Synchronous and metachronous occurrence of gastric adenocarcinoma and gastric lymphoma: A review of the literature

Abstract

The occurrence of both primary gastric lymphoma and gastric adenocarcinoma in the same patient is a rare entity. The possible causative factors of synchronous or metachronous occurrence of both malignancies and varieties in the treatment modalities are reviewed according to published cases in English language medical literature.

INTRODUCTION

Secondary malignancies associated with Hodgkin’s or non-Hodgkin’s lymphoma are commonly detected in relation with the improvement in overall survival rate of these patients. The most common type of secondary malignancy seen with lymphoma is acute myelogenous leukemia, however, epithelial malignancies are also reported[1-3]. Intensive radiotherapy and chemotherapy administered to these patients have raised questions about the long-term effects of these therapeutic modalities on the development of secondary malignancies. Primary gastric lymphoma is a relatively uncommon malignancy, occurring in only 1%-7% of all malignant neoplasms of the stomach[4]. The occurrence of both primary gastric lymphoma and gastric adenocarcinoma in the same patient is a rare entity. We review the possible causative factors of synchronous or metachronous occurrence of both malignancies and varieties in the treatment modalities according to published cases in English language medical literature.

INCIDENCE

Since the first description of multiple gastric cancers by Barth in 1855[5], case reports of benign and malignant multiple primary tumors have been appearing with an increasing frequency. The incidence of multiple simultaneous gastric cancers is high, ranging from 3.4% to 67.4%[6]. In the first published case series in Germany, authors did not mention the incidence of simultaneous occurrence of malignant lymphoma and adenocarcinoma in the stomach[7]. Thereafter, case series from Japan appeared in the literature. Kasahara et al[8] reviewed data of 35 Japanese patients without giving incidence rate for synchronous occurrence. Noda et al[9] found an association of both tumors in 2 of 2438 (0.08%) gastric carcinoma cases. The incidence of simultaneous occurrence was 3.7% (9/247) in primary gastric lymphomas and 0.098% (9/9150) in gastric carcinomas in series by Nakamura et al[10]. Despite definite expression of incidence rate for synchronous cases, the incidence of metachronous occurrence of both tumors has not been mentioned in the literature.

SYNCHRONOUS CASES

Since the first case reported by Rabinovitch et al[11], 56 cases of synchronous occurrence of gastric adenocarcinoma and lymphoma have been published in English language medical literature[7-31]. Majority of these reports included detailed analysis of histopathologic features of tumors instead of clinical follow-up of patients. Basic characteristics of the patients are summarized on Table 1. Twenty-three cases were from the Eastern and 33 cases were from the Western countries. The overall median age was 66 (range 27-85) years. The median age for the Eastern population was 67 and for the Western population was 72 years. Male predominance was observed in both the Western (1.75:1) and the Eastern (3:1) populations. Overall, 62.5% of patients had early gastric carcinoma (EGC) and 30.4% of patients had advanced gastric carcinoma (AGC), the type of gastric carcinoma was undefined in the rest of the patients. EGC constituted a majority of the Eastern cases (82%), whereas 48% of cases were from the Western countries. Before the report by Kelly et al[18] in 1994, the presence of H pylori was not mentioned by the authors. Since then, reported H pylori infection rate reached 79%. The infection rate in the East (86%) was higher than that in the West (72%). The prevalence of H pylori was higher in EGC (86%) than that in AGC (64%). There was no significant correlation between the prevalence of H pylori and the differentiation of adenocarcinoma. The declared results of adenocarcinoma histopathology were not uniform in relation to the variations in the classification systems used by the authors. However, differentiation of the tumor was clearly revealed by all authors. Poor and well differentiated adenocarcinomas showed an equal distribution in the Eastern (43.5% and 52%, respectively) and the Western cases (42% and 42%, respectively).

Table 1.

