Surgical Pathologic Spread Patterns of Endometrial

A Gynecologic Group Study

WILLIAM T. CREASMAN, MD,* C. PAUL MORROW, MD,t BRIAN N. BUNDY, PHD,$ HOWARD D. HOMESLEY, MD,§ JAMES E. GRAHAM, MD,() AND PAUL B. HELLER, MDlI

The surgical pathologic features of 621 patients with Stage I carcinoma of the endometrium are presented. All patients were treated with primary surgery consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, selective pelvic and paraaortic lymphadenectomy and peritoneal cytol- ogy. An appreciable number of patients (144-2296) with Stage I have disease outside of the uterus (lymph node metastasis, adenexal disease, intraperitoneal spread and/or malignant cells in peritoneal washings). Multiple prognostic factors particularly grade and depth of invasion are related to extrauterine disease. This study adds credence to the primary surgical approach with individualized postoperative therapy as indicated. Cancer 60:2035-2041. 1987.

ANCER OF THE ENDOMETRIUM is the most COm- monly reported absolute 5-year survival of about 75% C mon genital malignancy seen in the US today. for Stage I carcinoma of the end~metrium.~Although all Some studies in the literature would suggest that an ab- are in agreement that simple hysterectomy remains the solute survival of 90% with total abdominal hysterec- preferred therapy, the role of radiation therapy is less tomy and bilateral salpingo-oophorectomy is obtain- well delineated. Some investigators suggest that essen- able.'.2The 1985 Annual Report of FIG0 (International tially all patients with this disease should have some type Federation of Gynecologists and Obstetricians) as well of preoperative radiation, while others choose to give as other series in the literature indicate a more com- postoperative therapy. Still others suggest radiation ther-

Presented at the National Gynecologic Conference, Atlanta, Georgia, September 17-19. 1986. sity, Duke University Medical Center, Hahnemann Medical College/ Supported by the following National Cancer Institute grants: CA Jefferson Medical College/Temple University School of Medicine, 12484, CA 12534. CA 12478. CA 12482, CA 23501, CA 23088, CA University of Rochester Medical Center, Walter Reed Army Medical 37535, CA 13633, CA 15975, CA 13630, CA 37234, CA 16386, CA Center, University of Minnesota Medical School, University of South- 16938, CA 23073, CA 19502, CA 28160, CA 21720, CA 21946. CA em California Medical Center at Los Angeles, University of Missis- 23765. CA 37569. CA 27806, CA 35571, CA 34477, CA 16938, CA sippi Medical Center, Colorado Foundation for Medical Care, Univer- 12483. CA 12476, CA 15977. and the Gynecologic Oncology Group sity of California Medical Center at Los Angeles, University of Miami grant CA I9 189. School of Medicine, The Milton S. Hershey School of Medicine of * Professor, Department of Obstetrics and Gynecology, Director of Pennsylvania State University, Georgetown University Hospital, Uni- Gynecologic Oncology, Duke University Medical Center, Durham, versity of North Carolina School of Medicine, University of Iowa North Carolina. Hospitals and Clinics, University of Texas Health Science Center at t Professor of Obstetrics and Gynecology, Director, Division of Dallas, Indiana University Medical Center, Bowman Gray School of Gynecologic Oncology, University of Southern California Medical Medicine of Wake Forest University, The Albany Medical College of School, Los Angeles, California. Union University, University of California Medical Center at Irvine, $ Associate Group Biostatistician, Gynecologic Oncology Group, Tufts New England Medical Center, Illinois Cancer Council, Univer- Cancer Research Scientist Ill, Roswell Park Memorial Institute, Buf- sity of Pittsburgh School of Medicine, St. Louis University Medical falo. New York. Center, Stanford University Medical Center, State University of New Q Professor, Department of Obstetrics and Gynecology, Section on York Downstate Medical Center, Latter Day Saints Hospital, George Gynecologic Oncology, Bowman Gray School of Medicine of Wake Washington University Medical Center, New York Medical College, Forest University, Winston-Salem, North Carolina. State University of New York at Buffalo, University of Washington 11 Assistant Professor, Department of Obstetrics and Gynecology, Medical Center, University of Texas at Galveston, Hospital of the Rush Medical College, Rush Presbyterian St. Luke's Medical Center, University of Pennsylvania, University of Utah Medical Center, Uni- Chicago. Illinois. versity of Connecticut Medical Center, University of Michigan Medi- 7 Assistant Professor, Department of Obstetrics and Gynecology, cal School, University of Puerto Rico. Jacksonville University Hospi- Uniformed Services, University of Health Sciences, Chief, Gyneco- tal, and University of Kentucky. logic Oncology, Walter Reed Army Hospital, Washington, DC. Address for reprints: COG Headquarters, Suite 1945, 1234 Market The following institutions participated in this study: University of Street, Philadelphia, PA 19107. Alabama at Birmingham, The Oregon Health Sciences Center Univer- Accepted for publication April 30, 1987.

