Journal of Surgical Oncology 47:109-116 (1991)

Adenosquamous Carcinoma of the Pancreas: A Clinicopathologic Study KOjl YAMAGUCHI, MD, AND MUNETOM0 ENJOJI,MD From the Departments of Surgery I (K.Y.1 and Pathology I I (K.Y., M.E.}, Kyushu University Faculty of Medicine, Fukuoka, lapan

A total of eight patients with adenosquamous carcinoma of the pancreas were studied clinicopathologically. Histochemical and immunohistochemical studies were also done. The 8 patients were composed of 4 men and 4 women with a mean age of 56 years, which was 9 years younger than for other pancreatic carcinoma. The site of origin and size of the tumors were similar to those of usual pancreatic carcinoma. Histopathologically, all eight tumors showed an abrupt transition between adenocarcinoma and squamous cell carcinoma. Squamous cell carcinoma was located at the periphery of the tumors. Histochemistry and immunohistochemistry disclosed a different nature for both components. The cumulative 1-year survival rate of the 8 patients was 21.4%, compared to 42.1% of 72 with adenocarcinoma of the pancreas. The survival curve of the 8 patients with adenosquamous carcinoma was significantly less favorable than that of 36 patients with well-differentiated adenocarcinoma of the pancreas. These facts support the view that squamous cell carcinoma in adenosquamous carcinoma of the pancreas is squamous cell metaplasia of the pre-existing adenocarcinoma. The clinical course of adenosquamous carcinoma of the pancreas was unfavorable. KEYWORDS:keratin, histochemistry, immunohistochemistry

pancreatic carcinoma, which was examined through 5 INTRODUCTION Adenosquamous carcinoma of the pancreas is unusual mm stepwise tissue sections. The 89 tumors of the but well known [l-31. However, very few authors have pancreas were composed of 72 adenocarcinomas (36 well described adenosquamous carcinoma of the pancreas in the literature [4-61. There has been controversy about the histogenesis of the squamous cell component of adenosquamous carcinoma in various organs as well as regarding the appropriate nomenclature, i.e., adenosquamous carcinoma, adenoacanthoma, mucoepidermoid carcinoma, etc. It has been reported that the prognosis of adenosquamous carcinoma was good in the stomach and lung, while it was poor in the uterus, gallbladder, and pancreas. In this study we describe the clinicopathologic analysis of eight cases of adenosquamous carcinoma of the pancreas. Histochemistry and immunohistochemistry were also performed.

differentiated, 26 moderately differentiated, 10 poorly differentiated), 8 adenosquamous carcinomas, 5 mucinous cystadenocarcinomas, 3 undifferentiated carcinomas, and 1 mucinous carcinoma. The incidence of adenosquamous carcinomas was 9.0% of non-endocrine pancreatic carcinoma. Adenosquamous carcinoma showed an unequivocal area of malignant glandular differentiation and squamous epithelial differentiation with individual cell keratinization, keratin pearl, and/or intercellular bridges. All the tissue sections were stained with ordinary hematoxylin and eosin. The representative tissue sections were submitted to histochemical procedures including periodic acid Schiff (PAS) and alcian blue pH 2.5 (AB).

MATERIALS AND METHODS A total of 8 patients with adenosquamous carcinoma of the pancreas were selected from 89 patients with exocrine

Accepted for publication January 27, 1991. Address reprint requests to Koji Yamaguchi, M.D., Department of Surgery I, Kyushu University Faculty of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.

0 1991 Wiley-Liss, Inc.

110

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The representative tissue sections were also subjected to immunohistochemistry for two monoclonal antikeratin antibodies which were obtained from Enzo Biochem., Inc. (New York, USA). These antibodies corresponded to Gown’s monoclonal antibodies, 35PH11 and 34PE12 [7-9]. After deparaffinization, preliminary trypsinization was performed using Sigma-type I1 trypsin at a concentration of 25 mg/dl for 30 min at 37°C. For blocking endogenous peroxidase, a 15 min oxidation in 0.3% periodic acid was allowed. Following incubation with normal goat serum, sections were then incubated overnight at 4°C with primary antibodies at a dilution of X 200. The avidin-biotin reagents were obtained from Vector Laboratories (Vectastain ABC kit pk-402) and the avidin-biotin complex immunoperoxidase method as described by Hsu et al. [ 101 was used. The localization of antigens was visualized by placing the slides in 0.01% hydrogen peroxide and 0.05% diaminobenzidin in 0.05 M phosphate-buffered saline (PBS), pH 7.2, for 5 min. All the sections were counterstained with methyl green and the sections stained with 34PE12 were also counterstained with AB. The clinical data were available from all eight patients. The prognoses were obtainable for all eight patients and were updated as of June 30, 1990. The cumulative survival rates and survival curves of 8 patients with adenosquamous carcinoma, 72 with adenocarcinoma, 36 with well-differentiated adenocarcinoma, 26 with moderately differentiated adenocarcinoma, and 10 with poorly differentiated adenocarcinoma of the pancreas were calculated with the Kaplan-Meier method. The differences between the cumulative survival rates were measured by the Z-test. The differences between the survival curves were measured by a generalized Wilcoxon test.

