In 2012, it is estimated that more than 47,000 women will have new diagnosis of endometrial cancer and that more than 8,000 women will succumb to their disease.1 Whereas more than 80% of the newly diagnosed cases of endometrial cancer will be of the endometrioid histologic type, nonendometrioid endometrial carcinomas represent a small, yet important, group of histologic subtypes. The most common subtypes of nonendometrioid endometrial carcinoma are uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (CCC). Uterine papillary serous carcinoma and CCC represent only 2.9% and 2.2% of all endometrial carcinomas, respectively.2 Despite representing a minority of patients, nonendometrioid endometrial carcinomas account for a disproportionate number of endometrial carcinoma recurrences and deaths.3–5 In light of their relative infrequency, risk factors for poor outcome are poorly defined.6,7
Paraneoplastic syndromes represent a collection of signs and symptoms that are not directly caused by the primary or metastatic tumor and may confer negative prognostic significance.8,9 The primary anatomic systems affected by paraneoplastic syndromes include the central nervous system, and vascular, dermal, musculoskeletal, endocrine, and hematopoietic systems.9 Examples of hematologic paraneoplastic manifestations include thrombocytosis, anemia, and leukocytosis. We have recently reported that when considering both endometrioid and nonendometrioid endometrial carcinomas, preoperative leukocytosis was associated with an increased risk of death but did not impose an increased risk of recurrence.10 The objective of the current study was to evaluate the impact of preoperative leukocytosis, specifically among patients with nonendometrioid endometrial carcinoma.
MATERIALS AND METHODS
After obtaining institutional review board approval, we conducted a retrospective chart review of all patients with nonendometrioid endometrial carcinoma that underwent surgical treatment between January 2005 and December 2010 at the Brigham and Women’s Hospital. The extent of surgical staging (ie, pelvic and/or para-aortic lymphadenectomy) and tumor debulking was left at the discretion of the surgeon. All procedures consisted of at least a total hysterectomy and bilateral salpingo-oophorectomy (if the adnexa had not been previously removed).
All adjuvant therapies were discussed at a multidisciplinary tumor board. Adjuvant therapies were tailored to pathologic findings, patient’s preference, and physician’s discretion. Therapies consisted of either radiation therapy (RT) and/or chemotherapy. Adjuvant RT consisted of external beam whole pelvic RT and/or vaginal brachytherapy. Adjuvant chemotherapy varied over the years but was predominantly cisplatin based. Most of the patients treated with adjuvant RT or chemotherapy were treated at the Dana Farber Cancer Institute. The remainder received treatment at facilities closer to their homes. Advanced age alone was not a contraindication to adjuvant therapy or tumor debulking. As with surgical staging and tumor debulking, patients with multiple comorbidities were less likely to receive adjuvant therapy.
The patients were separated into 2 groups based on the presence or absence of preoperative leukocytosis. Leukocytosis was defined as a white blood cell (WBC) count of 10,000 or more cells per μL.10–14 The 2 groups were then compared with respect to the following: age, WBC count, histologic type, stage, primary tumor diameter, myometrial invasion, cervical stromal involvement, adnexal involvement, positive peritoneal cytology, lymphvascular space invasion (LVI), lymph node metastasis, and residual disease after surgery. The patients’ diseases were staged according to the 2009 classification of the International Federation of Gynecology and Obstetrics.15
Patients were excluded from analysis if their medical charts were incomplete or if their preoperative WBC value was drawn 2 weeks before the operation. Patients were also excluded based on the presence of any of the following: synchronous primary at the time of endometrial carcinoma diagnosis, neoadjuvant chemotherapy, pure sarcoma of the uterine body, coexisting hematologic malignancies, preoperative corticosteroid or recombinant granulocyte colony-stimulating factor (G-CSF) use, acute or chronic infection, or HIV/AIDS infection.
Differences in clinical and histopathologic factors between patients with and without leukocytosis were examined with the χ2 and Student t tests. We used Cox regression to examine the relationships between leukocytosis and other clinical variables for both recurrence and survival. A survival curve was generated by the Kaplan-Meier method. Associations are shown as hazard ratios (HRs) with 95% confidence intervals (CIs). The SPSS version 20.0 statistical package was used for all statistical analyses. P < 0.05 was considered to be statistically significant.
A total of 222 patients with a diagnosis of nonendometrioid endometrial carcinoma were identified. Preoperative leukocytosis was observed in 33 patients (14.9%). Table 1 displays a comparison between patients with and without preoperative leukocytosis. The leukocytosis group and nonleukocytosis groups were similar with respect to the patient’s age at cancer diagnosis, stage, histology, presence of myometrial invasion, presence of positive peritoneal cytology, the presence of lymphovascular space invasion, and the percentage of patients with less than 1-cm residual disease after surgery. However, the leukocytosis group was associated with a larger mean size of the primary tumor (6.8 vs 4.6 cm., P = 0.016) and a greater percentage of patients found to have cervical stromal involvement (36.4% vs 20.1%, P = 0.039), adnexal involvement (42.4% vs 22.8%, P = 0.017), and pelvic/para-aortic lymph node involvement (50% vs 27.4%, P = 0.025).
