GYNECOLOGK

ONCOLOGY

40,

207-217 (1991)

Clear Cell Carcinoma of the Endometrium: A Histopathological and Clinical Study of 97 Cases VERA Departments of *Pathology

M.

ABELER,

M.D.,’

and TGynecologic

AND KJELL

Oncology,

Norwegian

E.

KJORSTAD,

Radium Hospital,

M.D., PH.D.7 Montebello,

N-0310 Oslo 3, Norway

Received May 15, 1990

plications and which has become widely accepted. According to Scully and Barlow, the most telling evidence against a mesonephric derivation has been the sporadic reporting of CCC in the endometrium. Ultrastructural studies of single cases of ECCC also support the concept of a miillerian origin [6-S]. Most CCCs have been encountered in the ovary. During the last two decades, CCC of the vagina and cervix has been found with increasing frequency in young women. Some authors claim that this increase is linked to in utero exposition to diethylstilbestrol (DES) [9,10]. Prior to 1973 only single cases of CCC of the endometrium had been reported, the first by de Bonneville in 1911 [ll-171. The first to use the term clear cell was MBrza (“6pithClioma de l’uterus a cCllules Claire?) [12]. INTRODUCTION A detailed review of the early literature with case reClear cell (mesonephric) carcinoma (CCC) of the fe- ports was given by Silverberg and De Giorgi [6] who also male genital tract is now a well-established histopatho- published 12 of their own cases of CCC, 2 of which had logical entity [1,2]. The term mesonephroma was intro- been previously reported by Kay 1131. Studies of CCC duced by Schiller (31 in 1939 to describe a subtype of with special reference to the clinical implications were ovarian tumors which resembled renal carcinoma and the reported by Kurman and Scully [18], Eastwood [19], and tumors originating from the mesonephric duct system. Photopulos and co-workers [20]. Recently, ChristopherTwenty years later, Teilum [4] presented evidence that son and co-workers presented a population-based study these tumors were a heterogenous group made up of two of 56 patients with CCC [21]. The purpose of this report is to present the histopathdistinct clinical and biochemical entities: (1) a highly malignant germ cell tumor called endodermal sinus tumor ologic findings of all patients and the clinical findings in or yolk sac tumor, characterized by its production of CY- a subset of patients with CCC diagnosed in Norway from fetoprotein and occurring predominantly in children and 1970 to 1977. We have also studied the effect on survival young women; and (2) a less malignant carcinoma, oc- of extent of myometrial infiltration, vessel invasion, tucurring in elderly women and not producing cy- mor/host reaction, age, and stage. fetoprotein. Scully and Barlow [5] related the origin of the latter PATIENTS AND METHODS group of tumors to the miillerian epithelium rather than the mesonephros and proposed in 1967 the descriptive From 1970 to 1977, a total of 2090 patients with enterm clear cell carcinoma, which has no histogenetic im- dometrial carcinoma were reported to the Norwegian Cancer Registry. The diagnosis was histologically con’ To whom requests for reprints should be addressed. firmed by us in 1985 for 95% of the cases. Eleven cases In a histopathologic review of 1985 cases of endometrial carcinoma 97 patients (4.9%) had clear cell carcinoma (CCC). Mean age at diagnosis was 65.3 years. The crude 5- and lo-year survivals for all stageswere 42.3 and 30.9%, respectively. Fifty-nine percent of the patients in surgicopathological stage I and 27% in stage II survived 5 years. Myometrial infiltration and vessel invasion were important prognosticators. Ninety percent of the patients with intramucosal tumors survived 5 years, in contrast to only 15% of the patients with deep myometrial infiltration. Seventeen percent of the patients with vessel invasion survived 5 years, in contrast to 49% of the patients without this finding. CCC is one of the most aggressive subtypes of endometrial carcinoma. 0 1991 Academic Press. Inc.

207 WX-8258191 $1SO Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.

ABELER AND KJBRSTAD

FIG. 1.