RESULTS Clinical Findings A total of 8 patients with adenosquamous carcinoma ranged from 44 to 68 years old with a mean age of 55.8 years (Table I). Seventy-two patients with adenocarcinoma of the pancreas ranged from 37 to 78 years old with a mean age of 63.9 years. The 8 patients consisted of 4 men and 4 women showing a male to female ratio of 1:1. The 72 patients were composed of 46 men and 26 women, showing a male preponderance of 1.8. Six of the eight tumors were located in the head of the pancreas, one in the body, and the other in the tail, respectively. Of the 72 tumors, 60 were situated in the head of the pancreas, 9 in the body, and 3 in the tail. Five patients with adenosquamous carcinoma in the head of the pancreas complained of abdominal pain, four developed ictems, and one suffered from massive upper gastrointestinal bleeding. One patient with a tumor in the body of the pancreas and another with one in the tail of the pancreas

complained of abdominal pain. One was pointed out to be diabetic by the patient’s physician. Four of the six patients examined showed an elevation of serum carcinoembryonic antigen (CEA) levels. Six patients with adenosquamous carcinoma in the head of the pancreas received a pancreatoduodenectomy and two patients with adenosquamous carcinoma in the body or the tail of the pancreas underwent a distal pancreatectomy .

Macroscopic Findings Four of the eight tumors were nodular on the cut surface and the other four were infiltrative. Tumor size varied from 2.5 to 4.5 cm in the greatest diameter with a mean of 3.6 cm. One tumor had a cancerous ulceration of the supra-ampullary duodenum with an eroded artery at the ulcer base. Five tumors showed cystic degeneration. Microscopic Findings Eight adenosquamous carcinomas showed areas of unequivocal glandular structures and squamous epithelium. Two tumors were composed almost exclusively of adenocarcinoma and squamous cell carcinoma (Table 11). Six other tumors were composed of malignant tubules, atypical squamous epithelium, and poorly differentiated cells, arranged in cords or strands with eosinophilic cytoplasm and vesicular nuclei (Fig. 1). Squamous cell carcinoma was mainly located at the periphery of the tumor while the adenocarcinoma was situated in the center of the neoplasm (Fig. 2). In three patients there was about an equal distribution of glandular and squamous elements, while in five patients glandular carcinoma predominated over squamous cell cancer. Regarding adenocarcinoma, seven tumors were well differentiated and another was moderately differentiated. On squamous cell carcinoma, seven tumors were moderately to well differentiated with keratin pearls, individual cell keratinization, and/or intercellular bridges, and the other was poorly differentiated containing only focal areas of intercellular bridges. In all eight tumors there was an abrupt change between the adenocarcinoma and squamous cell carcinoma (Fig. 3). In four tumors there were foci of mucoepidermoid carcinoma-like structures, which were atypical mucous-producing cells surrounded by an atypical squamous epithelium. In three tumors, the surrounding pancreatic ducts or ductules showed benign squamous metaplasia. In all eight tumors, non-papillary, papillary, and atypical papillary hyperplasia were encountered in the surrounding non-cancerous pancreatic ducts or ductules. Five of six tumors in the head of the pancreas involved the duodenal wall and three invaded the distal common bile duct causing stenosis of the common bile duct. The adenocarcinoma infiltrated the lymphatic vessels in six patients, the vein in five patients, the perineural spaces in seven patients, and metastasized to the lymph nodes in four patients. Squamous cell

Adenosquamous Carcinoma of the Pancreas

111

TABLE I. Clinicopathologic Findings of 8 Cases of Adenosquamous Carcinoma and 72 Cases of Adenocarcinoma of the Pancreas*

Adenocarcinoma Adenosquamous carcinoma

T

Mean size (cm)

1 -year survival rate (%)

3 1

3.5 3.6

42.1 21.4

Sites

No. cases

Mean age

Sex (M/F)

Sex ratio

H

B

72 8

63.9 55.8

46/26 414

1.8 1.0

60 6

9 1

* M, male; F, female; H, head; B, body; T, tail.

