Journal of Obstetrics and Gynaecology, May 2015; 35: 372–376 © 2015 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.958441
GYNAECOLOGY
Undifferentiated uterine carcinoma: Analysis of eighteen cases I. Üreyen1, H. Ilgin1, T. Turan1, T. Taşçi1, A. Karalök1, N. Boran1, A. Özfuttu2 & G. Tulunay1
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1Gynecologic Oncology Division and 2Pathology Division, Etlik Zubeyde Hanim Women’s Health Teaching and Research Hospital, Ankara, Turkey
Analysis of the surgicopathological characteristics and clinical follow-up of patients with undifferentiated uterine carcinoma (UUC) was conducted. A total of 18 cases operated between January 1993 and December 2013 were included. Among 1,690 patients with endometrial cancer, 18 patients (1.1%) had UUC. Lymph node involvement was detected in 70.6%; depth of myometrial invasion was 0.5 in 55.6%; lymphovascular space invasion was detected in 99.3%; cervical stromal invasion was positive in 27.8%; omental and adnexal involvement were detected in 11.8% and 38.9%, respectively. The median follow-up time of the 12 patients evaluated in the survival analysis was 66 months. In the follow-up period, recurrence or progression during adjuvant therapy were observed in four patients (33.3%) and two patients (16.6%) died of the disease. UUC manifests as an aggressive tumour. In conclusion, a high rate of survival could be achieved with complete staging surgery, including an extensive lymphadenectomy with the contribution of adjuvant therapy. Keywords: Endometrial cancer, surgicopathological factors, survival, undifferentiated tumour
Introduction Endometrial cancer is the most frequent gynaecological cancer in developed countries, and in developing countries it is the second most frequent genital cancer following cervical cancer (Jemal et al. 2011). According to the 2010 Ministry of Health data, endometrial cancer is the second most frequent genital cancer following ovarian cancer and it is the seventh most frequent cancer in women in Turkey. In 2010, 1,364 new cases of endometrial cancer were identified and 726 patients died of the disease (Eser and Karakılınç 2010). Endometrial cancer is defined in two groups: type 1 and type 2, regarding the physiopathological and clinicopathological characteristics. Type 2 tumours behave more aggressively than type 1 tumours. They constitute 10–20% of the cases with endometrial cancer and are responsible for 40% of the disease-related deaths (Bokhman 1983; Felix et al. 2010). Grade 3 endometrioid tumours, serous, clear cell, mucinous, squamous, transitional, mesonephric and undifferentiated tumours are included in type 2 tumours. Undifferentiated endometrial cancer is rare. However, in many reports, undifferentiated uterine carcinoma (UUC) was defined as a grade 3 endometrioid tumour, high-grade sarcoma and
carcinosarcoma (Narita et al. 2003; Abeler et al. 1991; Wilson et al. 1990). Therefore, the prevalence of UUC is considered to be higher than originally thought. The rate of UUC was reported to range between 1% and 9% in the few studies reported (Nonnett et al. 2002; Altrabulsi et al. 2005; Silva et al. 2007). The significant difficulty related to the rarity of UUC is the absence of standardisation of the diagnosis. In WHO Classification, UUC was defined as a malign poorly-differentiated tumour without any differentiation (Tavassoli and Devilee 2003). Nevertheless, UUC may contain a differentiated component within it. In this condition, the differentiated and undifferentiated components are sharply separated from each other. The differentiated component is usually made of low-grade endometrioid tumour. The tumours that are a combination of these differentiated and undifferentiated tumours are defined as ‘dedifferentiated carcinoma’ (Silva et al. 2006). UUC is an aggressive tumour diagnosed at advanced stages and adjuvant therapy for this tumour has not been clarified. At advanced stages, median survival after diagnosis is 6 months and 5-year survival was reported to range between 25% and 60% (Abeler et al. 1991; Al-Loh and Al-Hussaini 2013). Although the differential diagnosis of UUC and grade 3 endometrioid tumours are usually confusing, UUC has a worse prognosis. Additionally, the likelihood of UUC to be associated with worse surgicopathological factors is higher. In this study, analysis of clinicopathological characteristics, applied therapies and recurrence patterns of the patients diagnosed with UUC was reported.
Material and method In the study, 18 cases with a final diagnosis of UUC between January 1993 and December 2013 were included. The surgicopathological data of the cases were obtained from the Gynecologic Oncological Surgery Clinic electronic database. The period from the surgery to the recurrence was defined as disease-free survival (DFS), while overall survival (OS) was accepted as the time from surgery to death due to the disease. Frozen/section is routinely performed in our clinic for the patients with endometrial cancer and patients reported to have non-endometrioid adenocancer in frozen/section analysis undergo staging surgery. Furthermore, patients with a preoperative diagnosis of cell type with high risk are staged directly. Staging surgery as standard involves total abdominal hysterectomy bilateral salpingo-oophorectomy systematic pelvic and para-aortic lymphadenectomy omentectomy cytological
Correspondence: I. Ureyen, Gynecologic Oncology Division, Etlik Zubeyde Hanim Women’s Health Teaching and Research Hospital, Etlik Street, Kecioren 06010, Ankara, Turkey. E-mail: [email protected]
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Undifferentiated uterine carcinoma sampling. In case of intraoperative identification of macroscopic disease, cytoreductive surgical techniques are used in addition to staging surgery. Lymphadenectomy was performed by skeletonising the pelvic and para-aortic regions in most of the patients. Undifferentiated tumour is defined as the tumour without glandular, papillary and squamous differentiation and with predominant solid architecture with haematoxylin-eosin staining in pathological evaluation. Only radiotherapy, only chemotherapy or sandwich therapy was applied to the patients as adjuvant therapy at the discretion of the attending surgeons. Patients were followed-up every 3 months for 2 years after adjuvant therapy; every 6 months until the 5th year following treatment; and yearly thereafter. In every follow-up, pelvic examination, abdominal ultrasonography, complete blood count and blood chemistry were performed. Chest X-ray was utilised yearly or in case of clinical suspicion. Thoracic and/or abdominal computerised tomography were used when needed. The CA125 level and Pap-smear test were utilised in the follow-up, even though they were not used routinely.
