCSG, the occurrence rate for new pulmonary cancers in patients with resected T1-N0 tumors was 0.009 (calculated as occurrences per eligible patient per year).70,71 After 5 years, however, this rate increased to 0.016, indicating a loss of protection by time for the development of a second lung cancer. In fact, multiple lung cancers can occur in 10% to 25% of all lung cancer patients who survive longer than 3 years.72 Subsequent survival is strongly influenced by the interval to occurrence and the stage of the second primary malignancy.72 The time interval between the development of asynchronous primary lesions may exceed 10 years.72 Johnson and colleagues have noted that a major cause of late mortality in patients with SCLC is NSCLC.

Patients who have been treated for small-cell malignancy have an increased risk for the development of acute leukemia as a late-term sequela of their chemotherapy.73 The risks of a second cancer following any malignancy of the respiratory system can range from 10% to 44%.74 In these studies, increased rates of second malignancies were seen in the bladder, kidney, oral cavity, and lung. As well, there was a significant increased risk of the development of a lung cancer following the occurrence of a primary laryngeal carcinoma. It is known that there is a definite increased risk of lung cancer in association with aerodigestive malignancies, in particular, laryngeal carcinoma. In a review of 415 patients treated for laryngeal carcinoma, 26% of patients developed lung cancer during the first 14 years of follow-up.75 Several other series have noted the incidence of a primary lung cancer following the treatment of a laryngeal carcinoma ranging from 4% to 9%.76 The most common histologic type of lung cancer in these patients with a history of head and neck malignancies is squamous cell carcinoma. However, nonsquamous tumors are noted and occur more frequently in women. In two series from Denmark and Connecticut, there was an increased risk of the development of second malignancies occurring in the breast, liver, pancreas, and the female reproductive system.

Pathology of Lung Cancer

The histologic classification of lung tumors and guidelines for their typing was originally published by the World Health Organization in 1968 and revised in 1981 (Table 92-3). The histologic types are based on analysis with light microscopy and with standard staining techniques, which allow interpretation of the various types to be replicated on a worldwide basis.77 Ultrastructural analysis with electron microscopy and immunohistochemical techniques was not used. The criteria for histologic classification have increased the consistency and reliability of the diagnosis of lung cancer, permitted improved evaluation of treatment protocols and response to therapy, contributed to a heightened understanding of the natural history of the various histologic types, and permitted identification of various risk factors associated with these malignancies.78 It remains the standard criteria used by most pathologists internationally. Four major cell types exist: squamous cell carcinoma, small-cell carcinoma, adenocarcinoma, and large-cell carcinoma. These neoplasms account for 90% to 95% of tumors, and 2% to 4% of these lesions will demonstrate combinations of squamous and glandular elements called adenosquamous cell carcinoma.

Table 92-3. World Health Organization Lung Cancer Classification.

Table 92-3

World Health Organization Lung Cancer Classification.

Recently, it has been recognized that some limitations in the classification criteria exist, and several recommendations to refine the criteria have been proposed. In 1988, the pathology panel of the International Association for the Study of Lung Cancer (IASLC) recommended revision of small-cell lung cancer into pure small-cell carcinoma, small-cell carcinoma with a large-cell component, and small-cell carcinoma combined with either adenocarcinoma or squamous cell carcinoma.79 It has been suggested that adenocarcinoma be reclassified into five cell types: (1) bronchial surface epithelial cell type, with little or no mucus, (2) goblet cell type, (3) Clara cell type, (4) type II alveolar epithelial cell type, and (5) bronchial gland cell type.80 Additionally, it has been emphasized that enhancement of future histologic classification may incorporate the use of monoclonal antibodies, flow cytometry, and genetic abnormalities, all of which may be useful in predicting the malignant potential of tumors and in acting as prognostic factors.