TABLE 11. Chicoaathologic Findings of Eight Patients With Adenosquamous Carcinoma of the Pancreas* No. cases

Age

Sex

Location of tumor

1-464

60

M

Head

1-2327

52

F

Head

1-2725

44

F

Head

1-2767

56

F

Head

1-3682

56

M

Head

1-4008

68

F

Head

1-1971

49

M

Body

1-3562

61

M

Tail

1Y V Pn n ad

sq

mod well ad > s q well mod ad > s q mod well ad 3 s q well well ad f sq well well ad sq well well ad > sq well por ad 3 sq well mod ad f sq

+

ad

sq

ad

sq

+

-

-

-

ad

sq

-

+ + +

-

f

-

-

-

-

-

-

+

-

-

-

-

-

-

-

sq

+ + + + + + + - - + + + + + + - 4-

+ + + + +

ad

-

-

-

-

-

-

-

-

-

+

-

-

Other organs

Prognosis

CBD (ad), Du (ad)

Died at 3 months

CBD (ad)

Died at 7 months

Du(ad)

Died at 5 months

Du(ad)

Died at 4 months

Du(ad>sq)

5 months alive

Du(ad

> sq),

CBD (ad)

5 months alive

Died at 5 months 1 year, 2 months alive

*CBD, common bile duct; Du, duodenum; mod, moderately differentiated; well, well differentiated; por, poorly differentiated; ad, adenocarcinoma; sq, squamous cell carcinoma; ly, lymphatic permeation; v, venous invasion; pn, perilieural invasion; n, lymph node metastasis; ad > sq, A pattern is more frequent than B pattern; ad sq, A pattern is almost equal to B pattern; ad % sq, A pattern is far more frequent than B pattern; present; -, absent.

+,

+

carcinoma invaded perineural spaces in two patients (Fig. 4) and metastasized to the lymph nodes in one patient. In two cases only one or two sections contained malignant squamous epithelium. The stroma was usually fibrous with an inflammatory infiltrate. The fibrous stroma was cellular in some areas and densely hyalinized in other areas.

Fig. 1. Clusters or nests of poorly differentiated cells are present around the malignant glands (H&E, x96, 1-4008).

Histochemistry and Immunohistochemistry The glandular element of adenosquamous carcinoma of the pancreas was positive for AB and PAS, but the squamous cell component was negative for AB and PAS in all eight cases (Table 111). Adenocarcinoma had 35PH11 immunoreactants in the cytoplasms of malignant glandular structures in all eight cases and also in the cytoplasm of poorly differentiated cells in three cases (Fig. 3-35PH11 was negative for squamous noma elements in all eight cases. Squamous cell carci-

112

Yamaguchi and Enjoji @

p

.......... .. .......... 1-464

..... ....... .... I

-

p

du

m

~

.... ........... ..... .. ..... -0.

1-2327

...... ..... ...

1-2725

1-2767

..... ...

I..

1-3682

1-3562

1-4008

:::A d P n o i a r c i n a m . i du:duodenum,

~ d’

~

S q u a m o u i c e l I c irclnom,q

pm:muscle c o a t ,

y/A

1-1971

Intermingled

Am:hmpulla of Vater

Fig. 2. Microscopic distribution of adenocarcinoma and squamous cell carcinoma of eight cases of adenosquamous carcinoma of the pancreas.

Fig. 3. A close relationship between adenocarcinoma and squamous cell carcinoma (H&E, X 100, 1-2767).

