Carcinoma of the Endometrium. II. Papillary Adenocarcinoma: A Clinical Pathological Study 46 Cases

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1 Carcinoma of the Endometrium. II. Papillary Adenocarcinoma: A Clinical Pathological Study 46 Cases WILLIAM M. CHRISTOPHERSON, M.D., ROBERT C. ALBERHASKY, M.D., AND PATRICK J. CONNELLY, M.D. Christopherson, William M., Alberhasky, Robert C, and Connelly, Patrick J.: Carcinoma of the endometrium. II. Papillary adenocarcinoma: A clinical pathological study 46 cases. Am J Clin Pathol 77: 1982; Forty-six patients with papillary carcinoma of the endometrium were studied. Forty-five were followed for at least five years or until death, and 41 were followed for 10 years. The remaining patient was alive at four years. The survival rate was 51.1 at five years and 46.3 at 10 years. At five years one-third had died of their disease. The median age at time of diagnosis was 63 years, and the age at diagnosis was an important determinant of survival. None of the seven black women survived for five years. Tumor grade was an important predictor of the course of disease and nuclear grading was a significantly more accurate indicator than was the histologic grading of the World Health Organization. Papillary carcinoma should be distinguished from the papillary type of clear cell carcinoma of the endometrium. While it has a somewhat better prognosis than mixed adenosquamous carcinoma or clear cell carcinoma, it appears to be more aggressive with a lower survival rate and higher rate of death from disease than the usual type of endometrial adenocarcinoma or adenoacanthoma. (Key words: Endometrial carcinoma, papillary type; Papillary, non-clear cell carcinoma; Papillary endometrial carcinoma, prognosis) AMONG PROGNOSTICATORS for endometrial carcinoma are: age at diagnosis, race, stage of disease, presence of residual tumor at time of hysterectomy, vascular invasion and depth of myometrial invasion. There are two other important determinants of treatment outcome that can be provided by the pathologist: the tumor subtype and the nuclear grade. These two factors have a profound independent effect on prognosis. Subtypes of endometrial carcinoma with a favorable prognosis include adenoacanthoma, secretory carcinoma and adenocarcinoma with no specific features (ECNSF), sometimes referred to as endometrioid type. Tumors that are the most aggressive in order of the least favorable prognosis are clear cell carcinoma Received June 15, 1981; received revised manuscript and accepted for publication July 20, Supported in part by the NCI Contract l-nc and the Kentucky Division, American Cancer Society. Dr. Alberhasky is a Clinical Cancer Fellow, Clinical Cancer Education Program, NCI 2 R Ca Dr. Connelly is a Regular Clinical Fellow, American Cancer Society. Address reprint requests to Dr. Christopherson: Department of Pathology, University of Louisville, Louisville, Kentucky Department of Pathology, University of Louisville School of Medicine, Louisville, Kentucky (CCE), mixed adenosquamous carcinoma, and papillary adenocarcinoma. Papillary adenocarcinoma of the endometrium can be readily subdivided into two types: a clear cell type and a non-clear cell type. We have previously documented the poor prognosis of CCE 6 as have others. I6M - 22 In our study only 35.7 of 56 patients with CCE survived for five years and 60.7 of the non-survivors died of their disease. Even among patients with Stage I disease only 44.2 survived for five years and 51.2 of the non-survivors died of disease. In an analysis of 989 patients with endometrial carcinoma, which were confirmed on slide review, we encountered 46 patients with papillary carcinoma which could usually be readily distinguished from papillary CCE. These tumors proved to have a more aggressive course than the ECNSF or adenoacanthoma, but a somewhat better prognosis than did CCE. The following study documents the clinical course of 46 patients with non-clear cell papillary adenocarcinomas, 45 of whom were followed for five years or until death. Materials and Methods A population based registry of all uterine tumors occurring in the residents of Louisville, Jefferson County, Kentucky, since 1953 has been maintained by the senior author. The registry is a cooperative project involving all the hospitals and radiation centers in the area as well as all the regional pathology laboratories. The community pathologists have generously allowed us to review their available material and have furnished paraffin blocks when indicated. The operation of the registry has been previously described. 18 Once entered into the study as a resident patient, follow-up has been maintained through various hospital tumor clinics, hospital records, directories and physician contact. The official death records were provided by the Kentucky Bureau of State Services, and in cases where the patient died outside of Kentucky by the appropriate state Bureau of Vital Statistics /82/0500/0534 $00.85 American Society of Clinical Pathologists 534