The relative incidence of the various histologic types appears to be gradually changing. The proportion of squamous cancers appears to be decreasing as the proportion of adenocarcinoma increases.81–83 In past decades, squamous cell carcinoma was clearly the most common type. In some series, this pattern remains.19 However, in other reviews, the trend appears to be changing.84 In the LCSG series of 1,121 patients, adenocarcinoma and squamous carcinoma appeared equal in incidence.19 In a recent review of all patients undergoing pulmonary resection for lung cancer at M.D. Anderson Cancer Center (MDACC) from 1987 to 1991, adenocarcinoma accounted for 49% of the group and squamous cell carcinoma for 36%. Adenocarcinoma now appears to be the most frequent histologic type in the United States and Japan, and squamous cell carcinoma continues to be the predominant type in Europe.85 In addition, since the 1970s, bronchioloalveolar cell carcinoma has become significantly more prevalent, particularly in patients with no history of smoking.86

The majority of lung cancers are histologically heterogeneous, a phenomenon that has an immediate impact on the diagnosis because of the potential variation in interobserver and intraobserver interpretation. Histologic heterogeneity is better recognized through evaluation of resected specimens than it is by biopsy or cytologic studies that sample only a small portion of the tumor. A study of 100 lung cancer specimens reviewed by five pathologists confirmed the presence of major heterogeneity (adenocarcinoma vs squamous cell carcinoma) in 45% of the cases. Minor (subtype) heterogeneity, with mixtures of acinar and papillary patterns in adenocarcinoma, for example, was found in 21% of the cases.87 Differences in bronchoscopic biopsy interpretation and final pathologic interpretation in subsequent resected specimens can occur in up to 38% of cases and is directly affected by histologic heterogeneity.88

Lung neoplasms are generally classified by the best differentiated region of the tumor and are graded by its most poorly differentiated portion. A tumor that shows characteristics of squamous differentiation by demonstrating the obvious presence of keratin pearl formation and intercellular bridges would be classified as a squamous cell carcinoma. If most of the cells of the remaining tumor did not show such features, the same tumor would be further labeled as a poorly differentiated squamous cell tumor.

Ultrastructural heterogeneity also exists with several studies that have shown electron microscopy to be more sensitive in detecting squamous or granular differentiation than light microscopy.89,90


The histopathogenesis of lung cancer is incompletely understood. It is felt that bronchial mucosal cells undergo metaplastic change as a response to chronic exposure and repeated injury from inhaled injurious agents. As a response to cellular injury, a compensatory reactive and inflammatory process evolves. Mucosal basal cells initiate a response by proliferating to generate mucus-secreting goblet cells. It is felt that metaplastic activity evolves through the replacement of columnar epithelium with stratified squamous epithelium. Further neoplasia evolves with cellular atypia and increased mitotic activity into eventual mucosal dysplasia. When the process involves the full thickness of the mucosa, carcinoma in situ is present. Invasion of the basement membrane and infiltration of malignant cells into the underlying stroma signals the first sign of invasive cancer. The length of such a process is speculative but may take 10 to 20 years to evolve.

The cell of origin for lung cancer is unclear. Two theories exist: (1) a pleuripotential cell (stem cell) theory, advocated by Auerbach, of one pleuriotential cell from which all cell types evolve, and (2) a small-cell theory, advocated by Yesner, of a type of small-cell neoplasm that undergoes transformation and evolves into the other cell types (Figure 92-3).91,92 The true site of origin of small-cell lung cancer is difficult to identify. It is also difficult to know the origin of adenocarcinomas or large-cell carcinomas because they may come from the bronchial epithelial surface or the underlying mucous glands. There is, however, increasing evidence that tumors arise from a common mucosal, pleuripotential stem cell. The heterogeneity found in various cell types of lung cancer, particularly large-cell anaplastic carcinoma and various small-cell lung cancer tumors, may explain the variations in response to therapy and may be explained by the common stem cell theory.

Figure 92-3. The stem cell theory of lung cancer pathogenesis as proposed by Auerbach.

Figure 92-3

The stem cell theory of lung cancer pathogenesis as proposed by Auerbach.

Histologic Types

Squamous cell carcinomas account for approximately one-third of all lung cancers. They usually originate within a central bronchus, and central cavitation from necrosis is a common gross and radiologic finding. Well-differentiated squamous cell cancers generally grow slowly with less likelihood of distant spread than the poorly differentiated type. Histologically, these tumors show keratin formation, keratin pearl formation, and intercellular bridging between adjacent cells (Figure 92-4).

Figure 92-4. Squamous cell carcinoma showing nests and cords of neoplastic cells.