Of the 33 patients in the leukocytosis group, there were 13 recurrences (39.4%); and of the 189 patients in the nonleukocytosis group, there were 49 recurrences (25.9%). The overall mean time to recurrence for the study population was 23.9 months (median, 17.5 months; range, 0–76 months). Kaplan-Meier curves for progression-free survival between patients with and without preoperative leukocytosis are displayed in Figure 1. The leukocytosis group had a significantly shorter progression-free survival compared to the nonleukocytosis group. On univariate analysis of prognostic factors–associated progression-free survival, leukocytosis was associated with an increased risk of recurrence (HR, 2.07; 95% CI, 1.12–3.84). When evaluated as a continuous variable, WBC was also associated with an increased risk of recurrence (HR, 1.13; 95% CI, 1.03–1.24). After adjusting for each variable, multivariate analysis confirmed that leukocytosis was independently associated with an increased risk of recurrence (HR, 2.54; 95% CI, 1.07–6.02). In addition, WBC count as a continuous variable was independently associated with an increased risk of recurrence (HR, 1.18; 95% CI, 1.01–1.37; Table 2).
Of the 33 patients in the leukocytosis group, there were 22 deaths (66.7%); and of the 189 patients in the nonleukocytosis group, there were 49 deaths (25.9%). The overall mean survival time for the study population was 26.7 months (median, 23 months; range, 0–76 months). Kaplan-Meier curves for overall survival between patients with and without preoperative leukocytosis are displayed in Figure 2. The leukocytosis group had a significantly shorter duration of overall survival compared to the nonleukocytosis group. On univariate analysis of prognostic factors associated with overall survival, preoperative leukocytosis was associated with and increased risk of death (HR, 3.33; 95% CI, 2.01–5.53). When evaluated as a continuous variable, WBC was also associated with an increased risk of death (HR, 1.22; 95% CI 1.13–1.31). After adjusting for each variable, multivariate analysis confirmed that leukocytosis was independently associated with an increased risk of death (HR, 3.37; 95% CI, 1.40–8.12; Table 3).
In the current study, we have shown that the incidence of preoperative leukocytosis among patients with nonendometrioid endometrial carcinoma is comparable to the incidence of preoperative leukocytosis when considering endometrial carcinomas as a whole (14.9% vs 13.6%).10 However, the impact of preoperative leukocytosis on prognosis seems to be greatest among patients with nonendometrioid histology. Our current evaluation of patients with nonendometrioid, endometrial carcinoma revealed that preoperative leukocytosis was independently associated with an increased risk of both recurrence and death.
Whereas no further investigations regarding leukocytosis and nonendometrioid endometrial carcinomas currently exist in the medical literature, similar findings have been reported for other hematologic paraneoplastic syndromes. Lerner et al examined 68 patients with uterine papillary serous carcinoma and showed a 12% incidence of preoperative thrombocytosis (>400 × 109/L). In addition, patients with thrombocytosis were found to have a greater incidence of stage IV disease and more than 1 L of ascites. The authors further examined prognosis in a subcohort of patients with advanced-stage disease and found that compared to patients without thrombocytosis, those with thrombocytosis had a significantly shorter disease-free survival (median, 17 months vs not yet reached, P = 0.0067) and overall survival (24 vs 45 months, P = 0.0026). On multivariate analysis, thrombocytosis was independently associated with decreased overall survival (HR, 3.05; 95% CI, 1.06–8.83).16
The underlying mechanism of tumor-related leukocytosis has been reported to be through the up-regulation of hematopoietic growth factors, such as G-CSF, granulocyte-macrophage colony-stimulating factor, IL-1, IL-6, and tumor necrosis factor α.14,17–19 However, the mechanism through which the deleterious consequence of leukocytosis is manifested has yet to be defined.It is theorized that the aggressiveness of G-CSF–secreting malignanciesis driven by autocrine stimulation of G-CSF–producing cells that carry its receptor on the cell surface. Previous studies have shown that exogenous administration of G-CSF to G-CSF–positive 20 Furthermore, G-CSF and GM-CSF have been shown to stimulate head and neck squamous cell carcinoma cell proliferation and migration in vitro, as well as promote enhanced and persistent tumor angiogenesis in vivo.21 Treatment strategies targeting these pathways may prove to be useful in the care of patients diagnosed with malignancies displaying tumor-related leukocytosis.
Whereas the current study is the first evaluation of the negative prognostic influence of preoperative leukocytosis among patients with nonendometrioid endometrial carcinoma, it has limitations. Surgical operations were not standardized with respect to lymphadenectomy. This resulted in variation as to the extent of procedures over the study period. Furthermore, the risk of underreporting of both positive and negative lymph nodes is certainly present. In addition, the retrospective nature of the current study carries the risk of underreporting of events/variables. However, underreporting was believed to be relatively minimal as variables of interest were standard preoperative laboratory values and pathologic variables routinely reported upon evaluation.
