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Annals of Clinical & Laboratory Science, vol. 32, no. 4, 2002

Case Report: Combined Adenocarcinoma and Carcinoid Tumor in Atrophic Gastritis Debasis Adhikari,1 Charles Conte,2 David Eskreis,3 Carlos Urmacher,4 and Ellen Kahn 1 1Pathology, 2Surgery, and 3Medicine Departments, North Shore University Hospital and NYU School of Medicine, Manhasset, New York; 4Cytopath Biopsy Laboratory, Mamaroneck, New York Abstract. The development of adenocarcinoma or carcinoid tumors in atrophic gastritis is widely documented. We report the simultaneous occurrence of gastric adenocarcinoma and carcinoid (composite tumor) in atrophic gastritis, a finding reported only twice before in the literature. This 52-yr-old man with rectal bleeding, epigastric pain, and iron deficiency anemia was noted to have multiple polypoid masses on upper endoscopy. Biopsy revealed features of both adenocarcinoma and carcinoid tumor in a background of atrophic gastritis, leading to a total gastrectomy, lymph node dissection, and liver biopsy. The gastrectomy specimen was characterized by a 6 cm pedunculated polyp and multiple sessile nodular masses between 0.4 and 2.5 cm in the background of a granular mucosa. On microscopic examination, the large polypoid mass corresponded to a well-differentiated adenocarcinoma, intestinal type, infiltrating the wall. The smaller nodules were composed of carcinoid tumors, restricted to the mucosa, or infiltrating the gastric wall. Carcinoid tumor was also seen in the large polypoid mass closely intermingled with adenocarcinoma. The carcinoid tumor metastasized to the liver. Lymph nodes showed both adenocarcinoma and carcinoid tumor. The gastric mucosa was characterized by atrophic gastritis with intestinal metaplasia, neuroendocrine hyperplasia, and microcarcinoids. The adenocarcinoma stained strongly for CK7, CK 20, MIB-1, and focally for chromogranin and synaptophysin. The carcinoid tumor was negative for CK7, CK 20 and MIB-l, and was positive for chromogranin and synaptophysin. Overexpression of p53 was noted only in the adenocarcinoma. Electron microscopy revealed neurosecretory granules in the carcinoid characteristic of a neuroendocrine tumor. Composite tumor can occur in the setting of atrophic gastritis. The findings in this patient reinforce the concept that the epithelial and neuroendocrine cells of the gastrointestinal tract both result from multidirectional differentiation of a primitive cell. (submitted 8 April 2002; accepted 21 May 2002) Keywords: atrophic gastritis, adenocarcinoma, carcinoid, stomach. Introduction The association of atrophic gastritis with adenocarcinoma or carcinoid has been widely reported [1-4]. Tumors having both the features of adenocarcinoma and carcinoid are designated as composite carcinoma-carcinoid tumor [5]. Occurrence of a composite carcioma-carcinoid Address correspondence to Ellen Kahn, M.D., Department of Pathology, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030, USA; tel 516 562 4183; fax 516 562 4591.

tumor in a background of atrophic gastritis has been reported only twice in the literature [6,7]. We describe a composite carcinoma-carcinoid tumor in atrophic gastritis of an adult patient, emphasizing the histochemical characteristics of the tumor and the background mucosa. Our findings are compared with those of the reported cases. Clinical history A 52-yr-old white man presented with rectal bleeding and mild abdominal pain of a few weeks

0091-7370/02/0400/0422 $1.50. © 2002 by the Association of Clinical Scientists, Inc.

Adenocarcinoma/carcinoid in atrophic gastritis Table 1. Details of the antibodies used in this study. Antibody

Source*

Antigen retrieval

Synaptophysin Chromogranin Gastrin Serotonin CK-7 CK-20 BCL-2 P 53 Ki 67/ MIB 1

Ventana Ventana Ventana Dako Ventana Ventana Ventana Ventana Zymed

AR§ + heat AR§ + heat none none protease treatment protease treatment AR§ + heat AR§ + heat AR§ + heat

*Ventana, Tuscon, AZ; Dako, Carpentia, CA; Zymed, San Francisco, CA. AR§ = using the premix from Ventana.