2035 2036 CANCEROctober 15 Supplement 1987 VoI. 60 apy should be used on an individual basis depending vena cava and lower aorta was opened. The fat pad over upon certain prognostic factors determined after review the major vessels beginning at the bifurcation extending of the surgical specimen. This latter approach has been to the proximity of the renal vessels was removed in toto. more recently emphasized as a result of data from a pilot In the pelvis the retroperitoneal spaces were opened and study which identified more precisely the surgical patho- the lymph bearing tissues over the external and com- logic spread patterns of clinical Stage I carcinoma of the mon iliac vessels were removed as well as the lymph endometrium. That study was undertaken by the Gyne- bearing tissue in the obturator fossa above the obturator cologic Oncology Group (GOG) and evaluated 222 pa- nerve. If a suspicious node was identified in any area, it tients with Stage l carcinoma of the uter~s.~’~As a result was removed and frozen section done. If positive for of that study, it was deemed important to verify the metastatis, no further surgery was required in that area. initial impressions with a larger study performed by the A simple abdominal hysterectomy and bilateral sal- entire membership of the COG. Not only would a larger pingo-oophorectomy was performed. study add credence to the initial study if confirmed, but All patients’ surgical material was reviewed to con- would also allow further evaluation of subsets from firm the diagnosis of carcinoma of the endometrium. which the pilot study could not draw conclusions be- The uterus was evaluated for site of the tumor, grade cause of small numbers. This report will deal with the and depth of invasion. A representative slide of tissue surgical pathologic findings and their correlation in this outside of the uterus which contained metastases as well group-wide prospective study. as slides of the primary site were reviewed by the GOG Pathology Committee. The following clinical, surgical, Methods and Materials and pathologic entities were recorded for analysis: size of the uterus (Ia or Ib), histologic type, grade, depth of The study was opened on June 20, 1977 and closed to invasion, lymph node metastases, (site and number), patients with Grade I, Stage I disease on October 8, status of peritoneal cytology, capillary-like space in- 1979 and with closure to all patients on February 5, volvement (CLS), adnexal metastases, location of tumor 1983. Forty-three institutions entered I 180 patients within the uterus, intraperitoneal metastases, and meno- during the approximately 6 study years. Through central pausal status. review of both the pathologic and surgical material, 425 The chi-square test6 was used to determine the signifi- were deemed ineligible. Pathologic evaluation identified cance of each factor to the frequency of positive pelvic 38 patients with cancers that were not endometrial car- and paraaortic nodes. The logistic model’ was employed cinoma, 43 with no invasive disease, and 49 without to simultaneously evaluate the relationship these same adequate material to make an accurate pathologic deter- factors had to the frequency of positive pelvic nodes. mination. Sixteen patients did not have Stage I or occult Stage I1 disease and 20 had prior radiotherapy and 208 patients received less extensive surgery than was pre- Results scribed by the protocol. Fifty-one patients were ex- The distribution of the study parameters are detailed cluded because the central review determined that they in Table 1. Although the difference was small, there had Stage I, Grade 1 disease and were entered after the were more patients with a small uterus (Ia). Seventy- study was closed to such patients. Not included were four percent of the patients had an adenocarcinoma. 134 patients who were identified with occult Stage I1 Twenty-five percent had poorly differentiated lesions disease by positive endocervical curettage. and 41% had significant myometrial invasion (middle or This study evaluated 62 1 patients with clinical Stage I carcinoma of the endometrium who had the following deep). Malignant cells were detected in the peritoneal surgical procedure: total abdominal hysterectomy, bilat- cytology of 12% of the patients. Sixteen percent of pa- tients were found to have disease in the isthmus of the eral salpingo-oophorectomy, selective pelvic and para- uterus. Thirty-four patients (five percent) had metas- aortic lymphadenectomy and the procurement of peri- tases to one or both of the adnexa, 58 patients (nine toneal cytology. Prior to surgery the endocervix was percent) had pelvic node metastases. Only 34 patients evaluated histologically to rule out occult Stage I1 dis- (six percent) had paraaortic node metastasis. Thirty-five ease. No patient had any form of preoperative irradia- patients (six percent) had other extrauterine (intraperi- tion. No patient was excluded if lymphadenectomy was toneal) metastases identified at the time of surgery. Fif- done irrespective of the number of lymph nodes re- teen percent of the patients had capillary-like space in- moved. volvement in the uterine specimen. Surgical Procedures The association of grade of tumor with depth of inva- sion was evaluated (Table 2). In general, the depth of Peritoneal cytology was obtained immediately on invasion increased as the grade became less differen- opening the peritoneal cavity. The peritoneum over the tiated. Seventy-eight percent of the Grade 1 lesions had No. 8 SURGICALPATHOLOGIC SPREAD PATTERNS - Creasman et al. 2037