Results In our clinic, 1,690 cases with endometrial cancer were operated between January 1993 and December 2013. Among these patients, 181 (10.7%) had non-endometrioid type endometrial cancer. Of these patients, 18 (1.1%) had UUC. The average age at diagnosis was 61.1 years and ranged between 45 and 75 years. According to 2009 FIGO, two patients (11.1%) had stage IVB disease; nine patients (50%) had stage IIIC2 disease; one patient (5.6%) had stage IIIC1 disease; two patients (11.1%) had stage IIIA disease; one patient (5.6%) had stage II disease and three patients (16.7%) had stage IA disease. Pelvic and para-aortic lymphadenectomy was performed in 17 patients. In one patient with lymph node involvement, the number of removed pelvic and para-aortic lymph nodes and the site of involvement could not be obtained (patient no. 4; Table I). The average number of removed lymph nodes was 57 (range, 25–80). The average number of removed para-aortic and pelvic lymph nodes were 20 (range,
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9–40) and 41 (range, 26–57), respectively. Lymph node involvement was observed in 12 patients (70.6%). Of these patients, two had isolated pelvic, one had isolated para-aortic and eight had both pelvic and para-aortic lymph node involvement. A total of 10 patients had myometrial invasion 0.5; 13 had lymphovascular space invasion (LVSI); five had cervical stromal invasion; four had positive peritoneal cytology and two had omental metastasis. Adnexal involvement was observed in seven patients. Non-nodal extrauterine disease other than adnexal and omental involvement was detected in two patients. One of these patients had disease in the pelvis and the other one had vaginal metastasis. None of the patients had synchronous tumour. Surgicopathological data is presented in Table I in detail. Six patients were not included in the survival analysis, since four patients were lost to follow-up, one patient died of pulmonary aspiration in early postoperative period (patient no. 17) and the last patient was still taking the adjuvant therapy (patient no. 18; Table II). Among the 12 patients included in the survival analysis, 11 took adjuvant therapy and one refused to take the therapy. Six patients took radiotherapy, four patients took chemotherapy and one patient took sandwich therapy as adjuvant therapy. Carboplatin paclitaxel were given as chemotherapy. Sandwich therapy was applied as 3 cycles of endoxan doxorubicin vincristine followed by radiotherapy and followed by 3 cycles of paclitaxel carboplatin (patient no. 14; Table II). We approached them as other endometrial high-risk tumour types, such as nonendometrioid endometrial tumours, as there was not much data about these tumours in the literature. The median follow-up time of 12 patients included in the survival analysis was 66 months and ranged between 6 and 144 months. Progression was observed in two patients (16.6%) during the adjuvant therapy and two patients (16.6%) developed recurrence in the follow-up period. These recurrences were in the left side of the introitus in one patient and in the vaginal cuff and lung in the second patient (patient no. 13 and patient no. 16, respectively). The time between surgery and recurrence were 12 and 14 months, respectively. These two patients had taken radiotherapy as adjuvant therapy. The first patient with recurrence
Table I. Patients’ surgicopathological features. Pt. no. Age (years) Stage (FIGO 2009) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
69 73 54 59 49 55 58 71 47 67 71 66 56 45 63 63 75 59
IIIC2 IIIA IV B IIIC2 III C1 IA IA IIIC2 IIIC2 IIIC2 IIIC2 IIIC2 IIIC2 IV B IIIC2 II IIIA IA
DMI
CI
PC
LVSI
MA
MO
1/2 Serosal 1/2 1/2 1/2 1/2 1/2 1/2 Serosal 1/2 1/2 1/2 1/2 1/2 1/2 Serosal 1/2 1/2
Stroma Stroma Stroma Stroma Stroma
NR NR NR
NR NR NR
NR
Tumour Removed Removed size (mm) PA LN (n) P LN (n) LN metastasis NNEUD 40 NR 55 NR 30 NR NR 60 100 40 NR 25 70 NR 90 NR 50 40
24 NR 30 NR 15 16 NR 13 23 10 NR 17 18 NR 40 NR 9 19
42 NR 50 NR 31 36 NR 44 49 31 NR 57 47 NR 34 NR 26 46
P PA P PA ND P P PA P PA P PA PA P PA P PA P P PA
Vagina Pelvis
Pt., patient; DMI, depth of myometrial invasion; CI, cervical invasion; PC, peritoneal cytology; LVSI, lymphovascular space invasion; MA, metastasis to adnexa; MO; metastasis to omentum; PA, para-aortic; P, pelvic; LN, lymph node; NNEUD, non-nodal extrauterine disease except for adnexal and omental metastasis; NR, not reported; ND, not detailed.
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Table II. Patients’ clinical features.