Figure 92-4

Squamous cell carcinoma showing nests and cords of neoplastic cells. Keratin pearl formation is easily identified. Intercellular bridges are also present and are more easily seen at higher magnification. (Four-color version of figure on CD-ROM)

Adenocarcinomas account for approximately 30% to 45% of lung cancers and appear to be increasing proportionally. They usually originate within the periphery of the lung and occur more commonly in women than in men. Grossly, central cavitation is uncommon. Adenocarcinoma tends to metastasize early to regional lymph nodes and to distant sites, particularly the brain. Patients with adenocarcinomas may have an associated history of chronic interstitial lung disease, such as scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, recurrent pulmonary infections, and other necrotizing pulmonary disease. The term scar carcinoma has been used when an adenocarcinoma is seen in association with a pulmonary scar from chronic disease; possibly the neoplasm results from the longstanding insult of the underlying disease. Histologically, these tumors usually demonstrate glandular formation or the presence of mucus production in a solid tumor as shown by mucicarmine or periodic acid-Schiff-D staining (Figure 92-5).

Figure 92-5. Well-differentiated adenocarcinoma showing gland formation by tumor cells.

Figure 92-5

Well-differentiated adenocarcinoma showing gland formation by tumor cells. (Four-color version of figure on CD-ROM)

The bronchioloalveolar subtype of adenocarcinoma represents approximately 2% to 4% of all lung cancers. Often, it is associated with previous lung disease leading to fibrosis, including repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, scleroderma, and Hodgkin's disease. Usually, its presence is not correlated with smoking. Bronchioloalveolar carcinoma commonly arises in the periphery of the lung and grows in a lepidic fashion along the alveolar septa. The cell of origin is in some dispute, but either Clara cells or type II pneumocytes are the most likely candidates.93,94 Grossly, these tumors may be categorized as solitary, multinodular, or diffuse. Also, the histologic classification may be further subcategorized into well-differentiated and poorly differentiated tumors or into mucin- and nonmucin-containing tumors. Histologically, pure bronchioloalveolar carcinoma is uncommon, accounting for approximately 3% of all invasive lung malignancies. Over half the tumors are mucin producing, whereas roughly one-third are nonmucin producing and the remainder are mixtures. The mucin-producing tumors show gross and microscopic mucin production and tend to be multicentric. The nonmucin-producing tumors are more likely to be solitary.95 Patients with the solitary well-differentiated bronchioloalveolar cell carcinoma have a much better prognosis than patients with the other forms. The diffuse and multinodular forms usually are not amenable to therapy.

Large-cell carcinoma accounts for approximately 9% of all lung cancers. Histologically, the tumor is characterized by large cells with large nuclei and prominent nucleoli (Figure 92-6). There is no evidence of squamous or glandular differentiation and no reaction to mucicarmine staining. Large-cell carcinomas often have poor differentiation and no evidence of maturation, with features of adenocarcinoma, squamous carcinoma, or small-cell carcinoma seen with electron microscopy. Giant- and spindle-cell subtypes have been reported and carry poor prognoses. Giant- and spindle-cell carcinomas account for less than 1% of lung cancers.17 Giant-cell carcinoma has been classified as a variant of large cell carcinoma, in which large bizarre pleomorphic and multinucleated tumor giant cells are found.96 The tumor cells contain abundant cytoplasm, and the nuclei are particularly large. Over 90% of giant cell carcinomas are associated with other histologic subtypes such as spindle-cell carcinoma, adenocarcinoma, and large-cell carcinoma.97

Figure 92-6. Large-cell undifferentiated carcionoma with large nuclei and fairly prominent nucleoli.

Figure 92-6

Large-cell undifferentiated carcionoma with large nuclei and fairly prominent nucleoli. These tumors lack any glandular, squaomous, or neuroendocrine differentiation. (Four-color version of figure on CD-ROM)

Spindle-cell carcinoma also is regarded as a variant of large-cell carcinoma. Fishback and colleagues have shown that only 9% of spindle-cell carcinomas are associated with squamous cell carcinoma and that many cases are associated with mixtures of other histologic types, including giant-cell carcinoma, adenocarcinoma, and large-cell carcinoma. The spindle-cell morphology is often indistinguishable from soft tissue sarcomas. Electron microscopy can be helpful in showing epithelial differentiation. Patients with these tumors often have a poor prognosis, with an overall 5-year survival of approximately 10%.97

