Mechanisms of Late Recurrence after Radical Surgery for Gastric

Carcinoma

Takeshi Iwanaga, MD, Osaka, Japan

Hiroki Koyama, MD, Osaka, Japan

Hiroshi Furukawa, MD, Osaka, Japan

Haruo Taniguchi, MD, l Osaka, Japan

Akira Wada, MD,* Osaka, Japan

Ryuhei Tateishi, MD,* Osaka, Japan

Recurrence of gastric carcinoma develops in most cases within a short time after surgery [I]. There also are reports of relapse a long time after surgery, and recently such cases have increased [2]. The results obtained from a study of the factors involved in the late recurrence of gastric carcinoma are presented herein.

Material and Methods

Of 924 patients who underwent radical surgery for gas- tric carcinoma at the Center for Adult Diseases in Osaka from 1961 to 1970, 230 (24.9 per cent) had died from re- currence of gastric carcinoma by the end of 1975. These included 129 patients (56 per cent) with early recurrence who died within two years after surgery, 76 (33 per cent) with intermediate recurrence who died between two and five years after surgery, and 25 (11 per cent) with late re- currence who died five or more years after surgery. Among the 230 patients with recurrence, 38 (17 per cent) were examined in detail at subsequent laparotomy and 50 (22 per cent) at autopsy. The data analyzed included time of onset of clinical symptoms, results of clinical examination, findings at the time of radical operation, results of histo- pathologic examination of the resected specimens, time of onset of recurrent symptoms, and states of recurrence. The findings were compared mainly between patients with late and early recurrence.

the initial phase of the recurrence was made by a detailed study of the macroscopic and histologic findings obtained at the time of the first operation and the recurrence found in those undergoing re- laparotomy or autopsy. (Table II.) All four routes by which cancer can spread from the stomach to other sites-that is, dissemination, contiguous invasion, lymphatic system, and hematogenic system-were observed in the patients with early recurrence, but in those with late recurrence only contiguous invasion (6 patients) and the lymphatic route (6) were ob- served. It was characteristic that there were twenty-six cases of cancer spread to the peritoneum by dissemination in the group with early recurrence but none in the group with late recurrence.

Supportive and Inappropriate Flndlngs for ConditIona Leading to Late Recurrence

As reasons for the cause of late recurrence after gastrectomy, the following four conditions were considered:

(1) The amount of cancer left at the time of surgery was small.

(2) The site of cancer left during surgery was un- favorable for the subsequent spread of cancer.

(3) The cancerous proliferation was slow. (4) The host had a high resistance to the cancer.

Results

Site and Route of Recurrence

Three indicators for each condition were selected from clinical and histopathologic findings, and each

The incidence of early and late recurrence by site was compared. (Table I.) A residual stomach or gas- tric stump had a higher rate of late recurrence than early recurrence, whereas the peritoneum and liver had a low rate of late recurrence.

TABLE I Incidence of Cases by the Recurrence Site

Number of Patients Site of Recurrence Late Recurrence Early Recurrence

Residual stomach or 4 (16%)’ 8 (6%)t stumo

An assumption as to the route of cancer spread in

From the Departments of Surgery and Pathology’, Tha Centar for Adult Diseases, Osaka, Japan.

Reprint requests should ba addressed to T. Iwanaga. MD, Department of Surgery, The Center for Adult Diseases, Osaka, l-3 Nakamichi, Higashi- nari-ku, Osaka 537, Japan.

Local 11 (44%) 53 (41%) Peritoneum 10 (40%) 74 (57%) Liver 4 (16%) 39 (30 % ) Lymph nodes 10 (40%) 42 (33%) Distant organs 5 (20%) 28 (22%)

l Per cent in 25 patients with late recurrence. t Per cent in 129 patients with early recurrence.