Solid pattern of clear cell carcinoma composed entirely of clear cells. H&E,

which were diagnosed at autopsy were excluded, leaving 1974 for further study. A more detailed description of patients and methods is published elsewhere [22]. Histopathology

Histologic material was available for all patients. All slides were routinely stained with hematoxylin and eosin. In selected cases, additional sections were stained by the periodic acid-Schiff (PAS) method or with Alcian blue, Gomorri, PTAH, and trichrome Masson. The tumors were classified according to the WHO histological typing of female genital tract tumors [l] with two modifications, that adenocarcinoma with benign squamous cell metaplasia was recorded separately as adenoacanthoma and that tumors with the special appearance of serous papillary carcinoma of the ovary were recorded as such. The WHO definition of clear cell (mesonephroid) carcinoma is “A malignant tumor composed of cells with clear cytoplasm and/or cells of the hobnail type. The growth pattern may be glandular, papillary, or solid” [l]. This definition is incomplete. As described in WHO histological typing of ovarian tumors [2] some CCCs are composed of cysts lined by flattened epithelium and tumors with this pattern were therefore included in this study (Figs. l-4). All hysterectomy specimens were evaluated for the presence of myometrial infiltration, vessel invasion, tumor/host reaction, cervical involvement, and ovarian stromal hyperplasia.

x

305.

The depth of myometrial infiltration was classified as (1) intramucosal, (2) less than half of the myometrium, (3) more than half of the myometrium, and (4) infiltration to the serosa. Vessel invasion was considered positive when tumor cells were demonstrated within spaces lined by endothelium (Fig. 5). The tumor/host reaction was evaluated by recording the intensity of lymphocyte infiltration surrounding the tumor using a 0 to 3+ scale. Histological demonstration of tumor involvement of the cervical mucosa or cervical wall, either in curettage or in hysterectomy specimens, was required as evidence of cervical involvement. Carcinomatous tissue floating free in the cervical fraction was disregarded. Clinical Features

The Norwegian Radium Hospital (DNR) is a central referral institution and treats approximately 75% of all patients with endometrial cancer in Norway. The hospital records of all DNR patients were reviewed for clinical and pathological stage, parity, previous history of malignant diseases, hypertension, diabetes, weight and height, and previous hormonal treatment. Patients with blood pressure exceeding 150 mm Hg systolic or 100 mm Hg diastolic, as well as those on hypertensive medication but with normal blood pressure, were defined as having hypertension. DNR patients have been treated according to the different treatment protocols used during the study period [23-251. In general, all operable patients with early-stage

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CLEAR CELL CARCINOMA

FIG. 2a. Papillary pattern of clear cell carcinoma composed of mostly eosinophilic cells. H&E, x30.5.

disease have been treated by surgery, but the details of pre- and postoperative irradiation changed during the period. A number of patients have been treated with adjuvant progestogen as part of a prospective randomized clinical trial [26]. Details of treatment and treatment ef-

FIG. 2b.

fects are not analyzed in this report. For patients treated in other hospitals (non-DNR patients) we have limited clinical information. Staging was done according to the rules agreed by the International Federation of Gynecology and Obstetrics

Papillary pattern of clear cell carcinoma composed of “hobnail cells.” H&E,

x

480

210

ABELER AND KJQRSTAD

FIG. 3. Tubular pattern of clear cell carcinoma with tubules lined with cuboidal clear cells. H&E, x305.

(FIGO)I[27]. In

addition the extent of tumor in all available openration specimens was assessedand noted as surgicopathcIlogical stage. Inform (ation on follow-up and cause of death is complete. In the case of DNR patients, information was re-

trieved from the hospital records and, if necessary, the patient or her attending physician was contacted for further information regarding relapse and site of recurrei rice. In non-DNR patients, survival data were provided by the Cancer Registry. If dead, the cause of death was retrie :ved

FIG. 4. Cystic pattern of clear cell carcinoma. The cysts are lined by flattened epithelial cells. H&E, ~76.