Fig. 4. Squamous cell carcinoma invades the perineural spaces (H&E, X200, 1-3682).

noma had 34PE12 immunoreactants in the cytoplasms of malignant squamous elements in all eight cases (Fig. 6). Poorly differentiated cells were positive for 34PE12 in six cases. The immunoreactants were from fine granules to diffusely dense granules in the cytoplasm of cancer cells. Poorly differentiated cells were also weakly positive for AB and PAS in two cases. Adenocarcinoma and squamous cell carcinoma were clearly counterstained with 34PE12 and AB in a rnucoepidermoid pattern (Fig. 7).

to 1 year and 2 months after surgery. The cumulative I-year survival rates of the 8 patients with adenosquamous carcinoma, the 72 with adenocarcinoma of the pancreas, the 36 with well-differentiated adenocarcinoma, the 26 with moderately differentiated adenocarcinoma, and the 10 with poorly differentiated adenocarcinoma were 21.4%*, 42.12%, 61.2*, 24.6%, and 11.1%, respectively (*the difference was significant, K 0 . 0 5 ) . The survival curve of 8 patients with adenosquamous carcinoma of the pancreas was significantly less favorable than that of the 36 patients with welldifferentiated adenocarcinoma ( K 0 . 0 5 ) (Fig. 8) and was as poor as those of the 72 patients with adenocarcinorna of the pancreas, the 26 with moderately differen-

Prognosis Five of 8 patients with adenosquamous carcinoma of the pancreas died from 3 months to 7 months after initial operation and the other 3 were still alive from 5 months

Adenosquamous Carcinoma of the Pancreas

113

TABLE 111. Histochemical and ImmunohistochemicalStudy of Eight Cases of Adenosquamous Carcinoma of &hePancreas* PAS

No. cases

ad

1-464 1-2327 1-2725 1-2767 1-3682 1-4008 1-1971 1-3562

++ ++ ++ ++ ++ ++ ++ ++

sq -

-

-

-

-

-

34PE12

AB por

/ / +a

ad

++ ++ ++ ++ ++ ++ ++ ++

sq

por

-

-

-

ad

-+ +++++ +++ ++ + ++ - +++ + ++

-

-

/ /

-

-

-

-

-

sq

+a

+a

-

+a

-

35PH11 por

ad

sq

por

++ + +++ - -+ ++ ++ / ++ / / ++ - / ++ ++ + -- + + ++ - + -

-

-

-

-

*ad, adenocarcinoma; sq, squarnous cell carcinoma; por, poorly differentiated cells; 1,none; -, negative; weakly positive; moderately positive; strongly positive. “Focally and weakly positive.

+,

++,

+++,

Fig. 5 . Adenocarcinoma is positive with 35PH11 and squamous cell carcinoma is negative with 35PHll (ABC method, X 170, 1.2767).

Fig. 6. Squamous cell carcinoma is positive with 34PE12 and adenocarcinoma is negative with 34PE12 (ABC method, X170, 1-2767).

tiated adenocarcinoma, and the 10 with poorly differentiated adenocarcinoma of the pancreas.

DISCUSSION Adenosquamous carcinoma of the pancreas is uncommon [l-31, but it is well known. The incidence has been reported to be from 3.4% to 3.9% in non-endocrine pancreatic carcinoma [4-61. Ishikawa et al. [6] reported a high incidence of 11% and said that there was a possibility that more careful studies might disclose the existence of small foci of squamous cell carcinoma in adenocarcinoma of the pancreas. Cihak et al. [5] also said that any squamous cell carcinoma of the pancreas must be thoroughly examined for adenocarcinomatous elements before it can be as being pure squamous in type. In Our study through mm stepwise tissue sections, the incidence of adenosquamous carcinoma of the pan-

Fig. 7. Mucous-secreting cells are positive with AB and squamous cell carcinoma is positive with 34PE12 (ABC method and AB, x250, 1-464).

114

Yamaguchi and Enjoji 100 %

90 %

A : Adenosquamous

carcinoma ( 8 patients)

: Well differentiated adenocarcinoma

80 %

I

(36 p a t i e n t s )