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lwanaga et al

TABLE II Route of Cancer Spread in the lnitlal Phase of Recurrence

Number of Patients

Route of Spread Late Recurrence Early Recurrence

Dissemination 0 26’ Contiguous invasion 6 23 Lymphatic spread 6 31 Hematoaenous soread 0 17

l All 26 patients had dissemination to the peritoneum.

indicator was evaluated as either a supportive or in- appropriate finding for the conditions leading to late recurrence. (Table III.)

(1) Three indicators representing the amount of residual cancer were: (i) depth of cancer invasion in the gastric wall; (ii) metastasis to the regional lymph node; and (iii) stage of gastric cancer at the time of radical operation. Findings of relatively early gastric cancer were selected as indicators of a small amount of residual cancer and findings of advanced cancer were considered representative of large amounts of residual cancer.

(2) Three indicators representing the spread of residual cancer were selected and classified as sup- portive and inappropriate findings: (iv) no lymphatic and no vascular vessel invasion (supportive), marked invasion into the vessels (inappropriate); (v) localized cancer lesion in the gastric serosa (supportive), nonlocalized lesion in the serosa (inappropriate); and (vi) extensive fibrous reaction around the cancer le- sion in the gastric serosa (supportive), no fibrous reaction (inappropriate).

(3) Three indicators representing the rate of cancer proliferation were: (vii) the mitotic index; (viii) the period from onset of recurrent symptoms to death; and (ix) the period from onset of gastrointestinal symptoms to the first radical operation.

(4) Three indicators representing host resistance were: (x) cellular stromal reaction around the cancer lesion; (xi) sinus histiocytosis of the lymph nodes neighboring on the cancer lesion; and (xii) peripheral lymphocyte count prior to surgery.

With regard to each indicator, the incidences of supportive and inappropriate findings were com- pared between the late and early recurrence groups. (Table IV.) A significant difference (p < 0.05) in the frequency of cases was observed between these two groups with regard to supportive findings for indi- cators (i), (ii), (iii), (v), (viii), (ix), and (x), and with regard to inappropriate findings for indicators (i), (iv), (v), (vi), (viii), (ix), (xi), and (xii). Indicators that showed a significant difference in both supportive and inappropriate findings were (i) the depth of cancer invasion, (v) a pattern of cancer infiltration in the serosa, (viii) the period from recurrence to

TABLE III Conditions Leadlng to Late Recurrence

Supportive Inappropriate Item Finding Finding

(1) Small amount of resldual cancer (i) Depth of cancer Mucosa and Serosa

invasion submucosa (ii) Metastasis to lymph No metastasis Positive in 10 or

node more nodes (iii) Stage of cancer Stage I Stage IV

(2) Unfavorable state for spread of remalning cancer (iv) Invasion into No invasion in Extensive invasion

lymphatic and either into lymphatic or vascular vessels vessel vascular vessels

(v) Type of cancer cell Localized lesion Nonlocalized lesion infiltration in the serosa

(vi) Fibrous reaction ++ around the cancer lesion in the serosa

(3) Slow proliferation of cancer (vii) Mitotic index <20/10,000 (viii) Period between 1 yr<

recurrence and death (ix) Period from onset 1 yr<

of symptoms to the first operation

50/10,000< <3 mo

<3 mo

(4) High host resistance (x) Cellular stromal ++ -

reaction (xi) Sinus histiocytosis ++ -

in the lymph node (xii) Peripheral 2,500< <1,500

lymphocyte count

death, and (ix) the period from onset of symptoms to surgery. A remarkable difference (p < 0.005) was observed in both supportive and inappropriate findings for indicators (i) and (v).

Patients with Residual Cancer Left In the Stump

Eleven patients were selected in whom cancer was observed in the resected stump by histologic exami- nation of the gastric specimen removed at the time of surgery. The periods from surgery to death from recurrence were compared by the amounts of residual cancer and positive sites in the gastric wall layer at the stump.

