Arch Gynecol Obstet DOI 10.1007/s00404-014-3609-6

GYNECOLOGIC ONCOLOGY

Tumor size is an independent predictor of lymph node metastasis and survival in early stage endometrioid endometrial cancer Haider Mahdi • Adnan R. Munkarah • Rouba Ali-Fehmi • Jessica Woessner • Shetal N. Shah • Mehdi Moslemi-Kebria

Received: 21 November 2014 / Accepted: 22 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Objective(s) To analyze the impact of tumor size (TS) on risk of lymph node metastasis (PLN) and prognosis in endometrioid endometrial cancer grossly confined to the uterus (EEC). Method(s) Patients with EEC grossly confined to the uterus were identified from Surveillance, Epidemiology, and End Results dataset from 1988 to 2007. Only surgically treated patients were included. TS was analyzed as a continuous and categorical variable (TS B 2 cm, [2–5 cm and [5 cm). Multivariable logistic regression and Cox proportional hazards models were used. Result(s) 19,692 patients met the inclusion criteria. In patients with TS B 2 cm, only 2.7 % (88/3,244) had PLN; this increased to 5.8 % (372/6,355) with TS [ 2–5 cm and 11.1 % (195/1,745) with TS [ 5 cm. The odds of PLN increased by 14 % for each 1 cm increase in TS after controlling for age, race, depth of myometrial invasion and grade (HR 1.14, 95 % CI 1.10–1.19, p \ 0.001). Further,

TS was an independent predictor of disease-specific survival (DSS) even after adjusting for age, race, grade, depth of myometrial invasion, lymph node status and adjuvant radiation therapy (HR 1.13 for each 1 cm increment in TS, 95 % 1.08–1.18, p \ 0.001). In multivariable analysis, larger TS ([5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31–3.35, p = 0.002); however, there was no significant difference between TS [ 2–5 cm versus B2 cm (HR 1.25, 95 % 0.85–1.83, p = 0.25). The impact of TS remained significant on DSS in subset of patients who underwent lymphadenectomy with negative lymph nodes. Conclusion(s) TS was an independent predictor of lymph node metastasis and disease-specific survival in patients with EEC grossly confined to the uterus. Tumor[5 cm was a predictor of disease-specific survival but no difference in outcome was noted between tumor [2–5 cm and tumor B2 cm. Keywords Stage I
Endometrioid endometrial cancer
Tumor size
Lymph node metastasis
Survival

H. Mahdi (&)
J. Woessner
M. Moslemi-Kebria Gynecologic Oncology Division, Ob/Gyn and Women’s Health Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA e-mail: [email protected]; [email protected] A. R. Munkarah Department of Women’s Health Services, Henry Ford Health System, Detroit, MI, USA R. Ali-Fehmi Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA S. N. Shah Department of Radiology, Cleveland Clinic, Cleveland, OH, USA

Introduction Endometrial cancer is the most common gynecologic malignancy in the United States. According to the latest statistics from the National Cancer Institute, it is estimated that 47,130 women will be diagnosed with endometrial cancer and 8,010 will die of the disease in 2012 [1]. Histology, grade and depth of invasion are well-known prognostic factors and predictors of extra-uterine spread [2–4]. The prognostic significance of tumor size is well acknowledged in many solid malignancies such as cervical, breast, and renal cancers [5–8]. In endometrial cancer,

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tumor size was first reported as a prognostic factor in 1960s by Gusberg et al. [9] who used uterine size as a surrogate to tumor size. Since then, many investigators have addressed the prognostic significance of tumor size with conflicting conclusions. Some have reported a significant correlation between tumor size and lymph node metastasis and survival [4, 10, 11] and have accordingly suggested the routine use of tumor size as an adjunct to identify low risk endometrial cancer patients [12]. In contrast, others have disputed such a correlation [13, 14]. Furthermore, tumor size in endometrial cancer is not a part of the FIGO staging system [15]. In a recent survey of the society of gynecologic oncology members, Soliman et al. [16] reported on the factors that were thought to be important in prompting the surgeons to perform lymphadenectomy for endometrial cancer. Interestingly, there was no consideration of tumor size in that survey [16]. The advantage of using tumor size is based on the fact that it is readily discernible and does not require extra resources or an experienced pathologist. On the other hand, intra-operative evaluation of other prognostic factors such as grade and myometrial invasion requires a well-trained pathologist, which is resource intensive and can vary depending on frozen or paraffin sections [17, 18]. The objectives of this study are to evaluate the relationship between tumor size and lymph node metastasis and prognosis in patients diagnosed with endometrioid endometrial adenocarcinoma (EEC) grossly confined to the uterus using the population database of the Surveillance, Epidemiology and End Results (SEER) program.