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Pt. no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Adjuvant therapy
Protocol
Clinical response
Recurrence
CT Lf-uaS Lf-uaS RT RT Refused treatment RT Lf-uaS CT RT Lf-uaS CT RT Sandwich therapy∗ CT RT No† RT
TP
CCR
No
CCR CCR CCR
No No No No
TP
CCR CCR
No No
TP
Pr CCR Pr CCR CCR
Yes Yes Yes No Yes
TP
Site of recurrence
DFS
Treatment of recurrence
Bone Vagina Pelvis
1 12 1
Palliative Surgery and CT Palliative
Cuff, Lung
14
CT
No
Last status
Follow-up (months)
NED Lf-uaS Lf-uaS NED NED NED NED Lf-uaS NED NED Lf-uaS DOD NED DOD NED NED DOOD Ongoing treatment‡
12 2 1 89 84 120 60 1 108 144 1 6 72 7 45 18 1 1
DFS, disease free survival (month); OS, overall survival (month); Lf-uaS, Lost to follow-up after surgery; CT, chemotherapy; RT, radiotherapy; TP, Taxane Platin; CCR, complete clinical response; Pr, progression; NED, no evidence of disease; DOOD, died of other disease; DOD, died of disease. ∗Sandwich therapy: 3 cycles endoxan-doxorubicin-vincristine followed by RT followed by 3 cycles paclitaxel carboplatin. †Patient died 1 month after surgery because of pulmonary aspiration. ‡In patients still receiving adjuvant treatment.
underwent re-surgery and took chemotherapy and the second patient took only chemotherapy. The first patient was free of disease in the control visit 6 years after treatment of recurrence. The second patient was lost to follow-up after treatment of recurrence. Two patients (16.6%) having progression during adjuvant therapy died of the disease. One of these two patients was taking chemotherapy and the other was taking sandwich therapy as adjuvant therapy (patient no. 12 and patient no. 14, respectively). Palliative therapy was given to these two patients for progression and they died of the disease 6 and 7 months after surgery, respectively. Ten patients were free of disease. The median follow-up time of these 10 patients was 75 months and ranged between 12 and 144 months (Table II).
Discussion In the limited number of the reports related to UUC, clinical follow-up had secondary importance. These reports focussed on the pathological diagnosis and on the standardisation of the pathological diagnostic criteria of UUC. The distribution of the surgicopathological factors was not demonstrated well (Table III). The number of the patients in the groups was very limited in these reports. Some of the reported analyses did not meet the diagnostic criteria of UUC (Abeler et al. 1991). All the above factors prevented the understanding of the clinicopathological characteristics of UUC and clarification of the management. The incidence of UUC was reported to be 1–2% among all endometrial cancers (Nonnett et al. 2002). However, Altrabulsi et al. (2005) demonstrated this rate as 9%. This high ratio was considered to be related to the absence of adequate diagnostic criteria and misdiagnosis of poorly-differentiated tumours, especially grade 3 endometrioid tumours. Immunohistochemical staining was reported to be used in the differential diagnosis (Altrabulsi et al. 2005; Tafe et al. 2010). In the presented report, 1% of the endometrial cancer cases were detected to be UUC in 20 years’ experience.
Age at diagnosis is usually above 50 years. However, younger individuals may also be effected. UUC is responsible for 7% of the patients with endometrial cancer above 40 years of age (Garg et al. 2009). The youngest patient shown to have UUC was 21 years old (Tafe et al. 2010). In our study, the average age of the patients at diagnosis was 61.1 years and ranged between 45 and 75 years. There was no patient under 40 years and only three patients (16.7%) were between 40 and 50 years. Eight of the patients were above 60 years of age (44.4%) (Table I). UUC is an aggressive tumour and is usually diagnosed at advanced stages. A total of 54–58% of patients were reported to
Table III. Surgicopathological factors and survival presented in the studies. Source of study Altrabulsi et al. Tafe et al. (2005) (2010) Present study n Age (years) Mean Range Med follow-up months (range) LN metastasis (%) 2009 FIGO Stage III–IV (%) DMI ( 0.5) CI PC LVSI MA MO Recurrence Death
16
32∗
18
59 40–69 70 (24–193) NR 54 NR NR NR NR NR NR NR 12
55† 21–76 9 (0.5–89) 63.20 58§ NR 10 NR 17§ NR NR NR 9§
61.1 45–75 66 (6–144) 70.60 77.70 10 5 4 14 7 2 4 2
LN, lymph node; DMI, depth of myometrial invasion; CI, cervical invasion; PC, peritoneal cytology; LVSI, lymphovascular space invasion; MA, metastasis to adnexa; MO, metastasis to omentum; NR, not reported; ND, not detailed. ∗26 endometrial 6 ovarian undifferentiated carcinoma. †Median age. ‡Mean value. §Endometrial undifferentiated carcinoma.
