Gastric Carcinoma in the Elderly T

Gastric Carcinoma in the Elderly

Tomio Arai

Introduction

Gastric cancer is currently the second major cause of death in Japan from malignancy [1]. As such, it affects a wide range of the Japanese population, from young adults to those older than 100 years of age. Despite the diversity of ages affected, this malig- nancy has come to be recognized as a disease of the aged. Peak incidence of gastric cancer death occurs in men between the ages of 75 and 79 and in women between 85 and 89 years of age [1]. Moreover, elderly patients eventually make up the greatest proportion of the victims of this disease: 75.2% of the men and 78% of the women who die of gastric cancer are older than 65 years of age [1].

As the geriatric population increases in Japan, an increasing number of elderly patients are presenting with gastric cancer. This rise in patient numbers highlights the need to elucidate the characteristics of this disease particular to the elderly popula- tion. Although it is generally believed that malignancies in the elderly tend to be well differentiated with slower growth rates and less metastatic potential, there are those tumors that exhibit aggressive biological behavior and which are resistant to therapy.

Analyses limited to surgical gastrectomy specimens can be misleading. The elderly are susceptible to many other sources of morbidity, such as heart failure, arteriosclerosis, cerebral infarction, and dementia. These comorbid disease states render many elderly patients, even those with early-stage cancers, poor operative candidates. Thus, when performing an analysis of clinicopathologic characteristics, unresectable and autopsy cases should be included in studies of the elderly.

In this chapter, I elaborate on the clinicopathologic features of gastric cancer among the elderly (Table 1), as well as the natural history, associated prognoses, and molecular aspects of this tumor in this age group.

159 Department of Pathology, Tokyo Metropolitan Geriatric Medical Center, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan

e-mail: arai@tmig.or.jp

Metaplasia of Gastric Mucosa

It has been widely believed that the gastric mucosa atrophies with age, thus giving rise to the increased incidence of intestinal metaplasia among the aged. This belief has been based upon pathologic analyses of post-operative gastrectomy specimens.

However, when a broader range of specimens are analyzed, the findings are markedly different. Examination of autopsy specimens reveals that intestinal metaplasia and fundic gland atrophy occur in only 40% to 50% of patients between the ages of 65 and 69 years. This percentage increases with advancing age, reaching 50% to 60% in those who are 90 years of age or older [2]. The gastric mucosa is thus well preserved in approximately half the elderly population, and the rate of intestinal metaplasia does not appear to occur on an incremental basis with aging. Atrophy and intestinal meta- plasia of the gastric mucosa appear then to be pathologic phenomena unrelated to the physiological process of aging.

Anatomic Location

Gastric cancers in the elderly are localized predominantly in the lower third of the stomach [3–12]. In those patients who are 60 years of age and older, 42% to 63% of gastric carcinomas occur in the lower third of the stomach, whereas in patients less than 40 years old, only 31% to 44% of these tumors are thus located [3–14]. The pre- disposition of this tumor for the lower third of the stomach is even more striking in those patients 85 years and older (Fig. 1). Given these findings, the risk of carcinoma developing in this particular region of the stomach appears to increase with advanc- ing age, particularly after patients reach the age of 85.

160 T. Arai

Table 1. Characteristics of gastric cancer in the elderly and the young

Elderly Young

Location Predilection for lower third Predilection for middle third Gross features

Early cancers Protruding type predominant (50%) Superficial depressed predominant (90%) Advanced cancers Type 2 & 3 predominant (70%) Infiltrating type predominant

(50%) Histology

Early cancers Differentiated type

>> Undifferentiated type >>

undifferentiated type

differentiated type Advanced cancers Differentiated type ⭌ Undifferentiated type >>

undifferentiated type differentiated type Patterns of metastases Relatively low rate of metastasis Peritoneal metastases

Liver metastases Lymph node metastases

Synchronous tumors 8 %–15% 3 %

a

Differentiated-type carcinoma includes tubular adenocarcinoma and papillary adenocarcinoma

b

Undifferentiated-type carcinoma includes poorly differentiated adenocarcinoma and signet-

ring cell carcinoma

lower third of the stomach increase with advancing age. Locations within the stomach are as follows: open rectangles with oblique lines, upper third; open rectangles, middle third; closed rec- tangles, lower third. (Data from Esaki et al. [3] and Inoshita et al. [6])

161

Conversely, there is no clear risk pattern for gastric carcinomas involving the upper third of the stomach. Some investigators have reported that these upper third stomach cancers are more common in younger patients whereas others have found no such significant differences.

Macroscopic Appearance

The macroscopic appearance of gastric carcinoma tumors varies according to age. In the elderly patient population, the incidence of tumors of the polypoid type or super- ficial elevated type increases with advancing age, whereas the incidence of infiltrating type or superficial depressed type tumors decreases [6,15]. This trend is observed not only in surgical specimens but also in autopsy cases [16].