Synchronous cases reported in the literature

Reference	Age/sex	Lymphoma type	H pylori	Adenocarcinoma type	Therapy	Survival months
Rabinovitch[11]	64/m	Lymphosarcoma	NM	EGC	S. gastrectomy	NM
Jernstrom[12]	72/f	Lymphocytic lymphosarcoma	NM	AGC, I, W	S. gastrectomy and 750 R radiotherapy	10
Manier[13]	65/m	Histiocytic	NM	EGC, P	T. gastrectomy and chemotherapy	24
	72/m	Histiocytic	NM	AGC, P	T. gastrectomy	1.5
Lin[14]	56/m	Diffuse lymphocytic	NM	EGC, W	T. gastrectomy and 4500 cGy Co60 radiotherapy	24
Kane[15]	74/m	Diffuse lymphocytic	NM	EGC, P	S. gastrectomy, radiotherapy and chemotherapy	12
Planker[7]	65/m	Immunocytoma	NM	EGC, I, M	T. gastrectomy, splenectomy and 4000 cGy Co60 radiotherapy	30
Czerniak[16]	74/m	Mix type	NM	EGC, W,	S. gastrectomy, radiotherapy and chemotherapy	12
Kasahara[8]	77/m	Small cleaved	NM	AGC, W	S. gastrectomy	24
Noda[9]	61/m	Diffuse large cell	NM	EGC, W	T. gastrectomy and chemotherapy	9
Akosa[17]	79/m	MALT, LG	NM	EGC, M	No treatment	NM
Kelly[18]	85/m	MALT, LG	+	?, I, M	No treatment	2
Von Herbay[19]	79/f	MALT, LG + HG	+	EGC, I, W	T. gastrectomy
Wotherspoon[20]	55/f	MALT, LG	+	AGC, P	NM	NM
	55/f	MALT, LG + HG	+	EGC, W	NM	NM
	NM/m	MALT, LG	-	AGC, W	NM	NM
	60/f	MALT, LG	+	AGC, W	NM	NM
	34/f	MALT, LG	+	AGC, P	NM	NM
	67/f	MALT, LG	+	EGC, W	NM	NM
	55/f	MALT, LG	+	EGC, W	NM	NM
	55/f	MALT, LG	-	EGC, P	NM	NM
	69/f	MALT, LG	+	AGC, W	NM	NM
Nishino[21]	71/m	Diffuse, large cell type	NM	EGC, tubular type, W	T. gastrectomy, splenectomy and cyclophosphamide, oncovin, prednisolone chemotherapy	120
Hardman[22]	56/m	MALT, LG	+	AGC, Signet-ring cell, P	T. gastrectomy and etoposide, cisplatin, adriamycin chemotherapy	NM
Nakamura[10]	27/m	MALT, LG	+	EGC, I, W	NM	57
	38/m	MALT, LG	+	EGC, D, P	NM	45
	70/m	MALT, HG	+	EGC, I, W	NM	81
	72/m	MALT, LG	+	AGC, I, W	NM	1
	75/f	MALT, LG	+	EGC, I, W	NM	13
	53/m	MALT, LG	+	EGC, I, W	NM	67
	67/f	MALT,LG	+	EGC, I, W	NM	31
	42/m	Immunoblastic	+	EGC, D, P	NM	91
	47/m	MALT, LG	+	EGC, D, P	NM	24
	78/m	T-cell pleomorphic	+	AGC, D, P	NM	1
Ishihama[23]	68/m	Diffuse, small cleaved	+	EGC, W	T. gastrectomy	NM
	61/m	Diffuse, large cell	+	EGC, P	T. gastrectomy	NM
	61/f	Diffuse, lymphocytic	+	EGC, P	S. gastrectomy	132
	77/m	Diffuse, large cell	+	EGC, W	Vincristine,endoxanpredonine, adriamicin chemotherapy and endoscopic mucosectomy	NM
Goteri[24]	51/M	MALT, LG + HG	+	EGC, I, W	NM	122
	55/f	MALT, LG	+	EGC, D, P	NM	33
	80/m	MALT, LG	-	EGC, I, W	NM	12
	57/m	MALT, LG	+	EGC, I, W	NM	10
	53/m	MALT, LG	+	AGC, I, W	NM	3
	66/m	MALT, LG	-	AGC, D, P	NM	10
	69/m	MALT, LG	-	AGC, D, P	NM	8
	69/m	MALT, LG	-	AGC, M, M	NM	3
Kanamoto[25]	47/m	MALT, LG	+	EGC, D, P	T. gastrectomy	24
Montalban[26]	77/m	MALT, LG	NM	GC	NM	NM
	68/f	MALT, HG	NM	GC	NM	NM
Cammarota[27]	47/m	MALT, LG	+	AGC, I, P	Etoposide, epirubicin, cisplatin chemotherapy and T. gastrectomy	NM
Chan[28]	71/m	MALT, LG	-	EGC, P	S. gastrectomy	NM
	58/f	MALT, HG	+	EGC, P	S. gastrectomy	NM
	75/f	MALT, HG	+	EGC, P	S. gastrectomy	NM
Kafes[29]	78/m	MALT, NM	+	EGC, I, P + stromal tumor	T. gastrectomy	20
Sakai[30]	51/f	MALT, LG	+	EGC, tubular, M	T. gastrectomy	NM
Suenaga[31]	73/m	MALT, LG	-	AGC, I, W	S. gastrectomy, D3 dissection	23

m: male, f: female, NM: not mentioned, EGC: early gastric carcinoma, AGC: advanced gastric carcinoma, GC: gastric carcinoma, I: intestinal type, D: diffuse type, W: well differentiated, P: poor differentiated, M: moderately differentiated, MALT: mucosa-associated lymphoid tissue, HG: high grade, LG: low grade, S. gastrectomy: subtotal gastrectomy, T. gastrectomy: total gastrectomy.