duration. He had a history of hemorrhoids. Physical examination was unremarkable. Further studies showed iron deficiency anemia. To determine the cause of the anemia, the patient underwent colonoscopy, which was normal, followed by an upper endoscopy that showed multiple polypoid masses in the stomach. Microscopic examination revealed both adenocarcinoma and carcinoid tumor. The patient underwent total gastrectomy with lymph node dissection and liver biopsy. The patient was treated with 5-fluorouracil and is well at 1 yr after therapy. Pathological examination The gastrectomy specimen was characterized by a pedunculated mass (6 x 4 x 4 cm) in the posterior wall. The mass was firm and the cut surface was white and tan. In addition, multiple sessile pink polyps and plaque-like lesions measuring from 0.5 to 2.5 cm were present (Fig. 1). The mucosa of the antrum was unremarkable. Margins of the specimen were negative for tumor. Tissues were stained with hematoxylin and eosin, Steiner, and Grimelius stains, and with immunohistochemical stains using antibodies listed in Table 1. Electron microscopy was performed from selected areas of the paraffin tissue blocks. The gastric biopsy had features of atrophic gastritis with both adenocarcinoma and carcinoid (Fig. 2), which was remarkable for such a small specimen. Histologic examination of the large

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polypoid mass of the gastrectomy specimen showed predominantly an adenocarcinoma, intestinal type, similar to that of the biopsy, that infiltrated through the gastric wall (Fig. 3). The adenocarcinoma was admixed with foci of carcinoid, which in other areas constituted the predominant component with a cord-like pattern. The distinction between carcinoma and carcinoid was sometimes less distinct, with transition between a solid and a more glandular pattern. The microscopic appearance of the smaller sessile polyps and the plaque-like lesions was that of a carcinoid with typical ribbon like pattern (Fig. 4A). This tumor also infiltrated the gastric wall. The metastasis in the liver was composed only of carcinoid tumor with the characteristic desmoplastic reaction. The lymph nodes showed both metastatic carcinoid and adenocarcinoma (Fig. 5). The background gastric mucosa of the body of the stomach had features of atrophic gastritis, with marked intestinal metaplasia and absence of parietal cells (Fig. 6). G-cell hyperplasia was demonstrated in sections from the antrum by immunohistochemical studies. No Helicobacter pylori was noted in the Steiner stain. The results of immunohistochemical studies are summarized in Table 2. The adenocarcinoma was strongly positive for keratin (CK7 and CK 20). In some areas, the tumor cells stained strongly with the neuroendocrine markers, chromogranin and Table 2. Immunohistochemical characterization of the adenocarcinoma, carcinoid, and background gastric mucosa. Carcinoma Carcinoid

CK 7 CK 20 Grimelius Chromogranin Synaptophysin Gastrin Serotonin p53 Calcitonin E-cadherin MIB1

Atrophic Gastritis Glands Neuroendocrine

+ + +(focal) +(focal)

+ +

+ + + +(focal)

+(focal) +(focal) + +(focal)

+(focal)

+

+(focal)

-

+(focal) +(focal) +(focal)

+ +(isolated) +(focal) +(focal) +(focal) +(focal) +(focal)

+(focal) -

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Fig. 1. Gastrectomy specimen showing large polypoid sessile mass (arrow) and smaller polypoid masses (bold arrows) in the gastric body.

Fig. 2. Gastric biopsy with (A) adenocarcinoma (arrow) and (B) carcinoid (bold arrows). Hematoxylin-eosin.

Fig. 3. Larger polypoid mass showing features of adenocarcinoma (arrows) and carcinoid (bold arrow).

Adenocarcinoma/carcinoid in atrophic gastritis

Fig. 4. Small polypoid mass composed of carcinoid tumor; (A) hematoxylin-eosin stain; (B) chromogranin stain. Note the overlying unstained gastric mucosa.

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Fig. 5. Lymph node metastasis with features of both carcinoma and carcinoid tumor. Chromogranin stain.

Fig. 6. Atrophic gastritis with intestinal metaplasia. Note the absence of parietal cells. Hematoxylin-eosin stain.

426 Annals of Clinical & Laboratory Science Table 3. Review of the literature: clinical data. Parameter

Age (yr) Sex Symptoms Site in stomach Satellite nodules Carcinoma type Atrophic gastritis Metastasis Prognosis

Table 4. Review of the literature: immunohistochemical staining patterns of the combined carcinoma-carcinoid tumors.

Caruso et al [6]