Methods Women with a diagnosis of endometrioid endometrial adenocarcinoma grossly confined to the uterus were identified using SEER data from 1988 to 2007 (n = 53,514) [19]. The inclusion criteria were: having hysterectomy with or without lymphadenectomy, disease grossly confined to the uterus, endometrioid histology, active follow-up, known age and tumor size. Patients were excluded if they were not surgically treated with at least hysterectomy (3,443), or have unknown tumor size (23,622). Other exclusion criteria were unknown status of lymph node dissection, pre-operative/intra-operative or unknown radiation therapy, and a diagnosis by autopsy or death certificate. The SEER database provides information on the disease stage based on clinical, intraoperative, and pathological findings sufficient to give a fair estimation of the disease extent. In this study, we labeled patients as having stage I disease if they have undergone surgical treatment with intra-operative and pathologic findings, suggesting that the disease is confined to the uterus according to FIGO 2009

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criteria without incorporation of lymph node status as previously reported [20–22]. Patients were classified as having: (1) low risk EEC if the tumor was grade I or II and no or \50 % myometrial invasion; (2) high risk EEC if tumor was grade III/IV or C50 % myometrial invasion. The SEER data report the largest dimension of tumor as reflected in the pathology report in the mother institution where the patient had her hysterectomy. Demographic, clinicopathologic, treatment, and survival information was extracted using the ‘‘Case Listing’’ option of the SEER Stat software. Tumor Size (TS) was analyzed as a categorical variable (TS B 2 cm and[2–5 cm and[5 cm) as well as a continuous variable with 1 cm increment. Associations between categorical and continuous covariates were assessed using Chi Square and student t tests. Survival comparisons were estimated using the Kaplan–Meier method and long rank statistics. Multivariate logistic regression models that include age, race, depth of myometrial invasion and grade were used to determine the association between tumor size and lymph node metastasis limited to those who had lymphadenectomy. All odd ratio values reported are based on multivariate models. Cancer-specific survival was examined using Cox proportional hazard models adjusting for age, race, depth of myometrial invasion, grade, lymph node status [no lymphadenectomy, lymphadenectomy with negative lymph nodes and lymphadenectomy with positive lymph nodes (PLN)] and adjuvant radiation therapy. Further, subset analysis was performed to assess the prognostic impact of tumor size in those who underwent lymphadenectomy with negative lymph nodes (9,840 patients). A p value of \0.05 was considered statistically significant. STATA 10.0 program (College Station, TX) was used for the data analysis.

Results 19,692 patients met the inclusion criteria. Mean age was 62 years. Lymphadenectomy was performed in 57.6 % (11,344/19,692) of the entire cohort. Larger tumor was associated deep myometrial invasion and high grade disease. Patients’ characteristics are listed in Table 1. Disease grossly confined to the uterus Among those who underwent lymphadenectomy, 5.8 % (655/11,344) had PLN. Lymph node metastasis was documented in 2.7 % (88/3,244) with TS B 2 cm; this increased to 5.8 % (372/6,355) and 11.1 % (195/1,745) with TS [ 2–5 cm and TS [ 5 cm, respectively. The correlation between tumor size and lymph node metastasis is illustrated in Fig. 1.

Arch Gynecol Obstet Table 1 Clinical and pathologic characteristics of patients diagnosed with endometrioid adenocarcinoma grossly confined to the uterus (n = 19,692) Variable

Overall (%) N = 19,692

Tumor size B2 cm (%) N = 6,954

Tumor size [2–5 cm (%) N = 10,173

Tumor size [5 cm (%) N = 2,565

p value

\0.001

Age Mean

62.1

60.8

63.1

61.2

\65 C65

12,280 (62.4) 7,412 (37.6)

4,640 (66.72) 2,314 (33.28)

5,995 (58.93) 4,178 (41.07)

1,645 (64.13) 920 (35.87)

Race White

17,130 (87.0)

6,110 (87.86)