: Tickmark indicates t h e last f o l l o r u p

70 % 60 %

50 % 40 % 30 %

20

z

10 %

0 % 1 Y‘

2 yrs

3 yrs

4 yrs

5 yrs

Fie. 8 Survival curves of the 8 patients with adenosquamous carcinoma and the 36 patients with wdl-differentiated adenocarcinoma of the pancreas

creas was relatively high (9.0%) and two tumors had small foci of squamous cell carcinoma in only one or two tissue sections. No pure squamous cell carcinoma could be identified. Several kinds of nomenclature have been used for carcinoma containing both adenomatous and squamous components: adenosquamous carcinoma [6,11-141, mucoepidermoid carcinoma of the bronchus [ 151 or salivary glands [16,17], adenoacanthoma of the uterus [18,19], stomach [20], colon [21], or pancreas [5], mixed carcinoma of the uterus [22], mixed adenosquamous carcinoma of the uterus ,[23], mixed adenocarcinoma and squamous carcinoma of the uterus [24] , adenocancroid [25], adenocarcinoma with squamous metaplasia of the uterus [26], gastric carcinoma with squamous cell metaplasia [27], polymorphic epithelioma [28] , Malpighian tumor [29]. Adenosquamous carcinoma, muceopidermoid carcinoma, and adenoacanthoma have been used in various sites of organs. Mucoepidermoid carcinoma is applied for the bronchus [ 151 or salivary glands [ 16,171. It means carcinoma where glandular and squamous components intimately intermingle as well as third cells, which is predominantly epidermoid in character but with unequivocal mucin production. It is locally invasive and has a good 5-year survival rate of 98% for the low-grade variety and 56% for the high-grade type [17]. In the uterus [ 18,191, adenoacanthoma means adenocarcinoma with benign squamous elements and adenosquamous carcinoma means carcinoma containing both adenocarcinoma and squamous cell carcinoma. In our study 8 tumors had both malignant glandular structures and malignant squamous elements and the outcome was very poor (21.4% of cumulative 1-year survival rate). Therefore, we prefer the term “adenosquamous carcinoma of the pancreas.” Various hypotheses have been made on the squamous

elements at the sites where adenocarcinoma is generally found: ectopic squamous nest [30], non-neoplastic squamous metaplastic epithelium [5,13,21,31], squamous metaplasia of the pre-existing adenocarcinoma [6,12,32, 331, endothelium [ 111, multipotential stem cell [26], basal cell [34]. In the non-cancerous pancreas the pancreatic ducts or ductules often show benign squamous metaplasia. Adenocarcinoma arising from the pancreatic ducts or ductules can also develop into squamous metaplasia. In all eight tumors there was a close relationship between the glandular elements and the squamous components and both types showed both invasion and metastasis. Adenocarcinoma was situated at the center of the tumor and squamous cell carcinoma was located at the periphery of the neoplasm. Histochemistry and immunohistochemistry disclosed a different nature for both elements. We think that squamous components are metaplastic changes of pre-existing adenocarcinoma. Keratin proteins are a member of intermediate filaments and are classified into 20 keratin polypeptides, based on their molecular weight and isoelectric pH [35-371. An antibody, 35PH11, generated against the cytoskeleton of a human hepatocellular carcinoma cell line (Hep3B), accurately recognizes a 54 kd cytokeratin protein in many epithelial cell lines, stains all nonsquamous epithelium, and fails to recognize squamous epithelium [7,8]. Another antibody, 34PE12, made to human stratum corneum, recognizes the 57 and 66 kd cytokeratin proteins of human stratum corneum and reacts with squamous epithelium and some, but not all, non-squamous epithelium [7,8]. Squamous cell carcinoma was uniformly positive with 34PE12 and largely negative with 35PHl1, and ductal carcinoma of the pancreas was uniformly positive with 35PHll and 34PE12 [9]. Discrimination between adeno- or squamous cell carcinoma was also reported by different types of

Adenosquamous Carcinoma of the Pancreas

cytokeratin (CK 18 and CK 10) [38,39]. In our study of eight cases of adenosquamous carcinoma of the pancreas, the squamous cell carcinomatous element was uniformly positive with 34PE12 and uniformly negative with 35PH11. The adenocarcinomatous components were also uniformly positive with 35PH 1 1 and variably positive with 34PE12. These results are almost the same as those obtained by Gown and Vogel [9]. It was reported that the outcome of patients with adenosquamous carcinoma was poor in the gallbladder [40], uterus [22,23,41], or pancreas [5,6], and was good in the bronchus [ 151 or stomach [30]. In our study the cumulative 1-year survival rate of the 8 patients with adenosquamous carcinoma was poorer than that of the 72 patients with adenocarcinoma of the pancreas (21.4% and 42.1%, respectively). The survival curve of the 8 patients with adenosquamous carcinoma was significantly less favorable than that of the 36 patients with well-differentiated adenocarcinoma of the pancreas ( K 0 . 0 5 ) . We studied 8 cases of adenosquamous carcinoma of the pancreas clinicopathologically . Squamous cell carcinoma was located at the periphery of the tumor and there was a close relationship between adenocarcinoma and squamous cell carcinoma. Histochemistry and immunohistochemistry showed a different nature for both elements. These features suggested that the squamous cell carcinoma component was squamous metaplasia of preexisting adenocarcinoma. The prognosis of the 8 patients with adenosquamous carcinoma of the pancreas was worse than that of the 72 patients with adenocarcinoma of the pancreas and significantly less favorable than that of the 36 patients with well-differentiated adenocarcinoma of the pancreas.