TABLE1. Surgical-Pathologic Findings TABLE2. Histologic Grade and Depth of Invasion

Patients Grade Depth GI G2 G3 Total Stage IA 346 (56%) Endometrium IB 275 (44%) only 44(24%) 31 (11%) 11 (7%) 86(14%) Histology Superficial 96 (53%) 131 (45%) 54 (35%) 281 (45%) Adenocarcinoma 459 (74%) Middle 22(12%) 69(24%) 24(16%) 115(19%) Adenocanthoma 41 (7%) Deep I8 (10%) 57 (20%) 64 (42%) I39 (22%) Adenosquamous 99 (16%) Others 22 (4%) Total 180(100%) 288(100%) 153(100%) 621 (IOOYo) Grade I Well 180 (29%) 2 Moderate 288 (46%) The frequency of pelvic and paraaortic nodes by the 3 Poor 153 (25%) Myometrial Invasion clinical pathologic factors are displayed in Table 4. Endometrium only 86 (14%) When substage was compared to nodal metastases, 23 of Inner 113 281 (45%) Ia patients (seven percent) had pelvic node metastases. Middle 1/2 115(19%) In Ib patients, twice as many had pelvic node metastases Deep 113 I39 (22%) Peritoneal Cytology as compared to Ia. There were also more Ib patients with Positive 76 (12%) paraaortic node metastases than Ia patients. Negative 545 (88%) Site of Tumor Location Different histologic cell types were not significantly Fundus 524 (84%) correlated with pelvic node metastasis. The “Other” cat- Isthmus 97 (16%) egory which includes papillary and clear cell carcinomas Adnexa Involvement Positive 34 (5%) had more paraaortic node metastasis (18%) than the Negative 587 (95%) adenosquamous carcinoma (nine percent). Patients with Pelvic Node Metastasis adenoacanthoma tumors had zero percent paraaortic Positive 58 (9%) Negative 563 (91%) node metastasis, whereas patients with adenocarci- Aortic Node Metastasis nomas had five percent paraaortic node metastasis. Positive 34 (6%) Grade of tumor was correlated with the frequency of Negative 587 (94%) nodal metastases. Only three percent of well differen- Other Extrauterine Metastasis Positive 35 (6%) tiated tumors had pelvic node metastases. This in- Negative 586 (94%) creased to 18% in poorly differentiated cancers. The Capillary-LikeSpace Involvement same correlation is noted with regards to paraaortic Positive 93 (1 5%) Negative 528 (85%) node metastases. Menopausal status An excellent correlation exists between depth of inva- Premenopause 58 (10%) sion and nodal metastases. Only one percent of patients Postmenopause 549 (90%) (14 patients, status unknown) with endometrial only had metastases to either pelvic or paraaortic nodes. The relative frequency of pelvic node and paraaortic nodes increased to 25% and 17%,respec- endometrial or superficial muscle involvement only. In tively, for deep muscle invasion. contrast, 58% of Grade 3 lesions had mild or deep mus- Seventy-five patients (twelve percent) had positive cle invasion. There were, however, some notable excep- peritoneal cytology. Of patients with malignant cells in tions: eleven patients (seven percent) with Grade 3 le- the peritoneal washings, 25% had evidence of pelvic sions had endometrial invasion only while 18 patients nodal metastases. Thirty-five percent of patients with (ten percent) with Grade 1 tumors had deep myometrial extrauterine disease (adnexa, nodes, or intraperitoneal invasion. disease) had positive washings. Thirty-nine patients (52 Grade of tumor and relationship to size of uterus (Ia percent) with positive washings had no other evidence of and Ib) did not appear to be related. There was no dif- extrauterine disease. ference in grade distribution between Ia and Ib patients. There were a larger number of patients with Ib cancers TABLE3. Relationship of Positive Pelvic Nodes to Aortic Nodes who had deep myometrial invasion than those with Ia Aorta disease (29% versus 17%). Seventy patients (eleven percent) had metastases to Pelvic Negative Positive Total either pelvic and/or paraaortic nodes. Only 22 patients Negative 551 (89%) 12 (2%) 563 (91%) (three percent) had metastases to both the pelvic and Positive 36 (6%) 22 (3%) 58 (9%) paraaortic regions. Twelve patients (two percent) had Total 587 (95%) 34 (5%) 621 (100%) metastasis to the paraaortic nodes only. (Table 3). 2038 CANCEROctober 15 Supplement 1987 Vol. 60