Majority of the lymphomas were MALT (mucosa-associated lymphoid tissue) type lymphoma (69.6%) and low grade one (87.2%). The association of H pylori with MALToma was 86% in the Eastern cases and 72% in the Western cases. Six of 7 (86%) patients with other types of gastric lymphoma associated with gastric adenocarcinoma were H pylori-positive. There was no data about the size of the tumor found in 32% of the cases. The size of the lymphoma was larger than carcinoma in 57% of cases. Overall, lymph node metastasis was found in 41% of the cases. In patients with early carcinoma and positive lymph node metastasis, the origin of metastatic lymph node was usually lymphoma (89%). In the presence of advanced carcinoma, metastases originated from the adenocarcinoma, either alone or in combination with the lymphoma. The topographic interrelation of both tumors was also revealed in the reports (n = 53/56). Majority of the cases (n = 29, 54.7%) had independent tumors. There was no significant difference between the Eastern and the Western cases in this respect. Collision of both tumors was reported in 14 (26.4%) cases. There were 4 cases with contiguous and 5 cases with intermingling tumors.

METACHRONOUS CASES

In contrast to synchronous occurrence of gastric adenocarcinoma and lymphoma, majority of cases (90%, 27/30) with metachronous occurrence of both tumors were reported from the Western countries[10,32-47]. In 1950, McNeer et al[32] published the first case in the literature. The features of the 30 patients are summarized in Table 2. The median age was 50 (8-82) years. Of these patients, 18 were male and 12 were female. Previously detected malignancy in 28 patients was lymphoma. Only 2 cases reported by Nakamura et al[10] were diagnosed as lymphoma after the treatment of gastric adenocarcinoma. One of these tumors developed in the remnant stomach in the 7th year after subtotal gastrectomy and the other developed in the 13th month after endoscopic mucosal resection. Rest of the patients suffered from various types of lymphoma previously. Leading type of lymphoma was MALT lymphoma (30%), followed by large cell lymphoma (20%). The existence of H pylori was not mentioned in the reports published before 1997. Thereafter, 9 of 10 reported cases were found infected with H pylori. Median interval between the treatment of lymphoma and the diagnosis of gastric adenocarcinoma was 90 (6-408) mo. The reported interval after the treatment of MALToma (median 27, range 6-108 mo) was shorter than the other types of lymphoma (median 120, range 42-408 mo). Adequate description of histopathology of adenocarcinoma was determined in 26 of 30 cases. After the latent period, majority of cases suffered from advanced gastric adenocarcinomas (65%) and 9 patients had EGC.

Table 2.