2 Vol. 77 No. 5 PAPILLARY ADENOCARCINOMA OF ENDOMETRIUM 535 All available slides on specimens diagnosed as endometrial carcinoma were reviewed by each of the three authors. In cases where slides were not available, paraffin blocks were recut, and where indicated PAS with and without diastase digestion, alcian blue and mucicarmine stains were prepared. The patient's hospital records including the pathology report and operative notes, were then reviewed by one of the authors (RA) but only after recording the slide review data. Grading was performed using the method recommended by the World Health Organization. 21 Tumors that were well differentiated were coded as Grade 1, those with moderate differentiation Grade 2 and those that were poorly differentiated Grade 3. In addition, an assessment was made of nuclear grade on a cytologic basis. Those with oval or elongated nuclei with evenly distributed chromatin, inconspicuous nucleoli, and few mitoses were considered as being Grade 1. Those with enlarged and irregular rounded nuclei with prominent enlarged, at times multiple, nucleoli, and frequent mitoses were coded as Grade 3. Those falling somewhere in between Grade 1 and Grade 3 were designated as Grade 2. The staging system utilized was that of the International Federation of Gynecology and Obstetrics (F.I.G.O.): the TNM Committee of the International Union against Cancer (U.I.C.C.) and, the American Joint Committee for Cancer Staging and End Results Reporting (A.J.C.). The rules set down for staging are very precise. They state: "When there is doubt as to which stage a particular cancer should be allocated, the earlier stage is mandatory". 1 In patients where a hysterectomy specimen was available, we used the "postsurgical-pathologic staging". When a hysterectomy was not performed but biopsy material was available from cervix, vagina, bladder or rectum, we used the "surgical evaluative staging". In the remaining cases we could only use the "clinical diagnostic staging". By adhering strictly to the rules cited above we, no doubt, have a more conservative determination of stage than is usually reported for endometrial carcinoma. Results The relative frequency of the subtypes of endometrial carcinoma found on review of 989 confirmed cancers is shown in Table 1. Forty-five of the patients with papillary carcinoma were followed for at least five years or until death. The remaining patient was alive at four years. The five year survival rate was 51.5 with one-third of the non-survivors dying of disease. Follow-up of survivors ranged from 5 to 25 years and averaged 13.8 years. The 10 year survival rate was Table 1. Relative Frequency of Endometrial Carcinoma Subtypes No. Per cent Adenocarcinoma NSF* Adenoacanthoma Adenosquamous carcinoma Clear cell carcinoma Papillary adenocarcinoma Secretory carcinoma Total * No specific features. Stage of disease was an important determinant of treatment outcome. No patient with greater than Stage I disease lived for five years and 63.6 died of their disease. The average survival time of those dying of disease was 17.2 months. Patients with Stage I disease had a 69.7 survival and 21.2 died of their cancers. Only 47.8 had cervical biopsy prior to treatment. Those with no cervical biopsy and no hysterectomy had to be considered Stage I provided no more extensive disease was found at surgery. A comparison of end results at five years according to tumor type is shown in Table 2. Nuclear grading proved to be a much better predictor of the course of the disease than did histologic grading although both methods were good determinants of end results. The comparison of histologic and cytologic grade in reference to end results is shown in Table 3. Only 10 uteri had not been irradiated prior to hysterectomy. Three of these had no residual tumor and all three were alive at 10 years. Five uteri had invasion limited to the inner one-third of the myometrium and four of these were alive at 10 years. The fifth patient died of ulcerative colitis at 18 months. Two patients had tumor extending to the outer one-third of the myometrium but not to the serosa. One died of disease at 29 months, and the other is living at 16 years posttreatment. A correlation of treatment method with end results was difficult to evaluate in this small patient population treated by a variety of modalities. Total hysterectomy with bilateral salpingoophorectomy in 10 patients resulted in an year survival. This good result is confounded by the fact that all eight survivors had Stage I disease as did an additional patient dying of ulcerative colitis. Furthermore, seven of the eight survivors had Grade 1 tumors. Twenty-two patients had combined irradiation and hysterectomy with a five year survival of The fifteen survivors all had Stage I disease. Eleven had Grade 1 tumors. Two patients who died of their disease were Stage I and one Stage II. Among the 15 survivors,