8. 9. 10.

11.

12. 13. 14. 15. 16. 17. 18.

19. 20. 21. 22. 23.

ACKNOWLEDGMENTS The authors thank Mr. Brian T. Quinn for his critical reading of this manuscript.

24. 25. 26.

REFERENCES 1. Cubilla AL, Fitzgerald PJ: Tumors of the exocrine pancreas. In “Atlas of Tumor Pathology. Second Series, Fascicle 19.” Washington, DC: Armed Forces Institute of Pathology, 1984. 2. Kloppel G: Pancreatic non-endocrine tumours. In Kloppel G, Heitz PU (Eds): “Pancreatic Pathology.” Edinburgh: Churchill Livingstone, 1984, pp. 79-103. 3. Chen JIE, Baithun SI: Morphological study of 391 cases of exocrine pancreatic tumours with special reference to the classification of exocrine pancreatic carcinoma. J Pathol 146:17-29, 1985. 4. Sommers SC, Meissner WA: Unusual carcinomas of the pancreas. Arch Pathol 58:101-110, 1954. 5 . Cihak RW, Kawashima T, Steer A: Adenoacanthoma (adenosquamous carcinoma) of the pancreas. Cancer 29: 1133-1 140, 1972. 6. Ishikawa 0, Matsui Y, Aoki I, Iwanaga T, Terasawa T, Wada A: Adenosquamous carcinoma of the pancreas. A clinicopathologic study and report of three cases. Cancer 46:1192-1196, 1980. 7. Gown AM, Vogel AM: Monoclonal antibodies to intermediate

27. 28. 29. 30.

31. 32. 33. 34.