In conclusion, the presence of preoperative leukocytosis among patients with a diagnosis of nonendometrioid endometrial carcinomas was independently associated with an increased risk of recurrence and death. Studies defining the mechanism through which tumor-related leukocytosis affects prognosis are needed. Such studies may result in novel treatment strategies for this minority of patients who unfortunately represent a large percentage of endometrial carcinoma–related recurrences and deaths.
1. American Cancer Society. Cancer Facts and Figures 2012
. Atlanta, GA: American Cancer Society; 2012.
2. Creasman WT, Odicino F, Maisonneuve P, et al.. Carcinoma of the corpus uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet
. 2006; 95(suppl 1): S105–S143.
3. Sherman ME, Bitterman P, Rosenshein NB, et al.. Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features. Am J Surg Pathol
. 1992; 16: 600–610.
4. Levenback C, Burke TW, Silva E, et al.. Uterine papillary serous carcinoma (UPSC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC). Gynecol Oncol
. 1992; 46: 317–321.
5. Mendivil A, Schuler KM, Gehrig PA. Non-endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes. Cancer Control
. 2009; 16: 46–52.
6. Sagr ER, Denschlag D, Kerim-Dikeni A, et al.. Prognostic factors and treatment-related outcome in patients with uterine papillary serous carcinoma. Anticancer Res
. 2007; 27: 1213–1217.
7. Cirisano FD Jr, Robboy SJ, Dodge RK, et al.. The outcome of stage I-II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma. Gynecol Oncol
. 2000; 77: 55–65.
8. Brennan JT. Oncologic emergencies and paraneoplastic syndromes. Prim Care
. 1987; 14: 365–379.
9. Ashour AA, Verschraegen CF, Kudelka AP, et al.. Paraneoplastic syndromes of gynecologic neoplasms. J Clin Oncol
. 1997; 15: 1272–1282.
10. Worley MJ Jr, Nitschmann CC, Shoni M, et al.. The significance of preoperative leukocytosis
in endometrial carcinoma
. Gynecol Oncol
. 2012; 125: 561–565. E-pub Mar 29, 2012.
11. Qiu MZ, Xu RH, Ruan DY, et al.. Incidence of anemia, leukocytosis, and thrombocytosis in patients with solid tumors in China. Tumour Biol
. 2010; 31: 633–641. E-pub Jul 23, 2010.
12. Qiu MZ, Yuan ZY, Luo HY, et al.. Impact of pretreatment hematologic profile on survival of colorectal cancer patients. Tumour Biol
. 2010; 31: 255–260. E-pub Mar 25, 2010.
13. Kasuga I, Makino S, Kiyokawa H, et al.. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer
. 2001; 92: 2399–2405.
14. Mabuchi S, Matsumoto Y, Isohashi F, et al.. Pretreatment leukocytosis is an indicator of poor prognosis in patients with cervical cancer. Gynecol Oncol
. 2011; 122: 25–32. E-pub Apr 22, 2011.
15. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet
. 2009; 105: 103–104.
16. Lerner DL, Walsh CS, Cass I, et al.. The prognostic significance of thrombocytosis in uterine papillary serous carcinomas. Gynecol Oncol
. 2007; 104: 91–94. E-pub Aug 24, 2006.
17. Watanabe M, Katsuaki O, Ozeki Y, et al.. Production of granulocyte-macrophage colony stimulating factor in a patient with metastatic chest wall large cell carcinoma. Jpn J Clin Oncol
. 1998; 28: 559–562.
18. Sato K, Fujii Y, Ono M, et al.. Production of interleukin 1 alphalike factor and colony-simulating factor by a squamous cell carcinoma of the thyroid (T3M-5) derived from a patient with a hypercalcemia and leukocytosis. Cancer Res
. 1987; 47: 6474–6480.
19. Chen YM, Whang-Peng J, Liu JM, et al.. Leukemoid reaction resulting from multiple cytokine production in metastatic muco-epidermoid carcinoma with central necrosis. Jpn J Clin Oncol
. 1995; 25: 168–172.
20. Connor JP. Aggressive carcinosarcoma of the uterine cervix associated with high levels of granulocyte colony stimulating factor: case report and laboratory correlates. Gynecol Oncol
. 2006; 103: 349–353. E-pub Jun 16, 2006.
21. Gutschalk CM, Herold-Mende CC, Fusenig NE, et al.. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor promote malignant growth of cells from head and neck squamous cell carcinomas in vivo. Cancer Res
. 2006; 66: 8026–8036.
Keywords:Copyright © 2013 by IGCS and ESGO
Nonendometrioid; Endometrial carcinoma; Preoperative leukocytosis