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CLEAR CELL CARCINOMA

211

FIG. 5. Tumor cells within a lymph vessel deep in the myometrium. H&E, ~305

Sixty-six tumors were pure CCC. For the entire material the patterns were papillary (34%), solid (29%), and tubular (1%). None of the tumors were found to be of the pure cystic type. Usually there was a mixture of two patterns. Thirty-one tumors showed, in addition, ordinary adenocarcinoma, and one tumor showed areas with adStatistical Methods enosquamous carcinoma. The clear cell component, howStatistical significance in contingency tables was com- ever, was predominant in all mixed tumors. Myometrial infiltration was assessedin 58 specimens. puted according to the x2 and Fisher’s exact test when Ten tumors (17%) were intramucosal; 34 (59%) infilfeasible. F and t tests as well as uni- and multivariate trated less than and 13 (22%) more than half of the analyses were carried out on a microcomputer with the myometrium. Only one patient had a tumor which exhelp of a commercially available program based on SPSS. tended to the serosa. The myometrial involvement could RESULTS not be assessedin 16 specimens because of preoperative radiotherapy. Histopathology Vascular invasion was evaluated in 53 natients and was Of the 1974 patients with confirmed endometrial car- present in 12 (23%), 3 of whom had tumors infiltrating cinoma, 97 had CCC (4.9%). Endometrial carcinoma was less than half and 9 (75%) more than half of the myodiagnosed by fractional dilatation and curettage (D&C) metrium. Vessel invasion was not found among the inin 94 patients. We reviewed 75 of these specimens and tramucosal tumors or in the specimen with tumor infilfound 70 ECCCs (93%) and 5 adenocarcinomas of the trating to the serosa. common type (7%). The latter 5 cases showed CCC in Tumor-host reaction as measured by lymphocyte rethe hysterectomy specimen and are therefore included. action surrounding the tumor was assessedin 49 speciSeventy-four patients (76%) underwent total abdominal mens. In 34 (69%) some degree of lymphocytic reaction hysterectomy and bilateral salpingo-oophorectomy. CCC was found. All of these tumors infiltrated the myometwas found in 56 specimens. Atypical adenomatous hy- rium. Fifteen specimens showed no reaction. Of these, 8 perplasia was found in one case. In the remaining 17 were intramucosal and the remaining 7 infiltrated less than operation specimens no residual tumor was found. Sixteen half the myometrium. of these patients had received preoperative irradiation. The relation between myometrial infiltration, vessel infrom the death certificate at the Central Bureau of Statistics and was recorded as either death from endometrial carcinoma or death from intercurrent disease. Follow-up was closed in January 1988 which gave a minimum follow-up period of 10 years.

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ABELER AND KJQ)RSTAD

TABLE 1 Relationship between Myometrial Infiltration and Vessel Invasion and Lymphocyte Reaction

TABLE 2 Relationship between Clinical and Surgicopathological Stage in 57 Patients

Myometrial infiltration Intramucosal Vessel invasion Positive Negative Not stated Total

-

%

Surgicopathological stage

Serosa Total

3 (9)” 9 (69) 12 (21) 31 (91) 4 (31) 1 (100)41 (71) 5 (9) 34 (100) 13 (loo) 1 (loo)58 (101)

5 (50) 5 (50) 10 (100)

Clinical stage I II III IV Total

I

II

III

IV

Total

26 (87) 12 (52) 2 (50) 40 (70)

2 ( 7) 9 (39) 11 (19)

2(7) 2(9) 1 (25) -

1 (25) -

5 ( 9)

1 ( 2)

30 (loo) 23 (100) 4 WV 57 (loo)

a N(%).

Lymphocyte reaction 0 + ++ +++ Not stated Total

8 (80) -

7 (21) 15 (26) 4 (12) 2 (15) 1 (loo) 7 (12) 9 (26) 4 (31) 13 (22) 9 (26) 5 (39) 14 (24) 5 (15) 2 (15) 9 (16) 34 (loo) 13 (100) 1 (100)58 (100)

2 (20)

10 (100)

no difference in the age distributions of DNR and nonDNR patients. Only one patient was under 40 years of age. The age distribution is given in Fig. 6. Stage

a N(%).

vasion, and lymphocyte reaction is shown in Table 1. There was no difference regarding myometrial infiltration, vessel invasion, and lymphocyte reaction between the subgroups of CCC. Ovarian stromal hyperplasia was found in 9 of 67 (13%) operation specimens.