Pasquinelli Present et al [7] case

53 female not given body present intestinal present negative alive

79 female pain body present signet ring present liver, bone dead

52 male anemia body present intestinal present liver, nodes alive

synaptophysin, in contrast to the negative overlying gastric mucosa (Fig. 4B). These markers were both focally positive in the glands of the adenocarcinoma. All neuroendocrine cells showed Grimelius-positive granules corresponding to the neurosecretory granules seen by electron microscopy. E-cadherin stained focally both the carcinoma and carcinoid. MIB-l staining was focally positive in the carcinoma and to a lesser degree in the carcinoid. Positive immunoreactivity for p53 was evident only in the carcinoma. Atrophic gastritis, associated with neuroendocrine hyperplasia, was noted in the chromogranin stained sections, varying from increased number of neuroendocrine cells in gastric glands to linear and nodular hyperplasia, microcarcinoid, and invasive carcinoid. The carcinoid was also focally positive for serotonin. Discussion The development of adenocarcinomas or carcinoid tumors in atrophic gastritis is widely reported, but the simultaneous appearance of these tumors as composite adenocarcinoma-carcinoid in welldocumented atrophic gastritis is rare. We found only 2 other cases of composite carcinoma-carcinoid tumor associated with atrophic gastritis [6,7], ours being the third case. These tumors appear in the fifth to seventh decade; the presenting symptom was pain in one of the cases, anemia in ours. The body of the stomach was involved in all three. Multiple tumor nodules were described in all of the patients, and all had atrophic gastritis. Two of the patients developed metastases. Two of the patients are alive;

Caruso et al [6]

Pasquinelli Present et al [7] case

Adenocarcinoma Keratin Chromogranin Synaptophysin CEA CA 19 p53

ND + + ND

ND + ND ND ND ND

+ +(focal) +(focal) ND ND +

Carcinoid Keratin Chromogranin Synaptophysin Calcitonin p53

ND + + ND ND

ND + + + ND

+(focal) + + _ -

ND, not done

one died of the disease (Table 3). In all three cases positive staining for chromogranin was present in the carcinoid and weaker in the carcinoma. Keratin staining was strongly positive in the carcinoma and focally positive in the carcinoid. Positivity for calcitonin was described in one case, but was not noted in ours (Table 4). The patient described herein fits in the category of composite carcinoma-carcinoid tumor. Composite carcinoma-carcinoid tumor is defined as the intimate coexistence of adenocarcinoma with carcinoid [5]. This dual expression persists even in the metastatic sites, such as lymph nodes. The background gastric mucosa has features of gastritis with extensive intestinal metaplasia, demonstrated by the presence of goblet cells. No H. pylori was identified. The pathogenesis of both carcinoma and carcinoid in atrophic gastritis is well defined. Carcinoma follows the intestinal metaplasia dysplasia sequence [8]. On the other hand, atrophy of parietal cells characterizes well established atrophic gastritis. With decreased acid secretion, there is loss of inhibition of gastrin secretion. This results in an increase of gastrin production. Gastrin, by exercising a trophic effect on neuroendocrine cells, induces neuroendocrine hyperplasia,and micro- and invasive-carcinoid [9].

Adenocarcinoma/carcinoid in atrophic gastritis

The concept of composite carcinoma- carcinoid, as illustrated by our case not only in the primary tumor but also in metastases, reinforces the concept that an undifferentiated cell is capable of dual differentiation: epithelial, giving rise to an adenocarcinoma, and neuroendocrine, giving rise to a carcinoid tumor.

5.

6.

References 7. 1.

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Siurala M, Vans K, Wiljasalo M. Studies of patients with atrophic gastritis. A 10-15 year follow up. Scand J Gastroenterol, 1966;1:40. Yamashina M, Flinner R. Concurrent occurrence of adenocarcinoma and carcinoid tumor in the stomach: a composite tumor or collision tumor. Am J Pathol 1985;83:233-236. Klappenbach RS, Kurman R, Sinclair CF, James LP. Composite carcinoma carcinoid tumors of the gastrointestinal tract. 1985;84:137-143. Ooi A, Mai M, Ogino T, Ueda H, Kitamura T, Takahashi Y, Kawahara E, Isao N. Endocrine

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differentiation of gastric adenocarcinoma. Cancer 1988;62:1096-1104. Lewin K. Carcinoid tumors and the mixed (composite) glandular-endocrine cell carcinomas. Am J Surg Pathol 1987;11(Suppl 1):71-86. Caruso ML, Pilato FP, D’Adda T, Baggi MT, Fucci L, Valentini AM, Lacatena M, Bordi C. Composite carcinoid-adenocarcinoma of the stomach associated with multiple gastric carcinoids and nonantral gastric atrophy. Cancer 1989;64:1534-1539. Pasquinelli G, Santini D, Preda P, Cariani G, Bonora G, Martinelli GN. Composite gastric carcinoma and precursor lesions with amphicrine features in chronic atrophic gastritis. Ultrastruct Pathol 1993;17:9-24. Rugge M, Farinati F, Baffa R, Sonego F, Di Mario F, Leandro G, Valiante F. Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter retrospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology 1994;107:1288-1296. Lewin KJ, Riddell RH, Weinstein WM, Gastrointestinal Pathology and its Clinical Implications, Jgaku-Shoin, New York, 1992; pp197-257.