Of two patients having a small amount of residual cancer, with a width of less than 5 mm at the resected stump, one had early recurrence and one late recur- rence. On the other hand, among nine patients with relatively large amounts of residual cancer, exceeding 5 mm in width at the stump, four had early recur- rence and five intermediate recurrence, but none had late recurrence.

One patient with residual cancer only in the lamina propria mucosae of the gastric wall developed late recurrence, but ten patients with cancer in a layer deeper than the tunica submucosa developed either early recurrence (5 patients) or intermediate recur- rence (5), and none developed late recurrence.

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Recurrence of Gastric Carcinoma

TABLE IV Incidence of Cases with Supportive and Inappropriate Findings for Conditions Leading to Late Recurrence

Supportive Findings Con-

Inappropriate Findings Late Early Late Early

dition’ Indicator’ Recurrence+ Recurrence+ P Recurrence+ Recurrence+ P

(0 16% <0.005 46% 83 % <0.005 (1) (ii) 32% ;; <0.005 20% 39% >0.05

(iii) 16% 1% <0.005 4% 18% >0.05

(iv) 20% 8% >0.05 20 % 45% <0.05 (2)

I::) 40% 3 % <0.005 36% 90% <0.005 24 % 14% >0.05 32% 56% <0.05

(vii) 24 % 16% >0.05 40% 47% >0.05 (3) (viii) 24% 5% <0.005 20% 43% <0.05

(ix) 48% 23% <0.05 12% 43 % <0.005

I:;, 32% 12% <0.05 40% 51% >0.05

(4) 28% 14% >0.05 20% 52% <0.005 (xii) 28% 18% >0.05 8% 31% <0.05

l See Table Ill for details. + Incidence of patients with each finding in all patients with late recurrence. + Incidence of patients with each finding in all patients with early recurrence.

Comments

Recurrence of cancer develops after radical surgery because invisible cancer tissues have not been en- tirely removed at the time of surgery. McNeer et al [1] reported that most recurrences occurred within twenty-two months after gastric cancer surgery. Lumpkin et al [3] b o served. that gastric cancer often involved the liver, pancreas, omentum, and perito- neum, and spillage of tumor cells with subsequent implantation on the peritoneal viscera was the major cause of death. On the other hand, recurrence after an extended period of time after surgery was often associated with the gastric stump [4]. Also in our study, the peritoneum and liver had a high rate of early recurrence but the residual stomach or gastric stump had a relatively high rate of late recurrence.

According to Cole [5], cancer cells spread by the four major routes of local invasion through contiguity of tissue planes, lymphatic system, vascular system, and implantation. However, no report is available in the literature comparing routes of gastric cancer spread between early and late recurrence. Our de- tailed histopathologic studies of the resected primary lesion and the findings on recurrence showed that in patients with late recurrence, a small amount of cancer tissue was left only in the local site or in the lymphatic vessel, whereas in those with early recur- rence, dissemination and hematogenous spread served as important routes of cancer spread as well as contiguous invasion and lymphatic spread. For example, peritonitis carcinomatosa due to dissemi- nation to the peritoneum viscera is common in pa- tients with early recurrence, whereas in those with late recurrence, the scirrhous type of peritoneal in- volvement due to direct cancer invasion is a most

Volume 135, May 1978

common spread method among the several peritoneal involvement types [6]. Furthermore, the differences in the recurrence site (Table I) have probably arisen from these differences in the routes of spread be- tween early and late recurrence.

Lumpkin et al [3] reported that early recurrence after surgery was common in advanced gastric cancer cases. According to Hoerr [ 71 the extent of the lesions was often limited to the mucosa and muscularis in gastric cancer patients surviving more than five years after surgery, but seldom in patients with advanced cancer with contiguous involvement or regional node metastasis. Approximately 10 per cent of these five year survivors died of late recurrence [3]. In early gastric cancer, even though there may be cancer left after resection, residual cancer is considered to be minimal, so that recurrence will develop over a long term. Thus, as shown in Table III, the findings of relatively early gastric cancer were selected as the items representing a small amount of residual cancer and the findings of advanced cancer as the items showing large amounts of residual cancer.