Seventy-five patients were clinically staged according to FIGO. Thirty-five (47%) were allotted to stage I, 28 (37%) to stage II, 7 (9%) to stage III, and 5 (7%) to stage IV. Surgical staging was performed in 59 cases. Forty-one (70%) were in stage I, 11 (19%) in stage II, 5 (9%) in stage III, and 2 (3%) in stage IV disease. Fiftyseven patients were both clinically and surgicopathologically staged. The agreement between the two staging systems is shown in Table 2.

Patients The patients with CCC ranged in age from 36 to 91 years (mean 65.3 years). This is significantly older than patients with adenocarcinoma of the ordinary type who had a mean age of 62.7 (P < 0.001, t test). There was 4.5

-

Body Mass Height and weight was recorded in 70 patients. The average height was 160.5 cm (range 138-177 cm) and weight 66.3 kg (range 42-100 kg). The mean weight was lower than that for patients with common adenocarcinoma (P = 0.04, F test). Pregnancies

5 E 3 3.0c3

Parity was known for 76 patients and ranged from 0 to 8 (mean 2.3). Twenty-one patients (28%) were nulliparous, which contrasts with lo%, the average for all Norwegian women [28].

i

? iz 1.5 a 52

Hypertension Hypertension was found in 38 of 77 (49%) patients. The incidence of hypertension, according to the definitions used in the present paper, in Norwegian women over 40 is 41.4% [29].

I -.-

I 35

46

57

66

79

90

AGE FIG. 6. Age distribution of 97 patients with clear cell carcinoma of the endometrium.

Diabetes Five of seventy-seven patients (6%) had diabetes mellitus. This is approximately the same frequency as is en-

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CLEAR CELL CARCINOMA

TABLE 4 Relation between Clinical and Surgicopathological Stage and 5and lo-Year Crude Survival” Surgicopathological stage

Clinical stage

0

/

I

I

1

30

60

90

120

5 years

10 years

Total

5 years

10 years

Total

I II III IV

15 (43)b 14 (50) -

12 (34) 9 (32) -

35 28 7 5

24 (59) 3 (27)

18 (44) 2 (18)

41 11 5 2

Total

29 (39)

21 (28)

75

27 (46)

20 (34)

59

-

” None of the differences are statistically significant using xz or Fisher’s exact test. b N(%).

MONTHS SURVIVAL OF THE ENTIRE POPULATION

N=97

FIG. 7. Survival for 97 patients with clear cell carcinoma of the endometrium compared with survival for 1566 patients with ordinary adenocarcinoma and expected survival for a population with the same age distribution as all patients with endometrial carcinoma.

Survival

Crude survival for all patients with CCC compared with survival for patients with ordinary adenocarcinoma is shown in Fig. 7. Crude 5-year survival was 42.3% and lo-year survival was 30.9%. Survival in relation to age at the time of diagnosis is countered in the average Norwegian woman in the same presented in Table 3. age group [29]. Four of these patients also had Survival by clinical and surgicopathological stage is hypertension. shown in Table 4. No patient in stage III or IV survived 5 years. There was no difference in prognosis between clinical stages I and II. Previous Hormone Treatment Crude survival by depth of myometrial invasion is Only 2 of 77 patients (2.5%) had a history of exogenous shown in Table 5. Patients with intramucosal tumors had estrogen therapy. a 5-year survival of 90% in contrast to only 15% in patients with deep infiltrating tumors. Positive vessel invasion was also a very powerful progPrevious Malignant Disease nosticator. In the 12 patients with unquestionable tumor Of the 77 DNR patients, 3 (3.9%) had been treated cells within endothelium-lined spaces, only 2 (17%) surfor a previous malignant condition. vived 5 years and only 1 (8%) survived 10 years. This contrasts with the 49% 5-year survival and 42% lo-year survival for patients without vessel invasion. Depth of TABLE 3 Crude Survival in Relation to Age at the Time of Diagnosis” Survival