Occasionally, neuroendocrine features are found in association with large-cell carcinoma and justify the subtype referred to as large-cell neuroendocrine carcinoma. Large-cell neuroendocrine tumors have light-microscopic features that are commonly associated with other neuroendocrine tumors, such as palisading and rosette-like growth patterns. These tumors have low nuclear to cytoplasmic ratios, a high mitotic rate, and neuroendocrine features as determined by immunohistochemistry or electron microscopy.98 Large-cell neuroendocrine carcinoma is an aggressive malignancy with a prognosis that approaches that of small-cell lung cancer. Many patients have distant disease at the time of diagnosis. Patients with early-stage disease appear to do much better. The optimal therapy for this type of tumor is not yet clearly defined because a sufficient number of patients has not been gathered to determine the best therapy. There is evidence that suggests that neuroendocrine carcinomas may respond to chemotherapeutic regimens similar to those used for small-cell carcinoma.99–101

Adenosquamous carcinomas account for approximately 1% to 2% of lung cancers.102–105 A tumor is felt to fall in the category of adenosquamous carcinoma when at least 5% of the tumor is represented by one of the two histologic components, adenocarcinoma or squamous carcinoma. It has been suggested that adenosquamous carcinoma carries a worse survival rate, but this has not been confirmed.104,105

Pulmonary neuroendocrine neoplasia includes four major histologic subtypes: small-cell lung cancer, large-cell neuroendocrine carcinoma, typical carcinoid, and atypical carcinoid. Small-cell carcinoma is usually regarded as part of this spectrum. Histologically, high-grade neuroendocrine lung carcinomas usually include the small-cell lung cancers and the large-cell neuroendocrine carcinomas. In 10% to 20% of histologically ordinary NSCLCs such as squamous cell carcinoma, adenocarcinoma, or large-cell carcinoma, neuroendocrine differentiation may be identified with the use of immunohistochemistry or electron microscopy. The term “non-small-cell lung cancer” with neuroendocrine differentiation is sometimes used for these cases.98

Typical carcinoid and atypical carcinoid tumors are both characterized by an organoid growth pattern. Histologic patterns may include spindle cell, palisading, rosette-like, or papillary patterns. Atypical carcinoid is distinguished from typical carcinoid by the following criteria: (1) increased mitotic activity with one mitotic figure for 1 to 2 high-power fields, (2) nuclear pleomorphism, hyperchromatism, and an abnormal nuclear to cytoplasmic ratio, (3) areas of increased cellularity with disorganization of the architecture, and (4) tumor necrosis.106 Typical carcinoid tumors often have cytologic pleomorphism, but necrosis is absent, and mitotic figures are rare.

Carcinoid tumors are low-grade malignant neoplasms, which account for 1% to 2% of all lung tumors. Paraneoplastic processes can occur with carcinoid tumors, but these are rare. Usually, these tumors are asymptomatic, but the most commonly associated clinical manifestations are cough, hemoptysis, and postobstructive pneumonitis. Patients with typical carcinoid have an excellent prognosis and rarely die of the tumor. On the other hand, atypical carcinoids have a higher rate of associated metastatic disease, and survival is significantly reduced. The 5-year mortality can range from 27% to 47%.107–109 In a review of 25 patients who were surgically treated for bronchial carcinoids with metastatic disease to regional lymph nodes (N1 or N2), the overall 5-year survival was 75%, with a median survival of 62 months. No adjuvant therapy was given to the 10 patients with N1 disease. External beam radiotherapy was given to 9 of the 15 patients with N2 disease. No difference in survival was found between patients with N1 or N2 disease. Survival and recurrent rates differed in patients with typical and atypical carcinoids. In four patients with typical carcinoids, the 5-year survival was 92%, and in those with atypical carcinoids, the 5-year survival was 60%. The authors concluded that postoperative radiation therapy did not appear to be beneficial.110

SCLC accounts for 10% to 15% of all lung cancers, and approximately 28,000 new cases occur in the United States each year.17 SCLC has a very aggressive clinical course, with frequent widespread metastases. It is considered a distinct clinical pathologic entity due to its characteristic aggressive biology, propensity for early metastasis, sensitivity to chemotherapy, and overall poor prognosis. SCLC usually is not amenable to surgical treatment because of this propensity for diffuse disease. Conversely, squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma are less prone than SCLC to develop early metastases. More frequently than SCLC, these “non-small-cell” histologic types are amenable to surgical therapy in their early stages. In addition, in their advanced stages, NSCLCs lack significant differences in outcome. As such, SCLC has established itself as a unique histologic diagnostic group. Some difficulties may exist in distinguishing poorly differentiated non-small-cell tumors from SCLC. This may occur in up to 5% to 7% of cases.111 Immunohistochemistry for keratin and common leukocyte antigen can be very helpful in such difficult diagnostic circumstances.