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Undifferentiated uterine carcinoma be stage III–IV (Altrabulsi et al. 2005; Tafe et al. 2010). In our study, this rate was 77.7%. Adequate and detailed data related to lymphatic spread of these UUC cases has not been demonstrated until now. Lymphadenectomy was not reported to be a standard procedure and not all the patients were reported to be staged in the studies. Furthermore, the number of the removed lymph nodes was not shown and the extent of the lymph node involvement (pelvic vs para-aortic) was not reported in detail in the patients who underwent lymphadenectomy. In the study by Tafe et al. (2010) they evaluated UUC and ovarian undifferentiated carcinoma together; 63% of the patients were shown to have lymph node involvement. In our study, 70.6% of the patients were observed to have lymph node metastasis and 53.9% were shown to have para-aortic lymph node involvement. Therefore, the lower rate of lymph node metastasis in the studies in advanced stages could be explained by inadequate performance of surgical procedures. Data related to surgicopathological factors is limited similar to lymphatic spread. The high-risk surgicopathological factors were observed in high ratio in our study population. Depth of myometrial invasion was 0.5 in 55.6% of the patients; lymphovascular space invasion was detected in 99.3%; cervical stromal invasion was positive in 27.8%; positive peritoneal cytology was present in 26.7%; omental and adnexal involvement were detected in 11.8% and 38.9%, respectively. Gross cervical invasion and LVSI were detected in 38% and in 65.4% of the patients with UUC, respectively, in the study by Tafe et al. (2010). There was no adequate data related to recurrence and survival in the reported studies. Altrabulsi et al. (2005) and Tafe et al. (2010) showed in their studies with 70 months and 9 months of follow-up, respectively, that 75% and 34.6% of the patients died of the disease, respectively. However, data about the pattern of recurrence was not demonstrated in these studies. Progression or recurrence was observed in 33.3% of the patients during adjuvant therapy and 16.6% of patients were shown to die of disease in our study, that had a median follow-up time of 66 months. Recurrence was as distant recurrence in two patients (Table II). On the other hand, 83.3% of patients were observed to be free of disease. Prognosis is similar in cases that had a differentiated component (dedifferentiated tumour) compared with an undifferentiated tumour (Tafe et al. 2010). Worse clinical results were reported even in cases of the presence of a small undifferentiated component with a differentiated component (Altrabulsi et al. 2005; Tafe et al. 2010). No improvement was reported in clinical results, regardless of the amount of the accompanying differentiated tumour. Standardisation of the treatment was not possible. UUC is known to be more aggressive than grade 3 endometrioid cancer in terms of surgicopathological factors and clinical behaviour (Altrabulsi et al. 2005). Despite this, treatment of UUC is suggested to be similar to grade 3 tumours (Al-Loh and Al-Hussaini 2013). In spite of all the uncertainties of the treatment, standard management is surgery. Patients should have total abdominal hysterectomy bilateral salpingo-oophorectomy para-aortic and bilateral pelvic lymphadenectomy. Adjuvant therapy following surgical tumoral debulking is controversial. The controversy is regarding the type of therapy that should be applied. Chemotherapy and/or radiotherapy could be applied. However, there is no consensus on the chemotherapy combination that could be used as adjuvant therapy. Hayashi et al. (2004) showed 41 months of recurrence-free survival following surgery and chemotherapy
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(6 cycles of tetrahydropyranyl adriamycin, taxane and carboplatin) in a patient with UUC. Additionally, 104 months of recurrence-free survival was observed in a patient treated with chemotherapy following surgery (Altrabulsi et al. 2005). A total of 11 of 12 patients in the survival analysis took adjuvant therapy and one patient refused to take adjuvant therapy in our study. There was no recurrence in the 108 months’ follow-up of the patient with advanced stage disease (stage IIIC2) who took paclitaxel and carboplatin as adjuvant therapy (patient no. 9; Table II). Another patient with advanced disease (stage IIIC2) treated with adjuvant radiotherapy was reported to have 144 months of recurrence-free survival. The only patient who refused adjuvant therapy had 120 months of recurrence-free survival. Nevertheless, the stage of this patient was IA. The presented analysis is one of the studies limited in number related to UUC and the number of patients is quite large. Other advantages of the study were that it was the analysis of a single institution’s 20 years’ experience and that, in this long period, the staff of the pathology department did not change much, resulting in the absence of the interobserver diagnosis differences. Nevertheless, paraffin blocks were not reviewed again and immunohistochemical staining was not utilised during diagnosis. These were the limitations of the study, although it is known that immunohistochemical staining is not absolutely necessary. In conclusion, UUC manifests as an aggressive tumour. However, a high rate of survival could be achieved with complete staging surgery, including an extensive lymphadenectomy with the contribution of adjuvant therapy.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Abeler VM, Kjorstad KE, Nesland JM. 1991. Undifferentiated carcinoma of the endometrium: a histopathologic and clinical study of 31 cases. Cancer 68:98–105. Al-Loh S, Al-Hussaini M. 2013. Undifferentiated endometrial carcinoma, a diagnosis frequently overlooked. Archives of Pathology and Laboratory Medicine 137:438–442. Altrabulsi B, Malpica A, Deavers MT, Bodurka DC, Broaddus R, Silva EG. 2005. Undifferentiated carcinoma of the endometrium. American Journal of Surgical Pathology 229:1316–1321. Bokhman JV. 1983. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology 15:10–17. Eser SY, Karakılınç H. 2010. Cancer incidence in Turkey. In: Tuncer AM, Özgül N, Olcayto E, Gültekin M, editors. Cancer control in Turkey. Ankara: Turkish Ministry of Health. p 35–51. Felix AS, Weissfeld JL, Stone RA, Bowser R, Chivukula M, Edwards RP et al. 2010. Factors associated with Type I and Type II endometrial cancer. Cancer Causes and Control 21:1851–1856. Garg K, Shih K, Barakat R, Zhou Q, Iasonos A, Soslow RA. 2009. Endometrial carcinomas in women aged 40 years and younger: tumors associated with loss of DNA mismatch repair proteins comprise a distinct clinicopathologic subset. American Journal of Surgical Pathology 33:1869–1877. Hayashi M, Ueda Y, Takimoto T, Ohkura T. 2004. Undifferentiated endometrial carcinoma of the uterus: marked effect of chemotherapy with tetrahydropyranyl-adriamycin, paclitaxel, and carboplatin. International Journal of Gynecological Cancer 14:388–394. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. 2011. Global cancer statistics. CA: A Cancer Journal for Clinicians 61:69–90. Narita F, Sato A, Hamana S, Deguchi M, Otani T, Maruo T. 2003. Simultaneous immunohistochemical localisation of beta-catenin and cyclin D1 in differentiated but not in undifferentiated human endometrial carcinoma. European Journal of Gynaecological Oncology 24:129–134. Nonnett BM, Zaino JR, Hendric K. 2002. Endometrial carcinoma. In: Kurman RJ, editor. Blaustein’s pathology of the female genital tract. 5th ed. New York: Springer-Verlag. p 551–559.