3 536 CHRISTOPHERSON ET AL. Table 2. Vital Status at Five Years Endometrial Carcinoma All Stages () A.J.C.P.-May 1982 Status Adenoacanthoma Adenocarcinoma NSF Papillary Mixed Adeno Sq Clear Cell Alive DOD* DOD = Dead Of Disease. two had tumors of nuclear Grade 3, and one Grade 2. Four of the non-survivors were judged to be dead of other causes. Although nine of the 11 patients treated by radiation alone were Stage I, none survived for five years, and all but one died of disease. The remaining patient with Stage II disease died nine months later of heart disease. Two patients had palliative treatment only. One of these died of disease at four months and the other lived for 35 months and died of diabetes. Age at time of diagnosis was an important predictor of end results. The ages ranged from 38 to 80 years with a median age of 63 and an average age of 60. Sixteen patients were diagnosed prior to age 60 and 13 of these survived for five years (81.3). All three premenopausal women survived. The racial composition of the female population age 20 and older over the study period, , was 13.1 black. 7 Seven tumors occurred in black women (14.8), and none of these women survived. Six died of their disease and one of other causes. None had Grade 1 tumor and only two had Stage I disease. Twenty-five women had routine cervical or vaginal cell studies within one year of diagnosis, but not more than five days prior to endometrial biopsy or curettage, 11 or 44 were positive. One patient had an inconclusive smear which was not repeated and the others were reported to be negative. Abnormal vaginal bleeding was the first symptom in 43 of the 46 patients. One patient had a record of vaginal discharge not otherwise described. In one patient positive cytology led to the diagnosis, and no symptom was recorded in the remaining patient. Obesity, hypertension, diabetes, and parity are risk factors for endometrial carcinoma. A statement as to the presence or absence of obesity was made in 31 instances, and 16 or 50.6 were obese. Blood pressure was recorded 32 times and 50 had recordings above 150/90. Ten or 25.6 of 39 women were recorded as having diabetes. Forty-two patients had parity recorded; one-third were nulliparous. Pathology Review In the slide review of the 989 cases of endometrial carcinoma, we encountered 90 tumors with a predominantly papillary pattern. Forty-four were classified as CCE and 46 as non-clear cell papillary carcinoma. The majority of the papillary CCE had other patterns, such as solid, tubulocystic or tubuloglandular components. To be included as CCE we utilized the criteria of Kurman and Scully, 16 that at least 50 of the tumor be composed of glycogen-rich clear cells or "hob nail" cells (Fig. 1). The clear cell carcinomas had only a 35.2 survival rate. Forty-four of the papillary tumors had no clear cell component, and two had areas of CCE that made up only a minor portion of the tumor. Both types of papillary carcinoma were frequently associated with the usual glandular pattern of endometrial carcinoma. The papillary pattern and absence of a major clear cell component provided the basis for classification as papillary carcinoma. The cells were supported by a central stalk with multiple arborizations. The stalk contained endometrial stromal cells which were at times lipid-laden (Fig. 2). There was often one or more central vessels present which lacked the hyaline change so typical of papillary CCE (Fig. 3). The cells were stratified with innumerable tiny daughter papillae (Fig. 4). Unlike CCE, the cytoplasm was usually lightly basophilic or amphyophilic, rather sparse, and did not contain the FIG. 1 (upper, left). Clear cell carcinoma of the endometrium with papillary pattern. This is shown to compare with papillary carcinoma (non-clear cell) examined in this study. Note the dense fibrous stalk which stains intensely with PAS and is resistent to diastase. Note also the clear cells and irregularly enlarged hyperchromatic nuclei. Hematoxylin and eosin X 197. FIG. 2 (upper, right). Papillary carcinoma. Note the lipid-laden stromal cells in the stalk. Hematoxylin and eosin X 79. FIG. 3 (lower, left). Papillary carcinoma. Note the vasculature in the papillae and the stratification of the covering cells. Hematoxylin and eosin X 79. FlG. 4 (lower, right). Papillary carcinoma. Note the innumerable "daughter" papillae. Hematoxylin and eosin X 79.