Metachronous cases reported in the literature

Reference	Age/sex	Lymphoma type	Lymphoma therapy	Interval	Adenocarcinoma therapy
McNeer[32]	27/f	Reticulum cell sarcoma	S. gastrectomy; radiotherapy for local recurrence	6.5 yr	T. gastrectomy
Fleischer and Walker[33]	61/m	Lymphosarcoma	S. gastrectomy; 4000 cGy	5 yr	Supportive treatment
Bockus[34]	49/m	Lymphosarcoma	Radiotherapy	3.5 yr	T. gastrectomy
Komarov[35]	40/m	Round cell sarcoma	S. gastrectomy	19 yr	NM
Morgenstern[36]	46/f	Reticulum cell sarcoma	S. gastrectomy	25 yr	Resection
Ettinger and Carter[37]	55/m	Lymphosarcoma	S. gastrectomy; 2000-2600 cGy	16 yr	Palliative surgery
Shani[38]	47/m	Reticulum cell sarcoma	S. gastrectomy	31 yr	Resection
	29/m	Diffuse, poorly differentiated lymphocytic	S. gastrectomy; orthovoltage for whole abdomen (6 d)	34 yr	Exploration
	51/f	Diffuse, mixed lymphocytic histiocytic	S. gastrectomy; 1800 cGy X-R + 2000 cGy Co 60. 12030 cGy for recurrence (16 yr later)	16 yr	Exploration
	48/m	Diffuse, poorly differentiated lymphocytic	S. gastrectomy; 3000 cGy.	10 yr	Exploration; combined chemotherapy
Sellin[39]	45/m	Diffuse, large cleaved cell	2300 cGy; S. gastrectomy; 4000 cGy (4 yr later)	13 yr	Total gastrectomy
Brumback[40]	8/m	Diffuse undifferentiated (small noncleaved)	S. gastrectomy; cyclophosphamide, vincristine, prednisolone for 1 mo; 4075 cGy; 6-mercaptopurine, vincristine, prednisolone, methotrexate for 3 yr	6 yr	Gastrojejunal bypass; 5-FU, doxorubicine, mitomycin chemotherapy
	15/m	Hodgkin’s disease, nodular sclerosis type	3500 cGy to upper abdomen; 2000 cGy to left axillary-cervical-supraclavicular; cyclophosphamide, vincristine, procarbazine, prednisolone, adriamycin for 2 yr	10 yr	NM
	24/f	Reticulum cell sarcoma	S. gastrectomy; 4000 cGy	15 yr	No treatment
	60/m	Diffuse large cell	S. gastrectomy; cyclophosphamide, vincristine, prednisolone, doxorubicin chemotherapy	4 yr	T. gastrectomy and S. esophagectomy
	56/m	Well differentiated lymphocytic	S. gastrectomy; 3700 cGy; oral cyclophosphamide chemotherapy	12 yr	T. gastrectomy
Zorlu[42]	43/m	Diffuse, large cleaved cell	S. gastrectomy; cyclophosphamide, vincristine, prednisolone ( 2 courses); 4500 cGy; cyclophosphamide, vincristine, prednisolone (4 courses)	8 yr	Near total gastrectomy; 5-FU, mitomycin
	35/f	Diffuse, large cleaved cell	S. gastrectomy; 4000 cGy; cyclophosphamide, vincristine, prednisolone (6 courses)	8 yr	T. gastrectomy
Nakamura[10]	69/f	Immunoblastic	NM	7 yr	S.gastrectomy
	82/f	MALT, HG	NM	13 mo	Endoscopic mucosal resection
Zauber[43]	78/f	Large cleaved cell	S. gastrectomy; 4500 cGy; i.v. cyclophosphamide chemotherapy (9 courses)	4 yr	T. gastrectomy
Montalban[26]	42/m	MALT	Cyclophosphamide, doxorubicin, vincristine, prednisone	108 mo	NM
Hasegawa[44]	72/f	MALT	Antibiotic therapy for H pylori	6 mo	S. gastrectomy
Morgner[45]	74/m	MALT, LG	Antibiotic therapy for H pylori	4 yr	Endoscopic mucosal resection
	70/m	MALT, LG	Antibiotic therapy for H pylori	5 yr	Endoscopic mucosal resection and argon plasma coagulation
	77/f	MALT, LG	Antibiotic therapy for H pylori	4 yr	Endoscopic mucosal resection
Ghosdal[46]	32/m	MALT, LG	S. gastrectomy; Antibiotic therapy for H pylori (for 2 wk);	15 mo	No treatment
Raderer[47]	67/f	MALT	Antibiotic therapy for H pylori ( for 9 mo)	9 mo	S. gastrectomy
	61/f	MALT	Antibiotic therapy for H pylori ( for 14 mo); 2CdA chemotherapy (4 courses)	27 mo	S. gastrectomy

m: male, f: female, NM: not mentioned, MALT: mucosa-associated lymphoid tissue, HG: high grade, LG: low grade, S. gastrectomy: subtotal gastrectomy, T. gastrectomy: total gastrectomy,

¹Only 2 cases reported by Nakamura et al were diagnosed as lymphoma after the treatment of gastric adenocarcinoma.

PATHOLOGIC ASPECTS OF SYNCHRO-NOUS OCCURRENCE

The relation of both tumors in the stomach was classified in four categories: (1) separate tumors; (2) collision tumor; (3) contagious tumor, without any intermingling between malignant components; and (4) intermingling (admixture) of both tumors. Histological classification of gastric lymphomas is based on systems originally designed for nodal lymphomas as Musshoff modification of the Ann Arbor staging system, Working formulation or Kiel classification. However, these are not optimal for the documentation of specific relevant features of primary extranodal lymphoma in the gastrointestinal tract. Several modifications on TNM staging system and alternatives have been proposed[48,49]. Recently, the European Gastro-Intestinal Lymphoma Study Group (EGILS) proposed a new modification of TNM staging system for the gastric lymphomas[50]. In 1983, the histologic relationship of extranodal B-cell lymphomas and MALToma was recognized by Isaacson and Wright, and classification as a separate entity of MALT-NHL was proposed - the MALT lymphoma concept[51,52]. However, the first report of synchronous occurrence of MALToma with gastric adenocarcinoma appeared in the literature in 1990. Metachronous occurrence of MALToma was reported at the end of 1990’s. Therefore, it is easily speculated that authors are affected by the classification systems for nodal lymphomas before 1990.