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Silva EG, Deavers MT, Bodurka DC, Malpica A. 2006. Association of low grade endometrioid carcinoma of the uterus and ovary with undifferentiated carcinoma: a new type of dedifferentiated carcinoma? International Journal of Gynecological Pathology 25: 52–58. Silva EG, Deavers MT, Malpica A. 2007. Undifferentiated carcinoma of the endometrium: a review. Pathology 39:134–138. Tafe LJ, Garg K, Chew I, Tornos C, Soslow RA. 2010. Endometrial and ovarian carcinomas with undifferentiated components: clinically
aggressive and frequently underrecognized neoplasms. Modern Pathology 23:781–789. Tavassoli FA, Devilee P. 2003. Tumors of the uterine corpus. World Health Organization Classification of Tumors: tumors of the breast and female genital organs. Lyon: IARC Press. p 217–258. Wilson TO, Podratz KC, Gaffey TA, Malkasian GD Jr, O’Brien PC, Naessens JM. 1990. Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma. American Journal of Obstetrics and Gynecology 162:418–426.
GYNAECOLOGY
Undifferentiated uterine carcinoma: Analysis of eighteen cases I. Üreyen1, H. Ilgin1, T. Turan1, T. Taşçi1, A. Karalök1, N. Boran1, A. Özfuttu2 & G. Tulunay1
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1Gynecologic Oncology Division and 2Pathology Division, Etlik Zubeyde Hanim Women’s Health Teaching and Research Hospital, Ankara, Turkey
Analysis of the surgicopathological characteristics and clinical follow-up of patients with undifferentiated uterine carcinoma (UUC) was conducted. A total of 18 cases operated between January 1993 and December 2013 were included. Among 1,690 patients with endometrial cancer, 18 patients (1.1%) had UUC. Lymph node involvement was detected in 70.6%; depth of myometrial invasion was 0.5 in 55.6%; lymphovascular space invasion was detected in 99.3%; cervical stromal invasion was positive in 27.8%; omental and adnexal involvement were detected in 11.8% and 38.9%, respectively. The median follow-up time of the 12 patients evaluated in the survival analysis was 66 months. In the follow-up period, recurrence or progression during adjuvant therapy were observed in four patients (33.3%) and two patients (16.6%) died of the disease. UUC manifests as an aggressive tumour. In conclusion, a high rate of survival could be achieved with complete staging surgery, including an extensive lymphadenectomy with the contribution of adjuvant therapy. Keywords: Endometrial cancer, surgicopathological factors, survival, undifferentiated tumour
Introduction Endometrial cancer is the most frequent gynaecological cancer in developed countries, and in developing countries it is the second most frequent genital cancer following cervical cancer (Jemal et al. 2011). According to the 2010 Ministry of Health data, endometrial cancer is the second most frequent genital cancer following ovarian cancer and it is the seventh most frequent cancer in women in Turkey. In 2010, 1,364 new cases of endometrial cancer were identified and 726 patients died of the disease (Eser and Karakılınç 2010). Endometrial cancer is defined in two groups: type 1 and type 2, regarding the physiopathological and clinicopathological characteristics. Type 2 tumours behave more aggressively than type 1 tumours. They constitute 10–20% of the cases with endometrial cancer and are responsible for 40% of the disease-related deaths (Bokhman 1983; Felix et al. 2010). Grade 3 endometrioid tumours, serous, clear cell, mucinous, squamous, transitional, mesonephric and undifferentiated tumours are included in type 2 tumours. Undifferentiated endometrial cancer is rare. However, in many reports, undifferentiated uterine carcinoma (UUC) was defined as a grade 3 endometrioid tumour, high-grade sarcoma and
carcinosarcoma (Narita et al. 2003; Abeler et al. 1991; Wilson et al. 1990). Therefore, the prevalence of UUC is considered to be higher than originally thought. The rate of UUC was reported to range between 1% and 9% in the few studies reported (Nonnett et al. 2002; Altrabulsi et al. 2005; Silva et al. 2007). The significant difficulty related to the rarity of UUC is the absence of standardisation of the diagnosis. In WHO Classification, UUC was defined as a malign poorly-differentiated tumour without any differentiation (Tavassoli and Devilee 2003). Nevertheless, UUC may contain a differentiated component within it. In this condition, the differentiated and undifferentiated components are sharply separated from each other. The differentiated component is usually made of low-grade endometrioid tumour. The tumours that are a combination of these differentiated and undifferentiated tumours are defined as ‘dedifferentiated carcinoma’ (Silva et al. 2006). UUC is an aggressive tumour diagnosed at advanced stages and adjuvant therapy for this tumour has not been clarified. At advanced stages, median survival after diagnosis is 6 months and 5-year survival was reported to range between 25% and 60% (Abeler et al. 1991; Al-Loh and Al-Hussaini 2013). Although the differential diagnosis of UUC and grade 3 endometrioid tumours are usually confusing, UUC has a worse prognosis. Additionally, the likelihood of UUC to be associated with worse surgicopathological factors is higher. In this study, analysis of clinicopathological characteristics, applied therapies and recurrence patterns of the patients diagnosed with UUC was reported.