4 Vol. 77 No. 5 PAPILLARY ADENOCARCINOMA OF ENDOMETRIUM 537

5 538 CHRISTOPHERSON ET AL. Table 3. Vital Status at Five Years by Grade for 45 Patients* A.J.C.P. May 1982 Hi istologic Grade Nuclear Grade Total Gr. 1 Gr. 2 Gr. 3 Gr. 1 Gr. 2 Gr. 3 Alive DODf DOOCt One additional patient with grade 1 tumor is alive at four years. t DOD = Dead of Disease. t DOOC = Dead of Other Causes. PAS positive diastase resistent droplets characteristic of CCE. 6 Tumor within the vascular channel of the stalk was occasionally seen. The cells were always lying free and it was difficult to determine whether or not this was true vascular invasion or an artefact (Fig. 5). Desquamation of the cells was a prominent feature infrequently seen in other types of carcinoma. There was considerable variation in the nuclear morphology. One-half of the tumors had uniformity of nuclei. They were oval-to-round with a fine chromatin pattern and inconspicuous nucleoli. Fifteen percent of the tumors had large irregular nuclei with prominent, irregularly shaped, often multiple nucleoli. Thirty-five percent had nuclei of an intermediate grade with nuclear enlargement, margination of the chromatin and small, rather uniform, nucleoli. Five percent of the tumors had well-formed psammoma bodies in the curettage. Three additional specimens had psammoma bodies in peritoneal implants. These were also found in about 15 of the papillary CCE. We have encountered them more frequently in papillary tumors of both types seen in consultation but not included in this population based study. In four patients with local recurrences, the tumor retained its papillary configuration, as it did in peritoneal and omental implants. Discussion FIG. 5. Papillary carcinoma. Note the tumor within the vessel of the stalk. Hematoxylin and eosin X 79. The impact of the subtype of endometrial carcinoma Stage I on prognosis is shown in Table 4. Since we consider "secretory carcinoma" a variant of adenocarcinoma and since it has a good prognosis, it is included with adenocarcinoma NSF for purposes of comparing survival rates. Non-clear cell papillary carcinoma while being less aggressive than CCE or mixed adenosquamous carcinoma has a significantly worse prognosis than does non-papillary adenocarcinoma or adenoacanthoma. Even though it is not included as a subtype of endometrial carcinoma in the World Health Organization Histologic Typing of Female Genital Tract Tumors, 21 we believe it should be, based on its distinctive morphology and its clinical behavior. Prior analysis of endometrial carcinoma in our registry indicates important clinical prognosticators to include: age at diagnosis, race, and extent of disease. 5-7 Our current studies on pathologic determinants of prognosis are in agreement with other studies of these parameters. 2 ' 3 "' 1315 The cytologic grade of the tumor proved to be a better prognosticator than did histologic grade. This was true also for CCE. The W.H.O. grading system which is based on morphology did, however, prove to be an accurate determinant of survival for the usual type of endometrial adenocarcinoma. In comparison to CCE,

6 vol. 77-No. 5 PAPILLARY ADENOCARCINOMA OF ENDOMETRIUM 539 Table 4. Vital Status at Five Years Stage I Cases () Adeno- Mixed Adeno- carcinoma Adeno Clear Status acanthoma* NSFf Papillary^ Sq Cell" Alive DODH patients, one lost to follow-up. t No specific features, 501 patients, two lost to follow-up. X 34 patients, none lost to follow-up. 49 patients, none lost to follow-up. " 43 patients, none lost to follow-up. II DOD» Dead of Disease. where Grade 1 tumors comprised only about 11, almost one-half of the non-clear cell papillary carcinomas were Grade 1. Tumors that were Grade 2 comprised 37 for CCE and 36 for papillary carcinoma. Grade 3 tumors were 52 and 15 respectively. Papillary carcinoma of the endometrium has long been recognized as a morphologic variant of endometrial adenocarcinoma. Cullen illustrated it in Essentially all of the cases in this report were so designated by the pathologist making the original diagnosis. There have, however, been relatively few reports of papillary carcinoma in the literature. 