Acta Medics Scandinavica. Vol. 161, fasc. 5, 1959.

From the Medical Department, Maria Hospital (Head: Guido Totterman, M. D.) and the Roentgenological Department, Maria Hospital (Head: Ilmari Sallinen, M. D.),

Helsinki, Finland.

Pernicious Anemia and Gastric Carcinoma.

BY

M. SIURALA, E. ER- and J. TAPIOVAARA.

(Submitted for publication December 13, 1958.)

Many authors have found a relatively high incidence of gastric carcinoma in pernicious anemia (6, 11, 12, 13, 15, 23, 25, 26, 27, 31, 32, 33, 38). The percentage of gastric carcinomas detected varied from 3.2 to 12.3. Two cases of concomitant gastric carcinoma and pernicious anemia have been reported from Finland (28, 35). Hitchcock et al. (11) claimed that the incidence of gastric carcinoma is 21.9 times greater in cases of pernicious anemia than in the general population of the same age. However, some earlier authors have not been able to establish any con- sistent relationship between these diseases (3, 5, 7, 39).

Mosbech (22), Videbaek and Mosbech (36) and Zancan (40) have found a greater incidence of gastric carcinoma among the relatives of patients with pernicious anemia than in families of patients not suffering from pernicious anemia.

The aim of this investigation was to study the occurrence of gastric carcinoma in patients with pernicious anemia and their relatives. All these patients treated in an outpatient department during one year were studied by the authors them- selves. The diagnosis of pernicious anemia was confirmed by careful study. Three control series were used.

Material and Methods

Pernicious anemia (PA) series. All the patients diagnosed as having PA and treated a t the hematological outpatient department of the Maria Hospital, Hel- sinki, during 1957, were studied. Two of these, treated for several years as per- nicious anemia patients, revealed a urinary radioactivity of more than 10 % with the ordinary Schilling test. These two patients were excluded leaving 69 pa.tients for further study.

The mean age of the patients was 66.7 years, 13 were men and 56 women. Aided by a grant from Sigrid Jusblius Stiftelse foundation. 30-593317. Acta med. Scandinau. V o l . 164. 431

432 M. SIURALA, E. ERAMAA AND J. TAPIOVAARA

All 69 patients had macrocytic, hyperchromic and megaloblastic anemia a t the time the diagnosis of PA was made, and all responded adequately to treatment with Vitamin Bla. All had histamine achlorhydria (0.1 histamine phosphate per 10 kg of body weight, three samples were taken a t 30 min. intervals). Uropepsin excretion ranged from 0 to 6.5 UP units/hr (with the method of West et al. (37)) with a mean of 1 .26 f 0.20.

The Schilling test, ordinary and/or with carbachol stimulation, was performed on all the cases. The mean urinary radioactivity was 1.31 f 0.23 % and the range 0-4.5 %. On 45 patients Schilling test was performed with intrinsic factor and revealed a significant increase in the values in all except 3 cases. These patients, however, revealed no other signs of deficient absorption.

X-ray examination of the stomach was performed on all the patients. Gastros- copy was performed when the roentgenological examination led to suspicion of malignancy or of benign tumors. 154 mucosal specimens were obtained from the body of the stomach (suction biopsy method) of 44 PA patients. All the patients were examined by the authors themselves (M. S. and E. E.). One (J. T.) of the authors performed all the roentgenological examinations and another (M. S.) the histological and gastroscopical examinations.

A questionnaire was filled in concerning the occurrence of gastric carcinoma in 963 relatives (parents and sisters of the patients and sisters of the parents) of 60 PA patients.

Control series. The number of gastric carcinomas detected in Finland during 1954 (29) served as the first control material. The second control material con- sisted of patients admitted during 1957 from the medical outpatient department of this hospital for X-ray examination of the stomach. Only patients examined roentgenologically by one of the present authors (J. T.) were included. There was no other selection. When all patients below 55 years of age were excluded there remained 405 patients whose mean age (66.0 years) was of the same order of mag- nitude as that of the patients with pernicious anemia (66.7 years). 123 were men and 282 women. Gastroscopy was performed in all but 3 of those patients in whom X-ray examination of the stomach suggested the presence of benign or malignant tumors.