TABLE4. Frequency of Nodal Metastasis Among Risk Factors

Pelvic Aortic

Significance Significance Risk factor No. (%) (p-value) No. (%) (p-value)

Stage = 23 (7%) 1 I (3%) la (N 346) 0.0 1 0.008 Ib (N = 275) 35 (1 3%) 23 (87~) Histology Adenocarcinoma (N = 459) 40 (9%) 21 (5%) 0 (0%) Adenocanthoma (N = 41) 4 (10%) 0.8 0.006 Adenosquamous (N = 99) 12 (12%) 9 (Y%) Others (N = 99) 2 (9%) 4 (I 8%) Grade 1 Well (N = 180) 5 (3%) 3 (2%) 2 Moderate (N = 288) 25 (9%)

Site of tumor location was evaluated with regards to those patients with gross intraperitoneal spread had pos- lymph node metastases. If the fundus only was involved, itive pelvic nodes, whereas only 7% without gross spread eight percent of the patients had pelvic node metastases. had positive pelvic nodes. The relative frequency of pos- This doubles if the lower uterine segment is also in- itive paraaortic nodes for patients with and without in- volved. Only four percent of fundal lesions had metas- traperitoneal spread was 23% and 4%,respectively. tasis to paraaortic nodes while lower segment lesions Capillary-like space involvement with tumor was had over three times the incidence of paraaortic metas- present in 93 patients (15%). Pelvic lymph nodes were tases. positive approximately four times more often when ma- The adnexa were involved in 34 patients (six percent). lignant cells were found in CLS than if absent. This If there was metastasis in the adnexa, 32% of patients relative risk of nodal metastases was approximately six- had pelvic node metastases compared to eight percent fold for paraaortic nodes. with no metastases present. This same ratio is also Menopausal status was not associated with the status present with regard to aortic node metastasis. of either the pelvic or paraaortic nodes. Gross intraperitoneal spread (exclusive of adnexal Grade of tumor and depth of invasion are simulta- metastases) was highly correlated with metastases to neously evaluated for the likelihood of nodal metastases. both pelvic and paraaortic nodes. Fifty-one percent of Although both factors discriminated risk of nodal me- No. 8 SURGICALPATHOLOGIC SPREAD PATTERNS - Creasrnan et al. 2039

TABLE5. Grade, Depth of Invasion and Pelvic Node Metastasis TABLE6. Grade, Depth of Invasion, and Aortic Node Metastasis