Histopathological disorders of gastric mucosa are not specific for any neoplasm, but intestinal-type adenocarcinomas frequently showed atrophy, intestinal metaplasia, and not uncommonly, dysplasia of the surrounding non-neoplastic gastric mucosa. Diffuse-type adenocarcinomas did not frequently show such lesions. Primary lymphomas displayed expansive lymphoid follicles and also a high percentage of atrophy and intestinal metaplasia of the surrounding gastric mucosa[53]. In addition to the similar histopathological findings in the surrounding gastric mucosa of intestinal-type adenocarcinoma and primary gastric lymphoma, lymphocytic gastritis was found more frequently in patients with gastric carcinoma and primary gastric lymphoma than in unselected patients undergoing endoscopy[54]. This finding suggests that these two disparate gastric tumors may share an immunological dysfunction or a common pathogenesis. Zamboni et al[55] pointed out that foveolar lymphoepithelial lesions or signet-ring cells were found in 37% of MALT lymphomas. Like in MALT lymphomas, gastric carcinomas are invariably accompanied by lymphoid proliferations ranging from reactive lymphoid follicles to MALT lymphomas[56]. These observations also supplied the theory of common pathogenesis of MALT-type lymphoma and gastric carcinoma.

The incidence of early gastric carcinoma in synchronous tumors was remarkably high. Especially in the Eastern countries, routine screening for gastric carcinoma is practiced, and up to about 50% of gastric carcinoma diagnosed in the early stage[57]. This observation, together with the finding that most lymphomas were larger than adenocarcinomas, suggested that lymphomas might develop before adenocarcinomas or that the presence of MALT lymphoma might increase the risk of developing gastric carcinoma.

ETIOLOGIC FACTORS OF SYNCHRONOUS OCCURRENCE

H pylori

It is tempting to hypothesize that H pylori is a common etiological agent for synchronous occurrence of gastric adenocarcinoma and primary gastric lymphoma. Since 1994, the existence of H pylori has been investigated in almost every report. In the present analysis, in areas with high prevalence (Eastern) and low prevalence (Western) of H pylori, synchronous tumors are associated with H pylori infection rates of 86% and 72%, respectively, and are similar to or higher than the reported infection rates of isolated gastric adenocarcinoma and isolated MALT lymphoma or other primary gastric non-hodgkin lymphoma[20,58-60]. Therefore, H pylori may have an important etiological role for synchronous tumors in both high and low prevalence areas.

H pylori plays a key role in the natural history of gastric MALT lymphoma, representing an example of antigen-mediated tissue stimulation and lymphoproliferation, with possible subsequent lymphomagenesis[58,61]. Antigenic mimicry between H pylori and the host mucosa was held responsible for inducing autoimmune responses which lead to development of the disease[62,63]. Kawahara et al[64] found that the increase of antibody titers to HCG-27 cells in

H pylori-positive patients with MALT lymphoma compared to titers in patients with other gastroduodenal diseases and in healthy subjects. Lymphoid follicles which are not present in the normal stomach show development in the setting of chronic gastritis. Genta et al[65] have observed a strong correlation between follicular gastritis and H pylori infection. Wotherspoon et al[58] suggested that H pylori might trigger the acquisition of MALT in the gastric mucosa, and this lymphoid tissue is thought to harbor the precursor cells in MALT-NHL. These precursor cells change gradually into malignant lymphoma cells with autonomous and uncontrolled growth by accumulation of genetic alterations such as mutations, deletions, and amplifications. In vitro experiments have demonstrated that in the earlier phases of development, the growth of genetically altered lymphoid cell is not yet fully autonomous, and proliferation partly depends on H pylori-related proteins and T cells[66-69]. On the other hand, H pylori infection has been linked to the intestinal-type gastric adenocarcinoma through a chain of events that starts as acute gastritis and progresses to chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and eventually, adenocarcinoma formation[70,71]. A recent meta-analysis has revealed that H pylori infection is associated with a 2-fold increase in developing gastric adenocarcinoma[72]. These epidemiologic and pathologic data about the relation of H pylori infection with gastric adenocarcinoma and primary gastric lymphoma are supported by a recent genetic study[73]. H pylori genotyping on archived gastric tissue revealed that H pylori strains with certain combinations of virulence subtypes are associated with gastric carcinoma or MALT lymphoma. Thus, the virulence subtype composition vacA s1a and iceA1 occurs mainly in gastric carcinoma, whereas the vacA s1t/m2 iceA1 combination is found in MALT lymphoma[73]. Therefore, in the future studies, the composition of virulence subtypes might be taken into account during the evaluation of possible sequelae of gastric mucosal damage caused by H pylori infection.

Epstein-Barr virus

Studies of Epstein-Barr virus (EBV) suggest that an aberrant antibody response to infection may occur years before the appearance of a tumor[74]. The frequency of EBV detection has been reported to be 6%-18% in gastric lymphomas[75-77] and 7%-16% in ordinary gastric adenocarcinomas without lymphoid stroma[78-80]. Whether EBV plays a pathogenic role in either of these tumors is still unclear[81]. Although any mechanism related to EBV in tumorigenesis of gastric malignancies remains highly speculative, it has been demonstrated that there is a delay in apoptosis in EBV-positive gastric carcinomas (associated with up-regulation of BCL-2 and p53) and a decrease in cellular differentiation (associated with decreased E-cadherin expression)[82]. Nakamura et al[10] found no specific association between EBV infection and these double malignancies.