Material and method In the study, 18 cases with a final diagnosis of UUC between January 1993 and December 2013 were included. The surgicopathological data of the cases were obtained from the Gynecologic Oncological Surgery Clinic electronic database. The period from the surgery to the recurrence was defined as disease-free survival (DFS), while overall survival (OS) was accepted as the time from surgery to death due to the disease. Frozen/section is routinely performed in our clinic for the patients with endometrial cancer and patients reported to have non-endometrioid adenocancer in frozen/section analysis undergo staging surgery. Furthermore, patients with a preoperative diagnosis of cell type with high risk are staged directly. Staging surgery as standard involves total abdominal hysterectomy bilateral salpingo-oophorectomy systematic pelvic and para-aortic lymphadenectomy omentectomy cytological
Correspondence: I. Ureyen, Gynecologic Oncology Division, Etlik Zubeyde Hanim Women’s Health Teaching and Research Hospital, Etlik Street, Kecioren 06010, Ankara, Turkey. E-mail: [email protected]
J Obstet Gynaecol Downloaded from informahealthcare.com by Deakin University on 08/10/15 For personal use only.
Undifferentiated uterine carcinoma sampling. In case of intraoperative identification of macroscopic disease, cytoreductive surgical techniques are used in addition to staging surgery. Lymphadenectomy was performed by skeletonising the pelvic and para-aortic regions in most of the patients. Undifferentiated tumour is defined as the tumour without glandular, papillary and squamous differentiation and with predominant solid architecture with haematoxylin-eosin staining in pathological evaluation. Only radiotherapy, only chemotherapy or sandwich therapy was applied to the patients as adjuvant therapy at the discretion of the attending surgeons. Patients were followed-up every 3 months for 2 years after adjuvant therapy; every 6 months until the 5th year following treatment; and yearly thereafter. In every follow-up, pelvic examination, abdominal ultrasonography, complete blood count and blood chemistry were performed. Chest X-ray was utilised yearly or in case of clinical suspicion. Thoracic and/or abdominal computerised tomography were used when needed. The CA125 level and Pap-smear test were utilised in the follow-up, even though they were not used routinely.
Results In our clinic, 1,690 cases with endometrial cancer were operated between January 1993 and December 2013. Among these patients, 181 (10.7%) had non-endometrioid type endometrial cancer. Of these patients, 18 (1.1%) had UUC. The average age at diagnosis was 61.1 years and ranged between 45 and 75 years. According to 2009 FIGO, two patients (11.1%) had stage IVB disease; nine patients (50%) had stage IIIC2 disease; one patient (5.6%) had stage IIIC1 disease; two patients (11.1%) had stage IIIA disease; one patient (5.6%) had stage II disease and three patients (16.7%) had stage IA disease. Pelvic and para-aortic lymphadenectomy was performed in 17 patients. In one patient with lymph node involvement, the number of removed pelvic and para-aortic lymph nodes and the site of involvement could not be obtained (patient no. 4; Table I). The average number of removed lymph nodes was 57 (range, 25–80). The average number of removed para-aortic and pelvic lymph nodes were 20 (range,
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9–40) and 41 (range, 26–57), respectively. Lymph node involvement was observed in 12 patients (70.6%). Of these patients, two had isolated pelvic, one had isolated para-aortic and eight had both pelvic and para-aortic lymph node involvement. A total of 10 patients had myometrial invasion 0.5; 13 had lymphovascular space invasion (LVSI); five had cervical stromal invasion; four had positive peritoneal cytology and two had omental metastasis. Adnexal involvement was observed in seven patients. Non-nodal extrauterine disease other than adnexal and omental involvement was detected in two patients. One of these patients had disease in the pelvis and the other one had vaginal metastasis. None of the patients had synchronous tumour. Surgicopathological data is presented in Table I in detail. Six patients were not included in the survival analysis, since four patients were lost to follow-up, one patient died of pulmonary aspiration in early postoperative period (patient no. 17) and the last patient was still taking the adjuvant therapy (patient no. 18; Table II). Among the 12 patients included in the survival analysis, 11 took adjuvant therapy and one refused to take the therapy. Six patients took radiotherapy, four patients took chemotherapy and one patient took sandwich therapy as adjuvant therapy. Carboplatin paclitaxel were given as chemotherapy. Sandwich therapy was applied as 3 cycles of endoxan doxorubicin vincristine followed by radiotherapy and followed by 3 cycles of paclitaxel carboplatin (patient no. 14; Table II). We approached them as other endometrial high-risk tumour types, such as nonendometrioid endometrial tumours, as there was not much data about these tumours in the literature. The median follow-up time of 12 patients included in the survival analysis was 66 months and ranged between 6 and 144 months. Progression was observed in two patients (16.6%) during the adjuvant therapy and two patients (16.6%) developed recurrence in the follow-up period. These recurrences were in the left side of the introitus in one patient and in the vaginal cuff and lung in the second patient (patient no. 13 and patient no. 16, respectively). The time between surgery and recurrence were 12 and 14 months, respectively. These two patients had taken radiotherapy as adjuvant therapy. The first patient with recurrence
Table I. Patients’ surgicopathological features. Pt. no. Age (years) Stage (FIGO 2009) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
69 73 54 59 49 55 58 71 47 67 71 66 56 45 63 63 75 59
IIIC2 IIIA IV B IIIC2 III C1 IA IA IIIC2 IIIC2 IIIC2 IIIC2 IIIC2 IIIC2 IV B IIIC2 II IIIA IA
DMI
CI
PC
LVSI
MA
MO
1/2 Serosal 1/2 1/2 1/2 1/2 1/2 1/2 Serosal 1/2 1/2 1/2 1/2 1/2 1/2 Serosal 1/2 1/2
Stroma Stroma Stroma Stroma Stroma
NR NR NR
NR NR NR
NR
Tumour Removed Removed size (mm) PA LN (n) P LN (n) LN metastasis NNEUD 40 NR 55 NR 30 NR NR 60 100 40 NR 25 70 NR 90 NR 50 40
24 NR 30 NR 15 16 NR 13 23 10 NR 17 18 NR 40 NR 9 19
42 NR 50 NR 31 36 NR 44 49 31 NR 57 47 NR 34 NR 26 46
P PA P PA ND P P PA P PA P PA PA P PA P PA P P PA
Vagina Pelvis
Pt., patient; DMI, depth of myometrial invasion; CI, cervical invasion; PC, peritoneal cytology; LVSI, lymphovascular space invasion; MA, metastasis to adnexa; MO; metastasis to omentum; PA, para-aortic; P, pelvic; LN, lymph node; NNEUD, non-nodal extrauterine disease except for adnexal and omental metastasis; NR, not reported; ND, not detailed.