In patients younger than 40 years of age with early gastric cancers, approximately 90 % have tumors of the superficial depressed type. In patients older than 65 years of age, this superficial depressed type of macroscopic appearance accounts for only 46%

of gastric cancers whereas the polypoid and superficial elevated type makes up 43%

of the gastric tumors in this age group [6].

In elderly patients with advanced cancers, the fungating type or ulcerative-invasive type account for 70% of tumors. Although the infiltrating type of cancer makes up a small proportion of these advanced cases among the elderly, it is by no means a rarity.

In the elderly with advanced-stage tumors, up to 17.6% of surgical specimens [6], 16 .6% of autopsy specimens [17], and 11.4% of unresectable cases [16] reveal tumors of the infiltrating type. Additionally, among those patients older than 85 years of age, polypoid tumors constitute 10% of the advanced cancers.

Although macroscopic appearance generally reflects a tumor’s histology, there are some age-related differences. In those young patients where superficial depressed- type tumors account for the overwhelming majority of early-stage cancers, many of these tumors are signet-ring cell carcinomas or poorly differentiated adenocarcino- mas [5]. However, in the elderly with early cancers, those patients with the same type of tumor often have histologically well or moderately differentiated adenocarcinomas [6].

Histology

Tumor differentiation has long been believed to be related to age, with younger patients having predominantly poorer and elderly patients having better differenti- ated cancers [18]. Such observations appear to hold true in early cancers. In young patients, up to 90% of early gastric cancers are poorly differentiated adenocarcino- mas whereas 90% of those found in elderly patients are well differentiated [6,15].

These age-related differences are less striking in advanced cancers. Although most young patients continue to have poorly differentiated adenocarcinomas, 40% to 50%

of advanced tumors among the elderly also demonstrate these more aggressive characteristics [6,15,19]. This change in distribution of histologic patterns among the elderly suggests that gastric carcinoma in this age group may develop principally as a well-differentiated tumor that then progresses to a more poorly differentiated one over time (Table 2).

162 T. Arai

There are two hypotheses for this progression [6]. One theorizes that gastric cancer in the elderly may initially develop as a well-differentiated type of tumor and then progress to a less well differentiated type. The other hypothesis is that early-stage, poorly differentiated types of cancers are never identified because of their rapid growth in older patients. In all cases, however, histopathologic diversity appears to increase with tumor growth in the elderly.

In both early- and advanced-stage cancers, male elderly patients have a higher pro- portion of differentiated-type carcinomas compared to female elderly patients (Fig.

2 ). The proportion of differentiated-type carcinoma increases with age, except in cases of male advanced cancers [15].

Table 2. Histopathologic patterns of early and advanced gastric carcinomas in young and elderly patients

Early cancer Advanced cancer

Young patients Well-differentiated Well-differentiated

adenocarcinoma adenocarcinoma

Poorly differentiated Poorly differentiated

adenocarcinoma

adenocarcinoma

Elderly patients Well-differentiated Well-differentiated

adenocarcinoma

adenocarcinoma

(Poorly differentiated Poorly differentiated

adenocarcinoma)

adenocarcinoma

a

Most young patients with gastric carcinoma have tumors that are poorly differentiated ade- nocarcinomas exclusive of stage

b

Gastric cancer in the elderly may occur as a well-differentiated adenocarcinoma that progresses to a more poorly differentiated histology; these well-differentiated adenocarcinomas show increasing histological diversity with tumor growth

c

It is postulated that poorly differentiated adenocarcinomas in the early-stage gastric cancers of the elderly are missed because of rapid tumor growth

䉴

䉴

䉴

0 20 40 60 80 100 (%)

65-74 75-84 Age (years)

85-99

Fig. 2. Proportions of differentiated-type carcinoma of

the stomach in the elderly. Note the increased proportion

of differentiated-type carcinomas with advancing age in

early and advanced cancers, with the exception of male

advanced cancer. Open squares, male early cancer; open

circles, female early cancer; closed squares, male advanced

cancer; closed circles, female advanced cancer. (From Arai

et al. [15], with permission)

Multiplicity of Gastric Cancers

Across all tumor histologies, synchronous tumors tend to be more prevalent among elderly patients compared to younger patient populations. Although certain types of tumors, such as colorectal cancers, in the elderly show no predilection for increasing multiplicity with age [15,20,21], the incidence of multiple gastric cancers does increase with advancing age [9,15,22–24], particularly among the elderly population (Fig. 3).

In gastric cancer, synchronous tumors occur in 8% to 15% of patients older than 65 years of age [9,15,18,22,23], whereas patients less than 40 years old have significantly fewer such tumors (2.9%) [9].