Exposure to atomic blast

It is controversial whether the incidence of gastric carcinoma is higher in persons exposed to an atomic blast in comparison to non-exposed subjects[83-85], but Suehiro et al[83] suggested that the incidence is the highest in persons exposed within a 2.0-Km radius ground zero. The relation of primary gastric lymphoma and atomic bomb exposure is under debate. Recently, t (11; 18) (q21; q21) and t (1;14) (p22; q32) translocations have been reported to be associated with MALT-type lymphoma. The former translocation results in the formation of fusion protein API2-MALT1, and the latter in the fusion protein pf BCL10 and IgH. These fusion transcripts are thought to be molecular markers for MALT-type lymphoma not responding to H pylori eradication and highly correlated with aberrant nuclear BCL10 expression, which may serve as a screening tool for fusion[86-88]. These investigations support the etiologic role of atomic bomb blast on the formation of MALT-type lymphoma.

ETIOLOGIC FACTORS OF METACHRO-NOUS OCCURRENCE

Epithelial malignancies, the common cancers of adult-hood, are detected rarely in the post-treatment course of Hodgkin’s disease and other lymphomas[2,3,26]. However, Greene and Wilson[88,89] observed a significant increase in the incidence of gastric carcinoma in the period following the treatment of non-Hodgkin lymphomas.

Previous gastric surgery

Previous gastric surgery is a well known precancerous condition[90,91]. Gastroesophageal reflux and gastritis, formation of nitrosamines due to gastric pH decrease and untreated H pylori infection may play a role in carcinogenesis of the gastric remnant[92]. So-called “stump carcinoma” develops between 13-27 years after resection in patients treated with gastrectomy for benign conditions[91].

Radiotherapy and chemotherapy

Though the stomach is considered relatively radio-resistant compared to other parts of the gastrointestinal tract, side effects and complications progressively increased when the total dosage delivered was above 4500 cGy[93,94]. The effects of radiotherapy on the risk of carcinogenesis are well known[95]. Hirose et al[96] demonstrated that localized radiation induced gastric adenocarcinoma development in an experimental model. Brown et al[97] reported a slight increase in the incidence of gastric adenocarcinoma in patients with ankylosing spondylitis under radiation therapy. In contrast, when the relatively low dose (less than 3400 cGy) radiotherapy was used to decrease acid production in 2049 peptic ulcer patients, only two cases of leiomyosarcoma were reported. The elapsed time between radiotherapy and the diagnosis of these cases were reported as 14 and 26 years[98].

Both series reported by Stanford and Milan concluded that combined administration of chemotherapy and radiotherapy increases the occurrence rate of secondary malignancies[1,2]. In these series, the most common secondary malignancy was especially acute myelogenous leukemia. Its occurrence was associated with the administration of alkylating agents (nitrogen mustard, vincristine, prednisone, and procarbazine in Milan series)[2]. Solid tumors were commonly associated with radiation therapy[1,2]. Brumback et al[40] concluded that secondary gastric adenocarcinoma occurred in one of these cases probably due to oral administration of procarbazine for Hodgkin’s disease. In addition to these factors, H pylori infection was also held accountable for metachronous occurrence of both tumors, as discussed above.

DIFFICULTIES IN DIAGNOSIS

It may be difficult to diagnose the two different tumors in the stomach before surgery. Because most of the patients with gastric adenocarcinoma and coexisting primary gastric lymphoma are associated with H pylori infection, the presence of MALT-type or other types of primary gastric lymphoma should be taken into consideration when gastric adenocarcinoma with gastritis is detected on endoscopy. In surgical specimens, not only the lesions of adenocarcinoma but also the background mucosa of cancerous lesions must be examined with regard to infiltration of lymphocytes, and the presence of gastritis, as well as the presence of H pylori. Signet-ring cells around MALT lymphomas or lymphoid proliferations around gastric adenocarcinomas should be kept in mind against over-diagnosis during the histopathological examination. Considering the metachronous occurrence of gastric adenocarcinoma and gastric lymphoma, proper endoscopic follow-up should be performed in the remnant stomach, especially when H pylori infection is present.