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Table II. Patients’ clinical features.
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Pt. no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Adjuvant therapy
Protocol
Clinical response
Recurrence
CT Lf-uaS Lf-uaS RT RT Refused treatment RT Lf-uaS CT RT Lf-uaS CT RT Sandwich therapy∗ CT RT No† RT
TP
CCR
No
CCR CCR CCR
No No No No
TP
CCR CCR
No No
TP
Pr CCR Pr CCR CCR
Yes Yes Yes No Yes
TP
Site of recurrence
DFS
Treatment of recurrence
Bone Vagina Pelvis
1 12 1
Palliative Surgery and CT Palliative
Cuff, Lung
14
CT
No
Last status
Follow-up (months)
NED Lf-uaS Lf-uaS NED NED NED NED Lf-uaS NED NED Lf-uaS DOD NED DOD NED NED DOOD Ongoing treatment‡
12 2 1 89 84 120 60 1 108 144 1 6 72 7 45 18 1 1
DFS, disease free survival (month); OS, overall survival (month); Lf-uaS, Lost to follow-up after surgery; CT, chemotherapy; RT, radiotherapy; TP, Taxane Platin; CCR, complete clinical response; Pr, progression; NED, no evidence of disease; DOOD, died of other disease; DOD, died of disease. ∗Sandwich therapy: 3 cycles endoxan-doxorubicin-vincristine followed by RT followed by 3 cycles paclitaxel carboplatin. †Patient died 1 month after surgery because of pulmonary aspiration. ‡In patients still receiving adjuvant treatment.
underwent re-surgery and took chemotherapy and the second patient took only chemotherapy. The first patient was free of disease in the control visit 6 years after treatment of recurrence. The second patient was lost to follow-up after treatment of recurrence. Two patients (16.6%) having progression during adjuvant therapy died of the disease. One of these two patients was taking chemotherapy and the other was taking sandwich therapy as adjuvant therapy (patient no. 12 and patient no. 14, respectively). Palliative therapy was given to these two patients for progression and they died of the disease 6 and 7 months after surgery, respectively. Ten patients were free of disease. The median follow-up time of these 10 patients was 75 months and ranged between 12 and 144 months (Table II).
Discussion In the limited number of the reports related to UUC, clinical follow-up had secondary importance. These reports focussed on the pathological diagnosis and on the standardisation of the pathological diagnostic criteria of UUC. The distribution of the surgicopathological factors was not demonstrated well (Table III). The number of the patients in the groups was very limited in these reports. Some of the reported analyses did not meet the diagnostic criteria of UUC (Abeler et al. 1991). All the above factors prevented the understanding of the clinicopathological characteristics of UUC and clarification of the management. The incidence of UUC was reported to be 1–2% among all endometrial cancers (Nonnett et al. 2002). However, Altrabulsi et al. (2005) demonstrated this rate as 9%. This high ratio was considered to be related to the absence of adequate diagnostic criteria and misdiagnosis of poorly-differentiated tumours, especially grade 3 endometrioid tumours. Immunohistochemical staining was reported to be used in the differential diagnosis (Altrabulsi et al. 2005; Tafe et al. 2010). In the presented report, 1% of the endometrial cancer cases were detected to be UUC in 20 years’ experience.
Age at diagnosis is usually above 50 years. However, younger individuals may also be effected. UUC is responsible for 7% of the patients with endometrial cancer above 40 years of age (Garg et al. 2009). The youngest patient shown to have UUC was 21 years old (Tafe et al. 2010). In our study, the average age of the patients at diagnosis was 61.1 years and ranged between 45 and 75 years. There was no patient under 40 years and only three patients (16.7%) were between 40 and 50 years. Eight of the patients were above 60 years of age (44.4%) (Table I). UUC is an aggressive tumour and is usually diagnosed at advanced stages. A total of 54–58% of patients were reported to
Table III. Surgicopathological factors and survival presented in the studies. Source of study Altrabulsi et al. Tafe et al. (2005) (2010) Present study n Age (years) Mean Range Med follow-up months (range) LN metastasis (%) 2009 FIGO Stage III–IV (%) DMI ( 0.5) CI PC LVSI MA MO Recurrence Death
16
32∗
18
59 40–69 70 (24–193) NR 54 NR NR NR NR NR NR NR 12
55† 21–76 9 (0.5–89) 63.20 58§ NR 10 NR 17§ NR NR NR 9§
61.1 45–75 66 (6–144) 70.60 77.70 10 5 4 14 7 2 4 2
LN, lymph node; DMI, depth of myometrial invasion; CI, cervical invasion; PC, peritoneal cytology; LVSI, lymphovascular space invasion; MA, metastasis to adnexa; MO, metastasis to omentum; NR, not reported; ND, not detailed. ∗26 endometrial 6 ovarian undifferentiated carcinoma. †Median age. ‡Mean value. §Endometrial undifferentiated carcinoma.