Grade Grade

Depth of invasion GI G2 G3 Depth of invasion GI G2 G3

(N = 180) (N = 288) (N = 153) (N = 180) (N = 288) (N = 153) Endometrium only Endometrium only (N = 86) 0 (0%) 1(3%) 0 (0%) (N = 86) 0 (0%) 1(3%) 0 (0%) Inner (N = 281) 3 (3%) 7 (5%) 5 (9%) Inner (N = 281) 1 (1%) 5 (4%) 2 (4%) Middle (N = 115) 0 (070) 6 (990) 1(4%) Middle (N = 1 15) 1(5%) 0 (0%) 0 (0%) Deep (N = 139) 2(11%) 11 (19%) 22 (34%) Deep (N = 139) 1(6%) 8 (14%) 15 (23%)

tastases (i.e.,grade 3 with deep myometrial invasion has Discussion the highest nodal metastases, 34%pelvic nodes and 23% This study, with almost three times the number of paraaortic nodes respectively) depth of invasion was patients, confirms the result of the GOG pilot st~dy.~.~ more influential (Tables 5 and 6).Grades 1 and 3 endo- The two patient populations are relatively similar with metrium-only lesions have no pelvic or paraaortic me- regard to known prognostic factors although there are tastases. Only one patient with a Grade 2 endome- some differences (particularly depth of invasion). There trium-only lesion had nodal metastases. In contrast, two are some small variations but no substantial deviations patients (11 percent) with grade 1 deep invasion had from the initial results. These variations may be due to pelvic node metastases. the fact that in the pilot studies there were four surgeons The substages of FIGO Stage I were evaluated with involved in all surgery, whereas in this study the sur- regard to nodal metastasis. Within Ia and Ib as grade geons probably numbered 50 or more. Therefore, the increases there was a greater chance of having both pel- thoroughness of selective lymphadenectomy may have vic and paraaortic metastases (Table 7). The frequency varied considerably. This may explain the 10% inci- was greater in the Ib category compared to the Ia cate- dence of paraaortic node metastases of patients sampled gory. Clinical stage and grade were correlated with the in the pilot study and the only 6% incidence in the cur- risk of positive pelvic and paraaortic nodes. rent study. The incidence of pelvic node metastases The prognostic factors (Table 4) potentially available ( 10% versus 9% respectively), however, was essentially intraoperatively were subjected to a multivariant analy- the same. sis using the logistic model. Of those factors which were The generally accepted prognostic factors for adeno- available for analysis at the time of surgery, three were carcinoma were evaluated in this study. The frequently independently significant with regard to pelvic lymph used prognostic factors of grade and depth of myome- node metastasis. These factors were grade (P = 0.03), trial invasion were positively correlated (Table 2) (ie.,as depth of invasion (P= 0.0001), and intraperitoneal me- grade becomes less differentiated there is a greater ten- tastasis (P = 0.0001). Using these factors, low, moderate dency for deep invasion). However, exceptions do exist; and high risk categories were formed. The low-risk 9% of Grade 1 lesions have deep muscle invasion while group included patients with grade 1, endometrium- 7% of Grade 3 lesions are limited to the endometrium. only lesion with no intraperitoneal disease. None of the Depth of invasion appears to be more important with 44 patients who satisfied these criteria had lymph node regard to nodal metastases. As the depth of invasion metastasis (Table 8). Moderate-risk factors were defined increases, however, the grade appears to have an in- as having inner or mid muscle invasion and/or Grade 2 creased influence on pelvic node metastases. However, or Grade 3 lesions with no intraperitoneal metastasis. Depending upon whether one or both factors were present, the risk for nodal metastasis was three percent TABLE7. FIGO Staging and Nodal Metastasis and six percent, respectively. In the high-risk category Metastasis two factors were pertinent: deep invasion and intraperi- toneal metastasis. Pelvic lymph node metastasis was Staging Pelvic Aorta found in 18% of patients with deep muscle invasion only 1A GI (N = 101) 2 (2%) 0 (0%) and in 33% with intraperitoneal metastasis only. When G2 (N = 169) 13 (8%) 6 (4%) both high risk factors were present, 6 1% had nodal me- G3 (N = 76) 8 (1 1%) 5 (7%) tastasis. IB GI (N = 79) 3 (4%) 3 (4%) Age and menopausal status had no affect on nodal G2 (N = 119) 12 (10%) 8 (7%) metastasis. G3 (N = 77) 20 (26%) 12 (16%) 2040 CANCEROctober 15 Supplement 1987 Vol. 60