Age

5 years

10 years

1 (100)h

I (100)

3 (75)

3 (75)

Total 1

30-39 40-49 50-59 60-69 70-79 80-89 90+

12 (60)

10 (50)

14 (38)

12 (32)

8 (29) 3 (50)

3 (11) 1 (17)

28 6 1

Total

41 (42)

30 (31)

97

a 5 years: x2 (6) = 9.028, P = 0.175; 10 years: x2 (6) = 15.689, P = 0.016 (significant). ’ N(%).

4 20 37

TABLE 5 Relation between Myometrial Infiltration and S- and lo-Year Crude Survival in 58 Operated Patients” Myometrial infiltration 0 < ‘95 > 1% Serosa Total

5 years

10 years

Total

9 (90) 16 (47) 2 (15)

7 (70) 13 (38) 2 (15) 22 (38)

10 34 I3 1 58

27 ;47)

’ 5-year survival: xz (3) 13.53, P = 0.0018; lo-year survival: xz (3) = 7.786, P = 0.051. h N(%).

214

ABELER AND KJBRSTAD

myometrial infiltration and vessel invasion, however, were strongly intercorrelated. There was no correlation between tumor-host reaction and survival. Survival for the Different Subtypes of CCC Although the solid type had a 5-year survival of 57% compared with 45% for the papillary type and 29% for the mixed type, the differences are not statistically significant. DISCUSSION The reported frequency of CCC varies from 0.8 to 5.5% of all endometrial carcinomas [19-21,30-351 which is in agreement with our finding of 4.9%. Histopathology The descriptive term clear cell carcinoma is adequate only for those tumors in which there is a solid growth pattern, either alone or in mixed types where the solid component is prominent. Tumors with a papillary, tubular, or cystic pattern are composed predominantly of hobnail, cuboid cells (papillary and tubular) and flattened cells (cystic) which frequently do not fit with the description “clear cells.” However, some areas with clear cells are seen in most cases. The correct diagnosis of CCC in tumors with only small areas of clear cells is often difficult.

Serous papillary carcinoma and adenocarcinoma of the secretory type are to be considered differential diagnoses (Figs. 8 and 9). Hendrickson and co-workers found it difficult to separate some casesof serous papillary carcinoma from CCC (36). In the WHO definitions of CCC [1,2], clear cells, hobnail or peg cells, and flattened cells in the typical setting of solid, papillary, tubular, and cystic patterns are diagnostic of CCC. Hobnail or peg cells are also seen in serous papillary carcinomas, but there is usually less cytoplasm than in CCC. The distinction between these tumors appears to be mostly of academic interest, since both are clinically very aggressive. Secretory adenocarcinoma, a subtype of the common adenocarcinoma of the endometrium, is characterized by neoplastic glands lined by cells resembling those of a 17day secretory endometrium with subnuclear vacuolization and small inconspicuous nuclei and has been considered to be a form of CCC by some authors [6,17]. Secretory adenocarcinoma usually represents a well-differentiated adenocarcinoma with progestational changes and can easily be separated from CCC [l&21]. Christopherson and co-workers [21] found that patients with CCC were almost a decade older than those with secretory carcinoma, and the 5-year survival rate of 33.9% was significantly lower than the 86.7% for patients with secretory carcinoma. The latter group belongs to the subtypes of endometrial carcinoma with a favorable prognosis, and should not be included in CCC. In the present study, adenocarcinoma

FIG. 8. Serous papillary carcinoma of the endometrium is composed of cuboidal cells. Psammoma bodies are also seen (arrowheads). H&E, x480.

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FIG. 9.