Given this propensity for synchronous lesions, clinicians and pathologists should examine the stomach carefully, taking into consideration the possibility of multiple neoplasms when searching for foci of gastric cancer in elderly patients.

Metastatic Disease

In general, differentiated-type gastric carcinomas tend to metastasize to the liver whereas undifferentiated-type tumors tend to develop peritoneal implants and lymph node metastases. Among the elderly, metastases present more often in the liver (11%–32% of metastatic cases), compared to younger patients in whom peritoneal dissemination is more frequent and liver lesions make up only 4% to 10% of metas- tases [9,12,13]. Interestingly enough, most reports show no significant difference in the rate of lymph node metastases between younger and elderly patients [8–10,13–15].

In those patients with end-stage gastric cancer, younger patients will more often have evidence of peritoneal and lymph node disease, and both younger and older patients have developed hepatic metastases at the same rate [25].

Unresectable Gastric Cancer

Generally, gastric cancers deemed unresectable are those tumors that have grown beyond the stomach wall and have metastasized, through hematogenous or lymphatic means or by direct extension, to other organs. In elderly patients, gastric cancer metas- 164 T. Arai

(%) 25 20 15 10 5

0

65-74 75-84 Age (years)

85-99

Fig. 3. Multiplicity of gastric cancers. The rate of

multiple gastric cancers increases with advancing age

in both sexes. Closed squares, males; closed circles,

females. (From Arai et al. [15], with permission)

tasizes most frequently to the liver (54%). Additionally, although peritoneal implants are less frequently found in those patients 85 years of age or older [16,25], direct inva- sion into the esophagus or pancreas and distant metastases to the lung or skin tend to occur more frequently with advancing age [16].

In the elderly population, however, factors other than metastatic disease may pre- clude surgical extirpation. Comorbidity is an important issue in this population, and many pathologically resectable cases are deemed otherwise because of diseases such as pneumonia, arteriosclerosis, cerebrovascular disease, myocardial infarction, dementia, and even other malignancies. Among patients aged 70 or older, 12% have an additional malignant neoplasms. Elderly patients may eventually succumb to these metachronous lesions even if the gastric cancer could have otherwise been cured.

Psychological and social factors also may preclude surgical therapy. Refusal by patients or their families accounts for 10% to 30% of cases where surgery was not per- formed, even though these patients were deemed good operative candidates. More- over, the rate of refusal tends to increase with advancing age [16]. These psychological and social considerations may be quite important in this patient population. Although the survival rate for gastric cancer patients improves with aggressive treatment without any relation to age, there can be an unexpected decrease in the ability to perform activities of daily living (ADLs) after surgery in the elderly [16]. Conse- quently, the decision to proceed with gastrectomy or surgical therapy should be con- sidered carefully in elderly patients.

Prognosis

Prognosis for elderly patients with gastric cancer is uniformly dismal. In those patients with unresectable tumors, two-thirds will survive less than a month after diagnosis, and 80% of these patients eventually die of the cancer within 2 years [16].

Even with early-stage cancers, prognosis is poor. One-year and 2-year survival rates for elderly patients are 51% and 16% to 36%, respectively [16]. Eighty percent of these elderly patients with early cancers eventually die of other causes, and 20% succumb to their tumor [16].

When compared to young and middle-aged patients, elderly patients with gastric carcinoma have poorer long-term prognoses [5,11,12,18]. The overall 5-year survival rate, inclusive of all stages of tumor, is lower in the elderly (44.6%–53.2%) compared to that in younger patients (57.1%–82.0%) [5,11,12,18]. In early gastric cancer treated with curative resection, however, survival rates do not differ between young and elderly patients [8]. Even comparing those patients who undergo curative resection, survival rates among the elderly stage for stage are poorer than those rates for their clinically equivalent younger counterparts [5,14,18]. While it is unclear what might account for the elderly patients’ poorer prognoses, one possible explanation is their generally weaker host-defense status.

Molecular Aspects of Gastric Cancer in the Elderly

Several molecular alterations may play important roles in the development of gastric

cancer in the elderly. Promoter methylation, for example, has been found to be present

not only in tumors but also in normal tissues as an age-related and tissue-specific

phenomenon that can precede the development of neoplasms [26,27]. In gastric cancers, the frequency of absent hMLH1 expression and hypermethylation increases with age [26]. In addition, gastric carcinomas with microsatellite instability tend to present as poorly differentiated adenocarcinomas in the antrum of elderly patients.

These tumors display abundant T-cell infiltration and carry a relatively good prog- nosis [28]; they are considered to be a kind of gastric cancer counterpart of colorec- tal medullary-type poorly differentiated adenocarcinomas [29].

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