TABLE8. Determination of Risk Factors for Nodal Metastasis lymph node metastasis (by univariant analysis) and Using Multivanant Analysis known preoperatively or intraoperatively. Grade of tumor is known preoperatively and intraperitoneal me- Lymph node metastasis tastasis can be determined at the time of surgery. Depth Risk factor Pelvic Aortic of invasion can usually be ascertained intraoperatively with frozen section analysis. Using these three factors, Low Risk the incidence of lymph node metastasis can be estimated (No moderate or high risk factors) (Table 8). The clinician can then decide whether or not Grade I, endometrium lymph nodes should be removed. There were no pa- only, no intraperitoneal tients with Grade l endometrial-only tumors with pelvic disease 0/44 (0%) 0/44 (0%) or paraaortic node metastasis. Lymphadenectomies Moderate Risk would not appear to be indicated in these patients. (Inner mid invasion, Grade In the moderate-risk category, if Grade 2 or Grade 3 2 or 3-no intraperitoneal disease) tumors or inner or mid-myometrial invasion was Only one factor 4/158 (3%) 3/ 158 (2%) present, four of 158 patients (three percent) had pelvic Both factors 15/268 (6%) 6/268 (2%) node metastases. The frequency of node metastasis for High Risk patients with both Grade 2 or 3 tumors and myometrial (Intrapentoneal disease, invasion (superficial or middle) was 15 of 268 patients deep myometrial (six percent). This could be considered a gray zone as to invasion) Deep invasion only 21/116 (18%) 17/116 (IS%) whether or not pelvic and paraaortic nodes should be Intrapentoneal disease only 4/12 (33%) 1/12 (8%) removed. Some physicians would elect to perform lym- Both 14/23 (61%) 7/23 130%) phadenectomies particularly if two factors are present while others would not. Patients with high-risk factors certainly have a high irrespective of the grade, when only the endometrium is enough risk of lymph node metastases to warrant lym- involved, the risk of nodal metastases is extremely low. phadenectomies. Of the 1 5 1 patients in this group, 1 I6 Therefore, a patient with Grade 3 tumor only may not had deep invasion only and 18% of these had nodal necessarily have a poor prognosis. Conversely, some metastases. Depth of invasion is highly significant in Grade 1 lesions can have extrauterine disease. In our predicting nodal metastasis (P = 0.000 1). Therefore, it study, seven percent of the Grade 3 lesions had endo- appears warranted to ascertain this parameter intraoper- metrium-only involvement and none had nodal metas- atively when there is a question of whether a lympha- tases, whereas nine percent of the Grade 1 lesions had denectomy is indicated. deep muscle involvement and 1 1 % of these patients had An alternative way of looking at risk for nodal metas- pelvic node metastases. Obviously, some patients with tasis intraoperatively is to exclude the cases with obvious Grade I lesions have a potentially worse prognosis (as extrauterine metastasis (intraperitoneal metastasis, gross predicted by lymph node metastases) than some Grade 3 breakthrough of the uterine serosa, and gross adnexal patients. This information can be obtained only with the metastases). This leaves only grade and invasion as risk primary surgical approach and would have a major ther- parameters. In this schema, low risk (4%)have pelvic apeutic impact on the individual patients. It would ap- node involvement associated with absent myometrial pear that some Grade 1 patients may need adjunctive invasion or grade 1 histology with invasion (excluding radiation therapy while all Grade 3 patients may not. clear cell and papillary serous cases). Grade 3, outer 33% In this study, univariant analysis identified seven fac- invasion is high risk (> lo%),and all other cases have a tors that are significantly correlated with nodal metas- moderate risk (5% to 10%)for pelvic node metastasis. tasis (pelvic and paraaortic), with an additional factor Regarding the aortic nodes, all categories are at low risk significantly correlated with paraaortic nodal metastases (<5%) except the Grade 3, outer 33% group which are (Table 4). Using each of these factors in determining high risk. Two groups however, have too few cases to be when lymph nodes should be removed is unrealistic be- confidently categorized: the Grade 3, no invasion (zero cause some factors such as peritoneal cytology status are of nine pelvic or aortic node metastasis) and Grade 1, unknown at the time of the surgery and cannot be part outer 33% (one of 16 had both pelvic and aortic node of the decision-making process. metastasis). Multivariant analysis refined the data and indicated Two points concerning lymphadenectomy should be an approach useful to the clinician. The analysis was stressed: (1) adequate sampling must be done to make restricted to those factors which were predictive of this a worthwhile procedure, 2nd (2), the surgeon should No. 8 SURGICALPATHOLOGIC SPREAD PATTERNS - Creasman et a/. 204 I

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