8,912 (87.60)

2,108 (82.18)

African American

987 (5.0)

309 (4.44)

476 (4.68)

202 (7.88)

Asian

1,575 (8.0)

535 (7.69)

785 (7.72)

255 (9.94)

\0.001

Depth of myometrial invasion No or \50 %

14,660 (80.71)

4,720 (92.53)

7,774 (78.66)

2,166 (68.13)

C50 %

3,503 (19.29)

381 (7.47)

2,109 (21.34)

1,013 (31.87)

\0.001

Grade Low grade (1 and 2)

15,837 (80.4)

5,955 (85.63)

8,028 (78.91)

1,854 (72.28)

High grade (3 and 4)

2,667 (13.6)

599 (8.61)

1,552 (15.26)

516 (20.12)

Unknown

1,188 (6.00)

400 (5.75)

593 (5.83)

195 (7.60)

\0.001

Lymphadenectomy Yes No Lymph node metastasis

11,344 (57.6)

3,244 (46.65)

6,355 (62.47)

1,745 (68.03)

8,348 (42.4)

3,7110 (53.35)

3,818 (37.53)

820 (31.97)

Negative

10,689 (94.2)

3,156 (97.29)

5,983 (94.15)

1,550 (88.83)

Positive

655 (5.8)

88 (2.71)

372 (5.85)

195 (11.17)

\0.001

\0.001

Radiation therapy No

15,389 (78.2)

6,092 (87.60)

7,609 (74.80)

1,688 (65.81)

Yes

4,303 (21.8)

862 (12.40)

2,564 (25.20)

877 (34.19)

\0.001

Vital status Alive

17,408 (88.4)

6,336 (91.11)

8,910 (87.58)

2,162 (84.29)

Dead

2,284 (11.6)

618 (8.89)

1,263 (12.42)

403 (15.71)

In multivariate model, larger tumor ([2–5 cm and [5 cm compared to B2 cm) was significantly associated with higher likelihood of PLN (OR 1.41; 95 % CI 1.05–1.90, p = 0.022, OR 2.21, 95 % CI 1.61–3.04, p \ 0.001, respectively). Furthermore, the likelihood of PLN increased by 14 % with each 1 cm increase in TS (OR 1.14; 95 % CI 1.10–1.19, p \ 0.001). The rate and odd ratios of lymph node involvement using different cutoffs for TS stratified by grade/depth of invasion are illustrated in Tables 2 and 3. When stratified by grade and tumor size only, the rate of PLN increased from 4.0 % (289/7,306) in patients with low grade disease (I–II) and small tumor (B5 cm) to 10 % in patients with high grade (III–IV) disease or large tumor [5 cm (p \ 0.001). Similarly when 2 cm was used as cutoff, the rate of PLN increased from 2.4 % (63/2,597) in patients with low grade disease and small tumor B2 cm to 6.8 % (588/8,565) in patients with high grade disease or large tumor [2 cm (p \ 0.001).

\0.001

Kaplan–Meier (KM) analysis demonstrated that patients with TS [ 2–5 cm (p \ 0.001) and[5 cm (p \ 0.001) had significantly worse disease-specific survival (DSS) compared to those with TS B 2 cm (Fig. 2). In a multivariate cox proportional hazard model, tumor size was an independent predictor of DSS with hazard of death of 1.13 for each 1 cm increment (95 % CI 1.08–1.18, p \ 0.001). When analyzed as a categorical variable, larger TS ([5 cm) was significantly associated with worse DSS (HR 2.06, 95 % 1.52–2.77, p \ 0.001), however, there was no significant difference between TS [ 2–5 cm versus B2 cm (HR 1.29, 95 % 0.98–1.70, p = 0.063). In subset analysis including only patients who underwent lymphadenectomy with negative nodes, tumor size continued to be a significant predictor of disease-specific survival in multivariate analysis with hazard of death of 1.12 for each 1 cm increment (95 % CI 1.05–1.19, p \ 0.001). Further, larger TS ([5 cm) was significantly associated with worse DSS (HR 1.94, 95 % 1.31–2.87,

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** Adjusted for age and race

* Adjusted for age, race and grade and depth of myometrial invasion

2.34 (1.28–4.27) 0.005

2.64 (1.73–4.01) \0.001

3.71 (1.88–7.30) \0.001 25.0 % (15/60) 3.58 (0.77–16.56) 0.103 4.08 % (2/49) 5.23 (2.85–9.58) \0.001 14.05 % (17/121) C10