The remaining cancer that exists in the lymphatic and vascular vessels and dissemination of cancer from a nonlocalized lesion not surrounded by firm fibrous tissue in the gastric serosa are conducive to spread. Thus, indicators (iv), (v), and (vi) in Table III were selected as representing supportive or in- appropriate findings for spread of residual cancer.

As indicators representing a condition of cancer proliferation, mitotic index [8], survival period after recurrence [9], and duration of symptoms [IO] were used, and as indicators representing a condition of host resistance, stromal reaction of lymphoid infil- tration around the primary lesion [I I], sinus histio- cytotic reaction of the regional lymph nodes [ 111, and

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lwanaga et al

peripheral lymphocyte count [12], were selected. These six items have been shown to be significant indicators representing these two conditions in the literature.

All items in the four conditions-(l) amount of residual cancer, (2) spread of the residual cancer, (3) rate of cancer proliferation, and (4) host resis- tance-showed a higher rate of supportive findings in the late recurrence group than in the early recur- rence group and a low rate of inappropriate findings. A remarkable difference in both supportive and in- appropriate findings was demonstrated in indicators (i) depth of cancer invasion in the gastric wall and (v) infiltration pattern of cancer cells in the serosa. This fact suggests that the early recurrence group often has a condition conducive to the spread of cancer cells from the gastric serosa to the peritoneal cavity, and agrees with the aforementioned findings that peritoneal dissemination was the dominant type of spread in early recurrence.

On the other hand, (vii) the mitotic index, an in- dicator of cancer proliferation, did not show any significant difference in either supportive or inap- propriate findings between the early and late recur- rence groups. All three indicators representing host resistance, (x), (xi), and (xii), had a significant dif- ference in either only supportive or only inappro- priate findings, suggesting that the two conditions may not have an effect on the time of recurrence.

The amount and the site of the residual cancer are two conditions that have a significant influence over whether recurrence of gastric cancer will be late or not. Therefore, a detailed study was made on positive cases at the resected stump in which the amount and the site of residual cancer could be well estimated. Late recurrence of cancer was found only in a patient whose residual cancer tissue at the resected stump was less than 5 mm in width and located in the lam- ina propria mucosae, with a barrier for cancer inva- sion into the deeper layer. Furthermore, in a sixty- seven year old male patient, not included in the present series, who underwent subtotal gastrectomy, 2 X 2 mm of cancer tissue was detected in the mucosa on the oral stump side of the resected stomach. When the residual stomach was completely resected four years later, the cancer was 20 X 20 mm in size with limited infiltration only in the mucosa. These find- ings also demonstrate that the amount and the location of residual cancer play an important role in determining whether the recurrence will be late.

In order to prevent the late recurrence of cancer, efforts must be made during the surgical procedure to completely remove all the cancer tissue. Whether the residual cancer is prone to spread or not is de- termined by the state of the cancer at the time of

surgery. However, administration of anticancer drugs to suppress the proliferation of the residual cancer and immunotherapy to elevate the host resistance should be performed. We look forward to further improvement and development of effective anti- cancer drugs and immunotherapy.

Summary

Factors involved in late recurrence of gastric car- cinoma were investigated in 25 patients with late recurrence who died five or more years after radical surgery and 129 with early recurrence who died within two years after surgery. In the patients with late recurrence, the important routes of cancer spread in the initial phase of the recurrence were contiguous invasion and lymphatic spread. Whether early or late recurrence occurred had a high correlation with the following four conditions: (1) the amount of residual cancer left at the time of surgery; (2) the spread of the residual cancer; (3) the rate of cancer proliferation; and (4) the resistance of the host.

To prevent late recurrence, it is necessary not to leave any cancer tissue in these routes at the time of gastrectomy, as well as to employ adjuvant chemo- and immunotherapy for the inhibition of cancer proliferation and elevation of the host resistance.

References

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