The third control material was composed of 911 relatives (parents and sisters of patients and sisters of parents) of 54 successive patients - of the same age section as PA patients - treated in Maria Hospital. None of the patients had gastric carcinoma or pernicious anemia. Their mean age was 60.9 yers.

The t-test was used in statistical calculations.

Result s

Sixty-nine PA patients were studied. 6 were previously untreated, 2 in relapse and the remaining 61 in remission. The mean duration of PA was 8.1 years.

The number of benign and malignant tumours encountered is listed in Table I. It appears that five had gastric carcinoma (Ca) and four polyps, representing an

PERNICIOUS ANEMIA AND GASTRIC CARCINOMA

Table I.

The occurrence of gastric carcinoma and benign polyps in pernicious anemia.

43 3

3

1 19 4

4 69 67.5 66.7

- 2 I ;; -

Age groups 1 Pernicious anemia I Second control series

- 1 4 5 a

12 72.1

41 -50 . ........... 5 1 - 6 0 . ........... 7 1 - 8 0 . . ..........

> 80. ........... Total No. of cases Mean age ........

61-70.. ..........

Gaetric carcinoma

- -

2 3

5 71.8

-

Polype Total number Gastric I of cases I carcinoma

I I -

1 2 2

5 60.0

-

rota1 number of cases

- 189 128 88

405 66.0

incidence of 7 . 5 % and 6.0 % respectively. The percentage of Ca’s detected in the over-all population over 40 years of age in Finland (first control material) was 0 . 1 5 %, i. e. significantly lower. However, no Ca was detected in PA patients below 60 years of age. Above 60, the incidence of Ca in PA was 9 . 8 %, and corre- sponding percentage in the over-60s of the control material was only 0 . 3 4 %. The difference was statistically highly significant (p < 0.001) .

The second control series (patients admitted during 1957 for X-ray examination of the stomach from the medical outpatient department, Maria Hospital) con- sisted of 405 patients over 55 years of age, their mean age beiqg 66.0 years. X-ray examination of the stomach suggested the presence of neoplasm in 16 cases. Of these 16 cases four were excluded on the basis of roentgenological and gastro- scopical follow-up examinations. In the remaining 12 cases gastroscopy and ]or operation confirmed the roentgenological diagnosis of Ca. Thus the incidence of- Ca was 3.0 %. Statistical comparison revealed that the incidence of Ca was sig- nificantly higher in PA than in the second control series (p < 0.001) . Polyps which appeared to be roentgenologically and gastroscopically benign were encountered in the second control series in five out of 405 cases representing an incidence of

The diagnosis of Ca and polyps in PA cases was established roentgenologically and gastroscopically and, in three Ca cases, was verified histologically from speci- mens taken a t gastric resection. Two patients were not operated on because of advanced cardiovascular disease. One of the Ca cases had been examined many times in the course of the years both roentgenologically and gastroscopically, and every time multiple and apparently benign polyps were seen. The Ca had invaded the aboral parts of the body of the stomach and oral parts of the antrum in three cases, and in two cases i t was located in the prepyloric region. All three patients operated on were alive one year later, asymptomatic and without roentgenological signs of recurrence. Four of the five patients with Ca had no abdominal distress nor any general symptoms a t the time the diagnosis of Ca was made.

In addition to the 5 patients with Ca one of the PA patients had been operated

1.2 %.

434 M. SIURALA, E. ERAMAA AND J. TAPIOVAARA

on for Ca 8 years previously. X-ray examination and a gastroscopy in 1957 failed to disclose any signs of malignancy.

Histological examination (specimens taken a t operation or by means of the suction biopsy tube) of gastric body mucosa outside the Ca-invaded area revealed intestinal and/or pseudopyloric metaplasia and total loss of normal body glands. Histological changes of the same kind and degree were found in almost all PA cases without Ca. I n two cases only were groups or remnants of normal body glands found.