115

filament proteins of human cells: Unique and cross-reacting antibodies. J Cell Biol 95:414-424, 1982. Gown AM, Vogel AM: Monoclonal antibodies to human intermediate filament proteins. 11. Distribution of filament proteins in normal human tissues. Am J Pathol 114:309-321, 1984. Gown AM, Vogel AM: Monoclonal antibodies to human intermediate filament proteins. 111. Analysis of tumors. Am J Clin Pathol 84:413424, 1985. Hsu SM, Raine L, Fanger H: The use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 295777580, 1981. Straus R , Heschel S, Fortmann DJ: Primary adenosquamous carcinoma of the stomach. A case report and review. Cancer 24:985-995, 1969. Mori M, Iwashita A, Enjoji M: Adenosquamous carcinoma of the stomach. A clinicopathologic analysis of 28 cases. Cancer 57:333-339, 1986. Haqqani MT, Fox H: Adenosquamous carcinoma of the endometrium. J Clin Pathol 29:959-966, 1976. Salazar OM, DePapp EW, Bonfiglio TA, Feldstein ML, Rubin P, Rudolph JH: Adenosquamous carcinoma of the endometrium. An entity with an inherent poor prognosis? Cancer 40: 119-130, 1977. Carter D, Eggleston JC: Tumors of the lower respiratory tract. In “Atlas of Tumor Pathology. Second Series, Fascicle 17.” Washington, DC: Armed Forces Institute of Pathology, 1974. Thackray AC, Lucas RB: Tumors of the major salivary glands. In “Atlas of Tumor Pathology. Second Series, Fascicle 10.” Washington, DC: Armed Forces Institute of Pathology, 1974. Jakobsson PA, Blanck C, Eneroth CM: Mucoepidermoid carcinoma of the parotid gland. Cancer 22:lll-124, 1968. Silverberg SG, Bolin MG, DeGiorgi LS: Adenoacanthoma and mixed adenosquamous carcinoma of the endometrium. A clinicopathologic study. Cancer 30: 1307-1314, 1972. Badib AD, Kurohara SS. Vongtama VY, Selim MA, Webster JH: Biologic behavior of adenoacanthorna of endometrium. Am J Obstet Gynecol 106:205-209, 1970. Boswell JT, Helwig EB: Squamous cell carcinoma and adenoacanthoma of the stomach. ‘A clinicopathologic study. Cancer 18: 18 1- 192. 1965. Cook CB, Klickstein GD: Adenoacanthomas of the colon. Arch Pathol 65:681487, 1958. Ng ABP: Mixed carcinoma of the endometrium. Am J Obstet Gynecol 102306-515, 1968. Alberhasky RC, Connelly PJ, Christopherson WM: Carcinoma of the endometrium. IV. Mixed adenosquamous carcinoma. Am J Clin Pathol 77:655-664, 1982. Skinner 1, McDonald J: Mixed adenocarcinoma and squamous cell carcinoma of the uterus. Am J Obstet Gynecol40:258-266, 1940. Herxheimer G: Ueber heterologe Cancroide. Beitr Pathol Anat 41 : 3 4 8 412, 1907. Hertig AT, Gore H: Tumor of the female sex organs. 11. Tumor of the vulva. vaeina and uterus. In “Atlas of Tumor Pathology. Supplement.;’ Wishington, DC: Amied Forces Institute of Pat& ogy, 1976. Urban A, Oszacki J, Szczygiel K: Squamous cell metaplasia in gastric carcinoma. Pol Med J 65379-894, 1967. Oberling C, Wolf M. Sur un cas d’tpithClioma polymorphe (glandulaire, Cpidermoide et myxoi’de) du pylore. Bull Assoc Fr Etude Cancer 16:68-78, 1927. Gauthier Villars P, LCger L: Cancer gastrique B type d’CpithClioma malpighien spino-cellulaire, Ann Anat Pathol 16:1065-1067, 1940. Altshuler JH, Shaka JA: Squamous cell carcinoma ofthe stomach. Review of the literature and report of a case. Cancer 19331-838, 1965. Sheffler MM, Falk AB: Epidermoid carcinoma of the stomach. Am J Cancer 38:359-363, 1940. Donald KJ: Adenocarcinoma of the pyloric antrum with extensive squamous differentiation. J Clin Pathol 20: 136-138, 1967. Barr RJ, Hancock DE: Adenosquamous carcinoma of the liver. Gastroenterology 69: 1326-1 330, 1975. Comer TP, Beahrs OH, Dockerty MB: Primary squamous cell 1

116

35. 36.

37.

38.

Yamaguchi and Enjoji

carcinoma and adenoacanthoma of the colon. Cancer 28: 1 1 1 11117. 1971. Moll R, Franke WW, Schiller DL: The catalog of human cytokeratins: Patterns of expression in normal epithelia. tumors and cultured cells. Cell 3 I :11-24, 1982. Cooper D, Schermer A, Sun TT: Classification of human epithelia and their neoplasms using monoclonal antibodies to keratins: Strategies, applications and limitations. Lab Invest 52:243-256, 1985. Sun TT, Tseng SCG, Huang AJW, Cooper D, Schermer A, Lynch MH, Weiss R, Eichner R: Monoclonal antibody studies of mammalian eDithelial keratins: A review. Ann NY Acad Sci 455:307-329.’ 1985. Ramaekers F, Huysmana A, Moesker 0, Kant A, Jap P, Herman C, Vooijs P: Monoclonal antibody to keratin filaments specific for

glandular epithelia and their tumors. Use in surgical pathology. Lab Invest 49:353-361, 1983. 39. Meijer CJLM, Mullink H, Henzen-Longmans SC: Practical application of monoclonal antibodies to diagnostic tumor pathology and some future perspectives. In Ruiter DJ, Fleuren GJ, Wamaar SO (eds): “Application of Monoclonal Antibodies in Tumor Pathology.” Dordrecht. Martinus Nijhoff, 1987. 40. Muto Y, Uchimura W, Waki S, Hayashi T, Sameshima T, Okamoto K: Clinicopathologic study of adenosquamous carcinoma of the gallbladder and bile duct. Jpn J Cancer Clin 28:44&444, 1982 (in Japanese with English abstract). 41, Hachisuga T: Endometrial carcinoma. A histopathologic analysis of 155 cases with special reference to prognostic factors and background lesions. Fukuoka Acta Med 77:314-332, 1986 (in Japanese with English abstract).