410 ' ' 23 Some authors noted that the tumor type is more aggressive The papillary pattern was the most common one in our study of 56 cases of CCE. Since psammoma bodies were more frequent in the papillary CCE, one cannot help but wonder if at least some of the papillary carcinomas that have been reported are not examples of papillary CCE. Recently Hendrickson and colleagues 14 reported on what they term "uterine papillary serous carcinoma", because of the resemblence to ovarian papillary serous carcinoma. These authors found that 26 cases of such tumors accounted for 50 of treatment failures in a group of 256 cases of Stage 1 uterine adenocarcinoma treated at Stanford University. They noted that their papillary carcinoma had a high degree of cytologic anaplasia, and a significantly poorer prognosis than nonpapillary Grade 3 tumors. It is not entirely clear from the abstract of that study whether or not papillary CCE was included. By following the rules for staging of corpus cancer as published by the A.J.C. 1 it is quite likely that some cases not treated by primary hysterectomy or cases without adequate cervix sampling were understaged. This could account in part for the dismal results obtained in those cases treated by radiation without subsequent hysterectomy. Six of the 11 patients so treated did have cervical sampling and four of these were Stage II tumors. The remaining five without proof of cervix involvement, by the rules of staging, had to be considered as Stage I. Treatment by radiation only is apparently much less frequently utilized now than in the past since only one patient in this study was so treated after Radiation only was successful in achieving a survival rate of about 38 at five years for adenocarcinoma NSF. However, an inordinately large number of patients so treated died of their disease (30). Radiation alone does not appear to be an acceptable treatment for papillary carcinoma of the endometrium. The depth of myometrial invasion has been found to be an important prognosticator for endometrial carcinoma. 19 This was confirmed in our analysis of 294 patients with endometrial carcinoma NSF treated by hysterectomy alone, as well as in 339 patients irradiated prior to hysterectomy. 8 Data from the current study contributed little to this parameter because of the small number of cases available for evaluation. In conclusion it seems evident that the pathologic subtype and tumor grade are important determinants of the course of disease of endometrial carcinoma. Nonclear cell papillary carcinoma is in a mid-position in relation to prognosis. Adenoacanthoma and adenocarcinoma NSF have a more favorable outlook, while mixed adenosquamous carcinoma and CCE have a considerably less favorable prognosis. Acknowledgments. The following pathologists collaborated in the study by furnishing slides and, at times, tissue blocks for the review as well as by supplying additional information. We should like to thank them for their participation and cooperation: John D. Allen, Jr., M.D., and Edward T. Arnn, M:D., Louisville Baptist Hospitals; Lawrence H. Boram, M.D., Robert S. Howell, Sr., M.D., Lynn L. Ogden, M.D., and Frank T. Serratoni, M.D., Jewish Hospital; Edward L. Callahan, M.D., and Thomas S. Hutsell, M.D., SS. Mary and Elizabeth Hospital; Robert Carnighan, M.D., Jerry N. Clanton, M.D., Frederick K. Cressman, M.D., Cyrus Ghazi, M.D., Robert I. Lerman; M.D., and Anne C. D. Richman, M.D., St. Joseph Infirmary, Suburban Hospital, Audubon Hospital and Southwest Jefferson Community Hospital; Herbert Dickstein, M.D., Laszlo Makk, M.D., and Robert W. Morrissey, M.D., St. Anthony Hospital; Darwin K. Edwards, M.D., and Charles T. Lucas, M.D., Methodist-Evangelical Hospital; and, Ryland Byrd, M.D. and James G. Kuhns, M.D., Norton and Kosair-Children's Hospital. Mrs. Carrie Dean and Mrs. Lucille Chan were largely responsible for the excellent patient follow-up. References 1. American Joint Committee for Cancer Staging and End Results Reporting: Manual for Staging of Cancer. Chicago, American Joint Committee, 1977, p Annual Report on the Results of Treatment of Gynecologic Cancer, vol. 17, Stockholm, Radiumhemmet, p 45