15.75 % (20/127)

16.67 % (74/444)

3.0 % (3/100)

3.04 (0.85–10.83) 0.085

3.94 % (13/330)

9.88 % (24/243) 8–9.99

3.58 (2.15–5.97) \0.001

10.69 % (90/842) 6–7.99

4.01 (2.85–5.63) \0.001

3.67 (1.76–7.67) 0.001

2.10 (1.44-3.05) \0.001 13.56 % (161/1,187) 3.40 % (44/1,293) 8.0 % (213/2,655) 4–5.99

2.95 (2.20–3.95) \0.001

3.11 (1.75–5.51) \0.001

1.30 (0.90–1.90) 0.158

1 7.0 % (38/543)

8.90 % (143/1,606) 1.43 (0.81–2.52) 0.217

1 1.0 % (17/11,682)

1.61 % (43/2,666)

1

4.14 % (190/4,586)

OR (95 % CI) p value** High risk stage I OR (95 % CI) p value** Low risk stage I OR (95 % CI) p value*

1.50 (1.12–2.02) 0.007

2.50 % (61/2,438)

2–3.99

The rate of lymph node involvement was 2.0 % (121/ 6,047). PLN was documented in 1.0 % (23/2,136) of patients with TS B 2 cm; this increased to 2.3 % (75/ 3,261) in patients with TS [ 2–5 cm and 3.5 % (23/650) in patients with TS [ 5 cm. Larger TS ([2–5 cm and [5 cm compared to B2 cm) was significantly correlated with higher likelihood of PLN (OR 2.15; 95 % CI 1.34–3.44, p = 0.001, OR 3.38, 95 % CI 1.87–6.08, p \ 0.001, respectively) when adjusting for

0–1.99

Low risk EEC (grade I or II and no or \50 % myometrial invasion)

Stage I

p = 0.001), however, there was no significant difference between TS [ 2–5 cm versus B2 cm (HR 1.31, 95 % 0.95–1.82, p = 0.097).

Tumor size (cm)

Fig. 1 a The prevalence of nodal metastasis based on tumor size in patients with endometrioid endometrial cancer (EEC) grossly confined to the uterus (p \ 0.001), low risk EEC grossly confined to the uterus (p \ 0.001), and high risk EEC grossly confined to the uterus (p \ 0.001). b The prevalence of nodal metastasis based on tumor size in patients with endometrioid endometrial cancer with grade I, II and III disease

Table 2 Relation between tumor size and lymph node metastasis stratified by risk factors in patients with endometrioid adenocarcinoma grossly confined to the uterus

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Arch Gynecol Obstet Table 3 Relationship between tumor size and lymph node metastasis stratified by grade and depth of invasion in patients with endometrioid adenocarcinoma grossly confined to the uterus Tumor size (cm)

Grade I no invasion % (n)

Grade I \50 % invasion % (n)

Grade I C50 % invasion % (n)

Grade II no invasion

Grade II \50 % invasion

Grade II C50 % invasion

0–0.99

0 (0/289)

0.4 (1/255)

5.6 (1/18)

0.7 (1/132)

3.6 (6/165)

1–1.99

0 (0/265)

0.7 (3/425)

7.2 (7/97)

1.8 (3/164)

2.0 (9/441)

2.0–2.99

0 (0/222)

1.2 (6/512)

6.2 (9/146)

0 (0/149)

3.0–3.99 0.8 (1/132)

1.5 (6/410)

5.8 (8/138)

1.0 (1/104)

4.0–4.99 2.4 (2/82)

2.6 (6/228)

8.3 (10/121)

5.9 (3/51)

4.7 (14/295)

16 (30/189)

0 (0/12)

9.9 (16/162)

22 (31/141)

5.0–5.99

0 (0/26)

0.8 (1/122)

19 (14/75)

4.0 (1/25)

6.9 (9/130)

12 (12/104)

0 (0/5)

9.2 (6/65)

24 (19/78)

C6

0 (0/39)

4.3 (6/141)

15 (12/82)

6.3 (1/16)

3.3 (5/151)

20 (22/111)

11 (1/9)

8.3 (8/96)