Small lung cancers typically are situated in a peribronchial location, and they infiltrate the bronchial submucosa and peribronchial parenchyma tissues. Early and extensive metastases are common. Only the minority, less than 5%, of cases present as a localized peripheral Parenchymal lesion. In 1981, the World Health Organization proposed that SCLC be subclassified into three subtypes: (1) oat cell carcinoma, (2) intermediate cell type, and (3) combined oat cell carcinoma.112 However, this subclassification could not be consistently reproduced by expert lung cancer pathologists, and significant differences in survival could not be shown. For these reasons, in 1988, the International Association for the Study of Lung Cancer (IASLC) proposed that the intermediate cell type be dropped, and added the category of mixed small-cell/large-cell carcinoma.112 SCLC, by microscopy, is composed of cells that contain a paucity of cytoplasm and have finely granular nuclear chromatin and indistinct nucleoli (Figure 92-7). Nuclear molding due to “crush” artifact is a consistent finding but is not diagnostic. Mitotic rates are high, and the tumor often grows in sheets with a nonspecific pattern. On occasion, rosettes and peripheral palisading may be present. If necrosis exists, it usually is extensive.

Figure 92-7. Small-cell carcinoma showing cells with high nuclear and cytoplasmic ratios.

Figure 92-7

Small-cell carcinoma showing cells with high nuclear and cytoplasmic ratios. The cytoplasm is often so secret that is inconspicuous. The cells show nuclear molding and high mitotic rates. (Four-color version of figure on CD-ROM)

Approximately 4% to 6% of SCLCs show a mixture of small-cell and large-cell carcinoma, and approximately 1% to 3% of SCLCs may be combined with adenocarcinoma or squamous cell carcinoma.112–115

Solitary Pulmonary Nodule

A solitary pulmonary nodule (SPN) is an asymptomatic pulmonary mass measuring less than 3 cms in diameter, surrounded completely by parenchymal tissue with no associated atelectasis, pneumonitis, pneumonia, or adenopathy. The primary concern with any SPN is malignancy. The likelihood of an SPN being malignant directly correlates with the age of the patient, history of smoking, size of the nodule, and history of malignancy. A careful history and physical examination, therefore, are important in considering all benign and extrathoracic malignant possibilities. A history of smoking and age over 40 years are associated with a higher risk of malignancy. A concerted search for previous chest radiographs is imperative. The presence of the nodule on a previous film serves as a mark for comparison. Stability or no growth of an SPN for at least 2 years is a good indicator of a benign lesion. SPNs usually grow at a constant rate and are measured by doubling time (DT). A nodule with a DT between 20 and 400 days is usually malignant, whereas benign nodules usually have a DT greater than 400 days.116

CT, in particular thin-cut CT at 2 mm slices, is very helpful in determining the specific characteristics of an SPN that suggest malignant potential. CT of the abdomen should be performed in a patient with a previous malignancy. If an SPN is very dense or more dense than a phantom reference nodule by CT, the nodule has a high likelihood of being benign. Nodules that are less dense than the phantom nodule are indeterminate, and approximately 25% of these will be benign. Gurney used the Bayes theorem to quantitate the probability of malignancy of a given SPN.117 Likelihood ratios were derived for four clinical and six radiographic characteristics. For malignant nodules, the most important radiographic characteristics were thickness of the cavity wall spicular edge, and a diameter of more than 3 cm. For benign nodules, the most important radiographic characteristics were benign growth rate and a benign pattern of calcification (diffuse, laminated, dense central, or “popcorn” calcification). Routine preoperative bronchoscopy is usually not helpful in patients with SPNs.118 It should be performed at the time of surgery or reserved for patients in whom operative intervention poses a risk and who need a diagnosis to be made to determine the method of nonsurgical treatment. In such circumstances, fine-needle aspiration (transthoracic or transbronchial) can be performed for diagnosis. Thoracoscopy is a useful technique for removing indeterminate lesions that are peripherally located.119,120 It should be used with caution, though, in patients with SPNs that have a high likelihood for malignancy where the patient is a good operative candidate and the probability of thoracotomy for resection is high. The risk of tumor spillage is higher in video-assisted thoracoscopic sugery than open wedge resection, and the morbidity of a limited thoracotomy with wedge resection is minimal. The addition of positron-emission tomographic (PET) scanning in the evaluation of SPNs has shown great promise in differentiating between benign and malignant disease.37,38,121–124 Its use may help avoid more invasive diagnostic procedures in high-risk individuals.