TREATMENT

Treatment modalities for synchronous cases

Treatment of synchronous cases is generally applied according to the presence of adenocarcinoma. Distal or total gastrectomy is performed depending on the tumor localization. Preoperative chemotherapy was preferred only in two cases. Cammarota et al[27] decided to administer etoposide, epirubicin, cisplatin chemotherapy according to the presence of locally advanced tumor stage (T3 N1) in laparoscopic exploration. Older patients in the series by Ishihama et al[23] were exposed to 10 courses of vincristine, endoxan, predonisdone, adriamicin chemotherapy and endoscopic resection of the tumor. Postoperative chemotherapy was administered only to 6 (10.7%) patients.

Treatment modalities for metachronous cases

Eight of thirty patients underwent subtotal gastrectomy and radiotherapy against lymphoma. Chemotherapy was administered in different combinations with other treatment modalities in 7 patients. Two patients were treated by only chemotherapy. Radiotherapy was performed solely in 2 patients. Overall, 10 cases with lymphoma were treated without surgical treatment. All patients with MALToma were treated with antibiotic regimen against H pylori, except cases reported by Nakamura et al[10] and Montalban et al[26], the authors of both did not mention anything about the treatment of H pylori infection in their reports. Every patient with H pylori infection was eradicated and no one was re-infected or re-colonized during the follow-up period. Except cases with widespread metastasis, total gastrectomy or palliative resections were performed in patients with AGC. Patients with EGC were exposed to more conservative surgery, such as endoscopic mucosal resection[10,45].

Surgery

Clear guidelines for management have not been designed for synchronous adenocarcinoma and primary gastric lymphoma. Traditionally, aggressive surgical resection has been the mainstay of gastric lymphoma treatment because by this treatment modality it would be possible to collect definitive tissues for pathologic examination, allow exploration of the abdomen, reduce the tumor burden and obviate the concern that gastric hemorrhage or perforation would complicate medical treatment of lymphomas. Recently, radical gastrectomy is disputed and considered unnecessary for gastric lymphomas. Lesser procedures are now accepted where resection of the gross disease and involved lymph nodes will provide adequate results[99-102]. Some authors advocate wide resection and extensive lymph node dissection alone for adequate treatment of stage 1E or pure MALT lymphomas with a survival rate of > 95%[103,104]. In a retrospective study from Italy patients in different stages of gastric lymphoma who underwent surgical resection when feasible, the ten-year actuarial survival rates were markedly higher (100% and 80%, respectively) for stage IE and IIE as compared with stage IIIE and IVE (21% and 0%, respectively)[105]. Surgical resection with clear margins for lymphoma is advised in order to maximize the chance of cure[100,106]. However, others have found no difference in survival, whether the margin of resection was clear or not, as long as post-operative chemotherapy was given[107]. Operative mortality rates for gastric lymphoma reached 25% in cases with advanced tumor stage[108]. Therefore, aggressive surgery for gastric lymphoma is not indicated due to increased morbidity which outweighs the benefit gained in terms of survival[107]. Surgery for gastric lymphoma is now often reserved for patients with localized disease, residual disease after non-surgical therapy or for rare patients with complications[109]. If the coexisting adenocarcinoma is diagnosed correctly, surgical treatment, a first-line therapy, is preferred according to adenocarcinoma treatment principles. Total or subtotal gastrectomy with D1 or D2 dissection must be performed.

In metachronous cases, generally, the occurrence of primary gastric lymphoma precedes gastric adenocarcinoma, resection of the remnant stomach must be done with or without a combination of other treatment modalities. However, a close follow-up of the patients undergoing gastric lymphoma treatment allows early detection of carcinogenesis. Limited endoscopic resections might be an alternative treatment for these cases. Similar to gastric lymphoma as a previous malignancy, patients in whom limited resection is performed for gastric adenocarcinoma should undergo a close endoscopic follow-up. The H pylori status with histopathologic alterations in the resected stomach and in the remnant stomach must be detected and followed up for early detection of metachronous occurrence of gastric lymphoma.

Chemotherapy

The effect of chemotherapy as a sole treatment for gastric lymphomas is still under debate. The needs behind trying chemotherapy were the considerable morbidity and mortality associated with resection[108]. Some authors reported better survival rates in patients with primary gastric lymphoma treated by chemotherapy alone or combination with radiotherapy when compared to surgical treatment alone[110,111]. Other reports showed no apparent difference in survival between patients treated by chemotherapy or surgery and chemotherapy with survival rates of 67% and 60%, respectively. The fear of chemotherapy-related complications, for instance, bleeding and perforation, has been disputed, and less significant compared with surgical resection[111,112]. Therefore, chemotherapy has been suggested and adopted as a primary mode of treatment for primary gastric lymphomas. Whereas cyclophoshamide, vincristine and prednisolone were adopted for low grade lymphomas, high grade tumors were treated with doxurubicin, teniposide, cyclophosphamide and prednisolone. The combination of both regimens with surgical resection has increased the survival rates up to 80% and 100%, respectively[113]. In contrast to primary gastric lymphomas, chemotherapy regimens have not been used as a sole therapy in the treatment of gastric adenocarcinoma, except in cases with metastatic disease. Systemic chemotherapy for metastatic disease has a marginal survival benefit when compared with best supportive care, while no standard worldwide regimen has been established yet. In Japan, especially the number of patients treated with endoscopic mucosal resection for early gastric adenocarcinoma is increasing year by year. Chemotherapy may be a more important part of treatment protocols in these patients in near future, because of the increasing survival rates. Cisplatin, 5-fluorouracil and mitomycin C were commonly used in various combinations for patients with gastric adenocarcinoma[114].