25 (28/114)

age and race. Furthermore, the likelihood of PLN increased by 22 % with each 1 cm increase in TS when controlling for age and race (OR 1.22; 95 % CI 1.14–1.31, p \ 0.001). In a multivariate cox proportional hazard model including age, race, lymph node status and adjuvant radiation therapy, tumor size was an independent prognostic factor of DSS with hazard of death of 1.15 for each 1 cm increment (95 % CI 1.06–1.24, p \ 0.001). When analyzed as a categorical variable using two cutoffs ([2–5 cm and [5 cm compared to B2 cm), larger TS ([5 cm) was significantly associated with worse DSS (HR 2.09, 95 % 1.31–3.35, p = 0.002), however, there was no significant difference between TS [ 2–5 cm versus B2 cm (HR 1.25, 95 % 0.85–1.83, p = 0.25). In subset analysis including only patients who underwent lymphadenectomy with negative nodes, tumor size was also a significant predictor of DSS when adjusting for age, race and adjuvant radiation therapy with hazard of death of 1.15 for each 1 cm increment in TS (95 % CI 1.02–1.28, p = 0.013). Further, larger TS ([5 cm) was significantly associated with worse disease-specific survival (HR 2.15, 95 % 1.02–2.68, p = 0.043), however, there was no significant difference between TS [ 2–5 cm versus B2 cm (HR 1.59, 95 % 0.94–12.68, p = 0.079).

Grade III no invasion

Grade III \50 % invasion

Grade III C50 % invasion

10 (4/40)

0 (0/40)

7.7 (6/78)

10 (1/10)

14 (20/140)

0 (0/50)

3.7 (7/188)

10 (6/60)

2.6 (16/610)

13 (34/253)

1.9 (1/53)

3.3 (8/244)

18 (21/118)

4.3 (20/466)

15 (37/250)

8.8 (3/34)

4.0 (9/226)

17 (29/170)

adjusting for age and race. Furthermore, the likelihood of PLN increased by 16 % with each 1 cm increase in tumor size when controlling for age and race (OR 1.16; 95 % CI 1.11–1.21). In a multivariate cox proportional hazard model including age, race, lymph node status and adjuvant radiation therapy, tumor size was an independent predictor of disease-specific survival with hazard of death of 1.14 for each 1 cm increment (95 % CI 1.08–1.20, p \ 0.001). When analyzed as a categorical variable, larger tumor size ([2–5 cm, [5 cm compared to B2 cm) was significantly associated with worse DSS (HR 1.55, 95 % 1.02–2.35, p = 0.037, HR 2.45, 95 % CI 1.59–3.78, p \ 0.001, respectively). In subset analysis including only patients who underwent lymphadenectomy with negative nodes, tumor size continued to be a significant predictor of DSS when adjusting for age, race, grade, depth of myometrial invasion and adjuvant radiation therapy with hazard of death of 1.15 for each 1 cm increment (95 % CI 1.07–1.22, p \ 0.001). Further, larger tumor ([5 cm) was significantly associated with worse disease-specific survival (HR 2.36, 95 % 1.51–3.69, p \ 0.001). However, there was no significant difference between TS [ 2–5 cm versus B2 cm (HR 1.35, 95 % 0.90–2.03, p = 0.14).

High risk EEC (grade 3 or 4 or [ 50 % depth of invasion with any grade) Discussion The rate of lymph node involvement was 11.5 % (466/ 4,054). PLN was documented in 7.1 % (55/772) of patients with TS B 2 cm; this increased to 10.9 % (269/2,446) in patients with TS [ 2–5 cm and 16.9 % (142/836) in patients with TS [ 5 cm. Larger tumor ([2–5 cm and [5 cm compared to B2 cm) was significantly correlated with the likelihood of PLN (OR 1.64; 95 % CI 1.21–2.22, p = 0.001, OR 2.66, 95 % CI 1.91–3.69, p \ 0.001, respectively) when

In this large population-based study, we confirm that tumor size is an independent predictor of lymph node metastasis and survival in endometrioid endometrial cancer. Lymph node metastasis was seen in 2.7 % for patients with tumors B2 cm. This risk was increased to 11 % for patients with tumor [5 cm. Compared to other well-known prognostic factors in endometrial cancer, tumor size is an inexpensive, and limited resource tool that can be easily assessed at the

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Fig. 2 Kaplan–Meier curves for disease-specific survival based on tumor size in a patients with endometrioid endometrial cancer (EEC) grossly confined to the uterus (p \ 0.001), b low risk EEC grossly confined to the uterus (p \ 0.001), and c high risk EEC grossly confined to the uterus (p \ 0.001)

time of surgery. One of the limitations of using tumor size in endometrial cancer is the difficulty in defining the borders of the lesion when the tumor is diffuse involving more that one side of the uterine wall with a surface spreading pattern rather than a polypoid pattern.