7 540 CHRISTOPHERSON ET AL. A.J.C.P. May Boutselis JG: Endometrial carcinoma: Prognostic factors and treatment. Surg Clin North Am 1978; 58: Cefis F, Carinelli SG, Marzi MM, Senzani F: Endometrial adenocarcinoma with psammoma bodies. Tumori 1979; 65: Christopherson WM: Changing trends in morbidity and mortality in endometrial carcinoma. In: Endometrial Carcinoma and Its Treatment. Gray LA, Sr, ed. Springfield, Charles C Thomas, 1977, pp Christopherson WM, Alberhasky RC, Connelly PJ: Carcinoma of the endometrium. I. A clinical pathological study of clear cell carcinoma and secretory carcinoma. Cancer (In press) 7. Christopherson WM, Nealon NA: Uterine cancer: A comparative study of black and white women. In: Cancer Among Black Populations. Mettlin C, Murphy GP, eds. New York, Alan R Liss, 1981, pp Connelly PJ, Alberhasky RC, Christopherson WM: Adenocarcinoma of the endometrium: An analysis of 865 cases. (In preparation) 9. Cullen TS: Cancer of the Uterus: Its Pathology, Symptomatology, Diagnosis and Treatment. New York, D. Appleton, 1900, p Factor SM: Papillary adenocarcinoma of the endometrium with psammoma bodies. Arch Pathol 1974; 98: Frick HC, Munnell EW, Richart RM, Berger AP, Lawry MF: Carcinoma of the endometrium. Am J Obstet Gynecol 1973; 115: Hameed K, Morgan DA: Papillary adenocarcinoma of the endometrium with psammoma bodies. Histology and fine structure. Cancer 1972; 29: Hendrickson MR, Kempson RL: Surgical pathology of the uterine corpus. WB Saunders, Philadelphia, 1980, pp Henrickson MR, Ross JC, Kempson RL, Eifel PJ, Martinez W: Uterine papillary serous carcinoma. Lab Invest (abstract) 1981; 44:27A, (Abst) 15. Homesley HD, Boronow RC, Lewis JL: Stage II endometrial adenocarcinoma. Obstet Gynecol 1977; 49: Kurman RJ, Scully RE: Clear cell carcinoma of the endometrium: An analysis of 21 cases. Cancer 1976; 37: LiVolsi VA: Adenocarcinoma of the endometrium with psammoma bodies. Obstet Gynecol 1977; 50: Lundin FE Jr, Christopherson WM, Mendez WM, Parker JE: Morbidity from cervical cancer: Effects of cervical cytology and socio-economic factors. J Natl Cancer Inst 1965; 35: Ng ABP, Reagan JW: Incidence and prognosis of endometrial carcinoma by histologic grade and extent. Obstet Gynecol 1970; 35: Photopulos GJ, Carney CN, Edelman DA, Hughes RR, Fowler WC, Walton LA: Clear cell carcinoma of the endometrium. Cancer 1979;43: Poulsen HE, Taylor CW, Sobin LH: Histologic typing of female genital tract tumors. International Histologic Classification of Tumors. World Health Organization, Geneva, Silverberg SG, DeGiorgi LS: Clear cell carcinoma of the endometrium: Clinical, pathological and ultrastructural findings. Cancer 1973; 31: Spjut, HG, Kaufman RH, Carrig SS: Psammoma bodies in the cervico-vaginal smear. Acta Cytol 1964; 8: Erratum The article "Cellular Localization of Estrogen Binding Sites in Human Breast Cancer", which appeared in the April 1982 issue, contained an error. Figures 1-3 on p. 392 were not presented in the proper orientation. Rotation of the figures 90 to the right and the following adjustments to the legends are necessary: FIG. 1. This is an infiltrating duct carcinoma stained with the tracer estrogen. This area illustrates the variation in the intensity of fluorescence from ++ in the upper half to + in the lower half of the picture. X100 FlG. 2. At higher magnification X400 positive staining appears as fine granular green fluorescence of the cytoplasm around the negatively staining nucleus. FIG. 3A and B. This compares the hematoxylin and eosin section (a) and the fluorescence staining (b) of a solid infiltrating duct carcinoma which is formed by a heterogeneous population of ER positive (++ intensity) and negative cells. X250