Radiotherapy

In most instances, radiotherapy is used as an adjuvant to surgery, chemotherapy or both for primary gastric lymphoma. It has rarely been tried as a single mode of therapy[115,116]. However, limited trials have suggested that radiotherapy can be utilized as a primary mode of treatment with a reasonable outcome[116,117]. Radiotherapy has been studied in comparison with other treatment modalities for stage IE and IIE of primary gastric lymphomas with a comparable outcome of 80%-89% survival[115,118,119]. Radiation was used post-operatively in high- and low-grade lymphomas, for residual tumors in stages I and II to improve the disease-free survival[120]. Combination of radiotherapy with chemotherapy might improve the chance of stomach conservation of these patients which may approach 100%[121]. Contradictory studies have found combined radiotherapy with either resection or chemotherapy no significant difference in both modalities, with a survival rate of 82%-88%[116,119]. Radiation therapy has a limited but well established role in the care of those afflicted with gastric adenocarcinoma. Radiation therapy can provide considerable relief of local gastric cancer symptoms. Approximately 50% to 75% of patients have had symptomatic improvement of problems, such as obstruction, bleeding and pain in a variety of trials[122,123].

Antibiotic therapy

Because gastric MALT lymphomas have a high association with H pylori infection, eradication of H pylori with antibiotics is very important[58,60,124,125]. Isaacson et al[125] suggested that antibiotic eradication of H pylori removes the growth stimulus from gastric MALT lymphoma without necessarily eradicating the neoplastic B-cell clone. This clone may re-expand, but in the absence of concomitant re-infection with H pylori, this is likely to be a self-limiting event. Short and long-term follow-up results of medical eradication of H pylori in patients with gastric MALT lymphoma have been published in the literature[124,125]. However, patients still require periodic surveillance endoscopies and may require more traditional treatment of their lymphoma. Antibiotic therapy may fail to cure gastric lymphomas when there is a bulky tumor with a high-grade component or when the gastric lymphoma is associated with carcinoma. A combination of partial gastrectomy and antibiotic therapy might be an alternative treatment for primary gastric lymphomas. However, periodic surveillance endoscopies are required after partial gastrectomy and antibiotic therapy. There has been no defined role of antibiotic therapy against H pylori in the treatment of gastric adenocarcinoma. Eradication of H pylori infection can be placed in preventive measures of gastric adenocarcinoma. If H pylori infection is detected in the partially resected stomach secondary to adenocarcinoma, the postoperative antibiotic treatment against H pylori may be administered for hindering metachronous occurrence of primary gastric lymphoma.

PROGNOSIS

Reported period of follow-up for synchronous cases ranged from 1 to 132 mo. Overall, data about surveillance of patients were insufficient to perform analysis. Some authors did not mention follow-up data whereas others did not report treatment modalities. However, shorter postoperative survey was observed in cases with AGC (up to 23 mo) when compared to cases with EGC. The follow-up study conducted by Nakamura et al[10] revealed that the survival rate of patients with synchronous occurrence of gastric lymphoma and adenocarcinoma appeared to be similar to that for previously reported patients with gastric adenocarcinoma without lymphoma, and was significantly worse than patients with primary gastric lymphoma without adenocarcinoma. As discussed above, majority of metachronous cases suffered from advanced gastric adenocarcinomas after the latent period. Eleven of 17 patients with AGC died within 18 mo. Despite incomplete survival data of cases with EGC, Zauber et al[42] reported 96 mo disease-free survival after total gastrectomy. Nakamura et al[10] did not reveal any survival data regarding primary gastric lymphoma occurring after treatment of gastric adenocarcinoma.

In summary, with the help of case reports or series, the synchronous or metachronous occurrence of primary gastric lymphoma and gastric adenocarcinoma have evolved in various aspects. Clinicians should be alert for the possible synchronous or metachronous occurrence of both tumors during diagnosis or follow-up of each other. Authors suggest the application of principles for gastric adenocarcinoma treatment to cases with synchronous occurrence. The biologic behavior of the latest diagnosed tumor determines the accurate management of metachronous occurrence of primary gastric lymphoma and gastric adenocarcinoma.