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Tumor size has not been universally utilized in risk stratification of endometrial cancer. Prior single institutional studies have shown that tumor size has significant correlation with lymph node metastasis with negligible risk among low risk patients with tumor diameter B2 cm [4, 10, 12]. The correlation between tumor size and prognosis in endometrial cancer has yielded mutually controversial results [4, 13, 14]. Schink et al. [4] showed a significant decrease in 5-year survival among patients with clinical stage I disease with tumor [2 cm compared to those with tumor B2 cm. On the other hand, Lurain and Shah et al. [13, 14] found no significant effect of tumor size on tumor recurrence or survival. The current study shows a significant difference in survival based on tumor size with significant increase in the risk of death in patients with large tumor size even in patients with no nodal disease. These findings in this study support the intra-operative use of tumor size along with grade and depth of invasion as an adjunct to stratify patients into risk categories and to guide the extent of surgical staging decision. Mariani et al. [23] have shown that intra-operative assessment of tumor size is reliable and strongly correlates with final assessment in paraffin sections. We performed sub-analysis looking at the rate of lymph node involvement based on tumor size and tumor grade regardless of depth of invasion. Patients with low grade small size tumor were less likely to have positive nodes compared to those with high grade or large tumors (4 versus 10 %, respectively). In a prior study investigating the role of pre-operative tumor grade and tumor size, only 0.6 % patients with low grade disease and intra-operative tumor size B2 cm had lymph node metastasis [24]. Thus, one can rely on tumor grade from preoperative biopsy and tumor size alone in planning the extent of surgery in situations where frozen section is not available at the time of surgery. This study was intended to delineate the relation between tumor size and risk of lymph node metastasis with no intention to determine a better categorical cutoff or validate currently used cutoff by other studies. Interestingly, the impact of tumor size on risk of lymph node metastasis and survival seems to have linear correlation with progressive increase in risk of lymph node metastasis and death with larger tumors making finding a single cutoff difficult. The large sample size allowed us to provide detailed information about risk of lymph node metastasis with each 1 cm increase in tumor size stratified by grade and depth of myometrial invasion. This information is very helpful when counseling patients who underwent surgical treatment with no surgical staging about their risk of lymph node metastasis. This study suffers from certain limitations that include lack of information regarding central pathology review, surgeon subspecialty, medical co-morbidities, use of

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adjuvant chemotherapy and date and treatment of recurrences. Information regarding tumor size was not available in significant number of patients who met the inclusion criteria. Similarly, using historic data extracted from GOG LAP2 study, a significant number of patients with endometrial cancer had missing tumor size information [25]. Furthermore, lymphadenectomy was not performed in 42 % and the extent of lymphadenectomy was not adjusted for. The impact of tumor size in other solid cancers has been reported using SEER data [7, 8, 26]. The strength of large numbers in this study allowed us to assess the impact of tumor size in certain subgroups of patients based on risk categories. In conclusion, our data suggest that tumor size is an independent predictor of lymph node metastasis and survival in endometrioid endometrial cancer grossly confined to the uterus. Patients with small tumor size, low grade and no or superficial invasion have only minimal risk of nodal metastasis. Our data support the use of tumor size as an inexpensive adjunct to guide the intra-operative surgical staging decision especially in situations where access to reliable frozen section is limited. The lack of tumor size assessment in many databases and by many centers is concerning. Many believe that we do not currently have a uniform method of assessing tumor size in endometrial cancer. Should the largest dimension be measured? Should the size become the product of two dimensions? This is an important question that needs to be answered if all gynecologic surgeons are to use this parameter uniformly in planning the extent of surgical staging. Future prospective studies are needed to validate the prognostic impact of tumor size and its relation to risk of disease recurrence and death.

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19. Conflict of interest of interest.

The authors declare that there are no conflicts

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