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Undifferentiated uterine carcinoma be stage III–IV (Altrabulsi et al. 2005; Tafe et al. 2010). In our study, this rate was 77.7%. Adequate and detailed data related to lymphatic spread of these UUC cases has not been demonstrated until now. Lymphadenectomy was not reported to be a standard procedure and not all the patients were reported to be staged in the studies. Furthermore, the number of the removed lymph nodes was not shown and the extent of the lymph node involvement (pelvic vs para-aortic) was not reported in detail in the patients who underwent lymphadenectomy. In the study by Tafe et al. (2010) they evaluated UUC and ovarian undifferentiated carcinoma together; 63% of the patients were shown to have lymph node involvement. In our study, 70.6% of the patients were observed to have lymph node metastasis and 53.9% were shown to have para-aortic lymph node involvement. Therefore, the lower rate of lymph node metastasis in the studies in advanced stages could be explained by inadequate performance of surgical procedures. Data related to surgicopathological factors is limited similar to lymphatic spread. The high-risk surgicopathological factors were observed in high ratio in our study population. Depth of myometrial invasion was 0.5 in 55.6% of the patients; lymphovascular space invasion was detected in 99.3%; cervical stromal invasion was positive in 27.8%; positive peritoneal cytology was present in 26.7%; omental and adnexal involvement were detected in 11.8% and 38.9%, respectively. Gross cervical invasion and LVSI were detected in 38% and in 65.4% of the patients with UUC, respectively, in the study by Tafe et al. (2010). There was no adequate data related to recurrence and survival in the reported studies. Altrabulsi et al. (2005) and Tafe et al. (2010) showed in their studies with 70 months and 9 months of follow-up, respectively, that 75% and 34.6% of the patients died of the disease, respectively. However, data about the pattern of recurrence was not demonstrated in these studies. Progression or recurrence was observed in 33.3% of the patients during adjuvant therapy and 16.6% of patients were shown to die of disease in our study, that had a median follow-up time of 66 months. Recurrence was as distant recurrence in two patients (Table II). On the other hand, 83.3% of patients were observed to be free of disease. Prognosis is similar in cases that had a differentiated component (dedifferentiated tumour) compared with an undifferentiated tumour (Tafe et al. 2010). Worse clinical results were reported even in cases of the presence of a small undifferentiated component with a differentiated component (Altrabulsi et al. 2005; Tafe et al. 2010). No improvement was reported in clinical results, regardless of the amount of the accompanying differentiated tumour. Standardisation of the treatment was not possible. UUC is known to be more aggressive than grade 3 endometrioid cancer in terms of surgicopathological factors and clinical behaviour (Altrabulsi et al. 2005). Despite this, treatment of UUC is suggested to be similar to grade 3 tumours (Al-Loh and Al-Hussaini 2013). In spite of all the uncertainties of the treatment, standard management is surgery. Patients should have total abdominal hysterectomy bilateral salpingo-oophorectomy para-aortic and bilateral pelvic lymphadenectomy. Adjuvant therapy following surgical tumoral debulking is controversial. The controversy is regarding the type of therapy that should be applied. Chemotherapy and/or radiotherapy could be applied. However, there is no consensus on the chemotherapy combination that could be used as adjuvant therapy. Hayashi et al. (2004) showed 41 months of recurrence-free survival following surgery and chemotherapy
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(6 cycles of tetrahydropyranyl adriamycin, taxane and carboplatin) in a patient with UUC. Additionally, 104 months of recurrence-free survival was observed in a patient treated with chemotherapy following surgery (Altrabulsi et al. 2005). A total of 11 of 12 patients in the survival analysis took adjuvant therapy and one patient refused to take adjuvant therapy in our study. There was no recurrence in the 108 months’ follow-up of the patient with advanced stage disease (stage IIIC2) who took paclitaxel and carboplatin as adjuvant therapy (patient no. 9; Table II). Another patient with advanced disease (stage IIIC2) treated with adjuvant radiotherapy was reported to have 144 months of recurrence-free survival. The only patient who refused adjuvant therapy had 120 months of recurrence-free survival. Nevertheless, the stage of this patient was IA. The presented analysis is one of the studies limited in number related to UUC and the number of patients is quite large. Other advantages of the study were that it was the analysis of a single institution’s 20 years’ experience and that, in this long period, the staff of the pathology department did not change much, resulting in the absence of the interobserver diagnosis differences. Nevertheless, paraffin blocks were not reviewed again and immunohistochemical staining was not utilised during diagnosis. These were the limitations of the study, although it is known that immunohistochemical staining is not absolutely necessary. In conclusion, UUC manifests as an aggressive tumour. However, a high rate of survival could be achieved with complete staging surgery, including an extensive lymphadenectomy with the contribution of adjuvant therapy.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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