The mean duration of PA was 6.5 years in cases with no tumor, 11.7 years in those with polyps and 14.7 years in those with Ca.

The occurrence of Ca in relatives of PA patients was investigated. Of 963 rela- tives of 60 PA patients, 12 had Ca, one had suspected Ca and one had esophageal cancer. In the families of four PA patients Ca was present in more than two mem- bers. I n the control material (911 relatives of 54 patients without PA) four had Ca, two had suspected Ca and one had esophageal cancer. The difference was statistically significant (p < 0.01).

Discussion

The percentage incidence of gastric carcinoma (Ca) in this series of pernicious anemia (PA) was found to be 7.5, and in patients over 60 years 9.8. The incidence of polyps was 6.0 %. The incidence of Ca in PA patients was significantly higher than the frequency of Ca’s detected in the same section of the total population in Finland during 1954 (0.15 yo in the over-40s and 0.34 % in the over 60s). The latter figures, however, do not represent the real incidence of Ca in the population as a whole since cases of Ca diagnosed before 1954 in patients still alive a t the time and cases of Ca overlooked are not included. On the other hand, the in- cidence of Ca in PA was significantly higher than the incidence of Ca in patients on whom X-ray examination of the stomach was performed during the same year in the same outpatient department. All these patients had some kind of abdominal distress and many were admitted for the roentgenological examination because of clinical suspicion of gastric cancer. Hence, i t is reasonable to assume that the incidence of Ca in this control material is higher than in the general population.

The mean duration of PA was more than twice as long in PA patients with Ca than in those without Ca. The material is too limited, however, to warrant any definite conclusions on this point.

There was a higher incidence of Ca in the relatives of PA patients than in the control material. This is in agreement with the results obtained by other authors.

I n view of the high incidence of Ca in PA, it seems reasonable to conclude that PA patient?, especially those above 60 years of age, should have regular roent- genological examinations.

Histological examination of mucosal biopsy specimens from PA patients revealed in all cases atrophic changes with some kind of metaplasia. This is in agreement with the results obtained by most other authors. Many authors are of the opinion

PERNICIOUS ANEMIA AND GASTRIC CARCINOMA 435

that atrophic changes of the gastric mucosa are responsible for the absence of intrinsic factor leading to PA. Recent studies with radioactive vitamin B,, seem to support this view (1, 2, 4, 8, 9, 16, 18, 19, 30, 34). On the other hand, atrophic changes of the gastric mucosa occur in most cases with Ca and there is some evidence suggesting that the large bulk of Ca’s originate from atrophic gastritis, particularly from the areas of intestinal metaplasia (10, 14, 17, 20, 21, 24) which are commonly encountered in the gastric mucosa of Ca and PA.

From the considerations presented above it would appear that atrophic gastritis is the connecting link between gastric carcinoma and pernicious anemia.

Summary

In order to investigate the incidence of gastric carcinoma (Ca) in pernicious anemia (PA) patients and their relatives, 69 PA patients treated during 1957 a t the hematological outpatient department, Maria Hospital, Helsinki, were studied using the following methods: X-ray examination of the stomach, gastroscopy, gastric biopsy, histamine test, uropepsin excretion, Schilling test (ordinary, with carbachol and with intrinsic factor). Three control series were used.

The following findings were made: 1. The incidence of Ca in the total PA series was 7 . 5 %, and 9.8 yo in those over

60 years of age. This incidence was significantly higher than the frequency of Ca detected in the total population in Finland during 1954. It was also significantly higher than the incidence of gastric carcinomas (3.0 yo) in patients admitted for X-ray examination of the stomach during 1957 in the same outpatient department. Benign polyps were present in 6.0 yo of the PA series and in 1.2 yo of the controls.

2. Twelve of 963 relatives of 60 PA patients had Ca; only 4 of 911 relatives of 54 patients without PA had Ca. The difference was statistically significant.

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