Cancer Screening and Early Detection

Because symptoms of early-stage, localized disease are insidious and nonspecific, they are frequently attributed to the effects of smoking. By the time the patient seeks medical attention, the disease is usually advanced so that complete surgical resection is possible in less than 30% of cases, and the overall 5-year survival rate is less than 15%.125 Clearly, screening and early detection of cancer at a more treatable stage is an attractive option. Unfortunately, to date there have been no randomized controlled studies that have demonstrated a disease-specific mortality advantage attributable to screening methods.

In the 1970s the National Cancer Institute sponsored three separate randomized trials to assess the efficacy of lung cancer screening in male smokers (age ≥ 45 years who smoke ≥1 pack per day).126 By 1978, a total of 31,360 patients had been enrolled, with the results of their 5-year follow-up data published in 1984.127

One of the studies, the Mayo Lung Project, assessed the screening potential of routine chest radiographs versus symptom development. The other two projects, the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung cancer screening program, each evaluated the screening potential of routine sputum cytology with chest radiographs versus patients who underwent a chest radiograph alone. The addition of chest radiographs appeared to improve both the resectability of the lung cancer and the survival rate, whereas the addition of sputum cytology had no further impact on these parameters.128–131

However, when evaluating the efficacy of a screening modality, the measurement of resectability and survival are prone to a number of biases inherent to screening studies. For this reason, no screening test is considered effective unless it can lower the disease-specific mortality in the screened population.132,133 Unfortunately, all three studies were unable to achieve a disease-specific mortality reduction, and for this reason, there has been no standardized screening policy for lung cancer to date. In addition, a fourth randomized trial comparing chest radiographs versus symptom development was conducted in Czechoslovakia. This study also reached the same conclusion, with no disease-specific mortality reduction seen in the screened group.134

Although the results of the Mayo Lung Project did not justify recommending large scale radiological screening, the design of the trial has come under considerable scrutiny. Some of the more commonly cited errors in the study have included the limited statistical power as well as poor compliance in the screened and control groups.135 The screened group was on average only 75% compliant with scheduled testing. In the control group, 30% of the 160 confirmed lung cancer cases were identified on nonstudy radiographs obtained during routine medical examinations or for clinical indications other than suspicion of lung cancer. These errors may have allowed a subtle advantage resulting from routine chest radiographic screening to go undetected. On the other hand, critics of mass screening have cited the prevalence of overdiagnosis bias as a common mitigating factor leading to the failure of screening-derived reduction in disease-specific mortality.133,136

In light of these questions about the validity of the previous screening studies and advances in imaging technology, there has been a renewed interest in screening high-risk individuals for early lung cancer. The introduction of low-dose spiral CT evaluation of the chest has been the driving force behind this interest. Initial prevalence data is now available from three separate centers performing low-dose spiral CT screening.137–139 The conclusions drawn from these studies are similar. CT has a nearly 4- to 10-fold improvement in the detection of malignant disease but at the cost of a significantly increased false positive rate. These false positive cases required either further radiographic or invasive evaluation. To date, none of these trials have evaluated the impact on disease-specific mortality because their follow-up has been limited. Unfortunately this has not prevented some medical establishments from advocating the use of low-dose spiral CT screening to the community at large. Thousands of Websites advising patients to get a screening CT scan are present despite a lack of any data to support or refute its potential as a screening modality. Until data regarding its screening effectiveness, cost effectiveness, and safety are available, it cannot be recommended as a standard of care.

The National Cancer Institute has charged the American College of Radiology Imaging Network (ACRIN) to address the issue of lung cancer screening. In late 2002 they initiated a national trial that will randomize 50,000 participants to either routine chest radiograph or low-dose CT. After prevalence screening the participants will be screened for 3 years then followed. The study is 90% powered to detect at least a 20% reduction in disease-specific mortality. We await the results of this trial with eager anticipation.

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