215

CLEAR CELL CARCINOMA

Well-differentiated adenocarcinoma of the secretory type. H&E,

of the secretory type was included among the ordinary adenocarcinomas. Most studies of CCC are of limited numbers [6,18-201 and some do not have adequate follow-up [18]. All imply that the prognosis is bad. The aggressive clinical behavior of CCC was confirmed by Christopherson and co-workers in their large population-based study [21]. The 5-year survival rate for patients with CCC was 33.9%, which is somewhat lower than the crude 5-year survival rate of 42.3% in our series, despite the fact that the pathological stage distribution was more favorable in the study by Christopherson. Stage of disease, depth of myometrial infiltration, and vessel invasion are the most widely recognized prognostic parameters for endometrial carcinoma. The age of patients with CCC differed significantly from that of patients with common adenocarcinoma, but the histologic parameters had approximately the same distribution [37]. In contrast to our findings in ordinary adenocarcinomas, age was not correlated with the histological parameters. This would imply that the diagnosis of CCC itself is the most important prognostic factor. It is an important observation that CCC had such a characteristic histologic pattern that the correct histologic diagnosis could be made on the D&C specimen alone in 93% of the cases. Myometrial infiltration has been shown to be of value in predicting prognosis in patients with CCC [18,21]. Our experience is similar as 9 of 10 patients with intramucosal

x

190.

tumors survived 5 years in contrast to 16 of 34 patients with tumors infiltrating less than half of the myometrium. Only 2 of 13 with tumors infiltrating the outer half survived 5 years. The importance of vessel invasion has recently been demonstrated in different types of endometrial carcinoma [23,34,37-401. To our knowledge this phenomenon has not been studied in CCC. The demonstration of tumor cells within spaces lined by endothelium was a very powerful prognosticator in this study. Statistical Considerations In a univariate analysis the histopathological factors myometrial infiltration and vessel invasion were strongly correlated. In a multivariate analysis, depth of infiltration came second in significance to age as prognosticator for both 5- and lo-year survival. Age was not correlated with depth of myometrial infiltration, stage of disease, or histological subtype. When age was excluded, a multivariate analysis revealed that myometrial infiltration was the only significant factor for 5- and lo-year survival. Clinical Characteristics The mean age of patients with CCC reported in the literature varies from 60 to 70.1 years [6,18-21,351. In our study, the mean age was 65.3 years, 2.6 years older than the mean age of patients with ordinary adenocar-

216

ABELER AND KJQ)RSTAD

cinema in Norway. In general, CCC is a disease of elderly women, but it has also been reported in two women in their twenties [l&41]. Neither of these had been exposed to DES in utero. The youngest woman in our study was 36 years of age. The reported clinical features of patients with CCC [6,18-211 resemble those of patients with ordinary adenocarcinoma of the endometrium. This is also true for the patients in the present study with regard to stage distribution, hypertension, and diabetes. Age and weight differed significantly. Stage at diagnosis is important as regards prognosis [l&21]. The crude 5-year survival for our patients with surgicopathological stage I tumor was 59%, and for patients with stage II tumor, 27%. There were no survivors among the patients with stage III and IV tumors. CONCLUSIONS Clear cell carcinoma is a rare subtype of endometrial carcinoma. The histological diagnosis can be made on the D&C specimen in a very high percentage of the cases. This is important in the planning of treatment. Patients with clear cell carcinoma of the endometrium have an overall death rate significantly higher than that of patients with ordinary endometrial adenocarcinoma. Extent of myometrial infiltration and vessel invasion are important prognosticators. The fact that only patients with intramucosal tumors had a prognosis comparable to that of common endometrial adenocarcinoma could be a reason to consider alternate treatment methods based on histological subtype at least for patients with more than minimal disease. REFERENCES 1. Poulsen, H., Taylor, C. W., and Sobin, L. H. International histologic classification of tumors. No. 13. Histological typing of female genital tract tumors. World Health Organization, Geneva (1975). 2. Serov, S. F., Scully, R. E., and Sobin, L. H. International Classification 3. 4.

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Clear cell carcinoma of the endometrium: a histopathological and clinical study of 97 cases.

In a histopathologic review of 1985 cases of endometrial carcinoma 97 patients (4.9%) had clear cell carcinoma (CCC). Mean age at diagnosis was 65.3 y...
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