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Available online at www.sciencedirect.com Journal of the Chinese Medical Association 76 (2013) 583e587 www.jcma-online.com Original Article Primary fallopian tube carcinoma: A clinicopathologic analysis and literature review Hei-Yu Lau a,b, Yi-Jen Chen a,b, Ming-Shyen Yen a,b, Ru-Fen Chen b,c, Shu-O Yeh b,c, Nae-Fang Twu a,b,* a Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC b Department of Obstetrics and Gynecology, National Yang-Ming University, Taipei, Taiwan, ROC c Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC Received November 22, 2012; accepted March 6, 2013 Abstract Background: Primary fallopian tube carcinoma (PFTC) is a rare tumor, and it is very difficult to diagnose preoperatively. The aims of this study were to evaluate the clinicopathologic features of primary fallopian tube carcinoma (PFTC) and to review the current available literature on PFTC. Methods: The medical records of 16 patients who were diagnosed with PFTC at Taipei Veterans General Hospital between January 2001 and December 2011 were analyzed retrospectively. Results: The mean age at diagnosis was 63 years (range, 41e86 years), and the mean follow-up period was 39.8 months (range, 4.0e102.8 months). Fourteen (87.5%) patients were menopausal women. The most common clinical presentation was nonspecific pelvic pain (37.5%), followed by abnormal vaginal bleeding (31.2%), pelvic mass (18.8%), and gastrointestinal symptoms (12.5%). One patient was diagnosed with PFTC preoperatively; 11 (68.6%) patients were diagnosed as having adnexal mass of unknown origin, but primarily in the ovary. Other diagnoses included endometrial cancer, cervical cancer, colon cancer, and rectum cancer in one patient each. Three (18.8%) patients were in Stage I, two (12.5%) in Stage II, nine (56.2%) in Stage III, and two (12.5%) in Stage IV. The serous type was histologically predominant (75%), and six patients were of a high grade (37.5%). The 5-year disease-free survival rate was 73.3%. Conclusion: PFTC is infrequently diagnosed preoperatively or intraoperatively due to its rarity, and has a varied and nonspecific presentation. Only 6.3% of the patients had typical symptoms suggestive of tubal carcinoma. This report may benefit surgeons by providing additional information about the clinicopathologic behavior of PFTC so that patients can be appropriately counseled. Copyright Ó 2013 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved. Keywords: disease-free survival; intraoperative assessment; primary fallopian tube carcinoma; residual tumor 1. Introduction Primary fallopian tube carcinoma (PFTC) is an uncommon tumor and accounts for approximately 0.14e0.18% of female genital malignancies.1 Based on data obtained from nine population-based cancer registries in the USA, the average annual incidence of PFTC is 3.6/million women/year.2 * Corresponding author. Dr. Nae-Fang Twu, Department of Gynecology and Obstetrics, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, ROC. E-mail address: [email protected] (N.-F. Twu). Recently, several studies have reported an increase in the incidence of PFTC, especially among the higher social classes.3 A study from Finland reported that the incidence of PFTC is increasing, with an age-adjusted incidence of 1.2/ million for 1953e1957 to 5.4/million for 1993e1997.4 Furthermore, from 1993 to 1997, an average of 21.6 cases of PFTC/year were newly registered in the Finnish Cancer Registry; during the year 2000, 46 cases were registered. Nevertheless, most studies involve small cohorts, and few data regarding a well-defined protocol for chemotherapy or the influence of prognostic factors are available. Although the treatment protocols follow those used in epithelial ovarian 1726-4901/$ - see front matter Copyright Ó 2013 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved. http://dx.doi.org/10.1016/j.jcma.2013.06.010 584 H.-Y. Lau et al. / Journal of the Chinese Medical Association 76 (2013) 583e587 cancer, owing to the similarities in clinical and pathologic features, several distinct differences should be emphasized based on additional clinical data.5 Because of the rarity of this disease and the low level of suspicion of the attending physicians, this cancer is typically not diagnosed preoperatively. The symptom complex of hydrops tubae profluens, in which a patient presents with a pelvic mass, profuse watery vaginal discharge, and pelvic pain that is greatly relieved by the sudden disappearance of the mass is rarely encountered, but is almost pathognomonic. Patients with PFTC are rarely diagnosed preoperatively by a positive Papanicolaou smear, negative endometrial/endocervical curettage, and the presence of a pelvic mass on ultrasonography.6 The aims of the present study were to analyze the clinicopathologic features, assess the survival rate, and identify the prognostic factors of women diagnosed with PFTC in a single institute. 2. Methods Patients who were eligible for enrollment in this study met the diagnostic criteria of PFTC established by Hu et al7 and later modified by Sedlis8 and Yoonessi.9 The exclusion criteria included neoadjuvant chemotherapy, tumor with a low malignant potential, or primary debulking surgery performed at another hospital. After obtaining approval from the Institutional Review Board, 16 patients who were diagnosed with PFTC between January 2001 and December 2011 at Taipei Veterans General Hospital were identified. Medical records were analyzed for demographic characteristics (the age at diagnosis, parity, presenting signs and symptoms, menopausal status, preoperative diagnosis), surgical findings, and clinical outcomes at follow-up. Criteria of the International Federation of Obstetrics and Gynecology (FIGO) were used for tumor staging. Histological grading was based on the architectural feature of the tumor, comprising Grade 1 for well-differentiated, Grade 2 for moderately differentiated, and Grade 3 for poorly differentiated tumors. Complete resection was defined as no residual tumor measuring >1 cm in maximal dimension after the initial surgery. Surgery was the first treatment for all patients, followed by chemotherapy for 15 patients. There were two chemotherapy protocols: paclitaxel plus platinum with carboplatin or cisplatin; and cyclophosphamide plus platinum. KaplaneMeier curves were used to calculate the mean overall survival (OS) and disease-free survival (DFS), and the log-rank test was applied for univariate analysis. All statistical analyses were carried out using SPSS 17 software (SPSS Inc., Chicago, IL, USA). The differences were considered significant at a level of p < 0.05. 3. Results The mean age at the time of diagnosis was 63 years (range, 41e86 years). Patient demographics are shown in Table 1. Only one of the 16 patients diagnosed with PFTC was Table 1 Clinicopathologic features of 16 women with primary fallopian tube carcinoma. Characteristics n (%) Nulliparity Menopause at diagnosis Presenting signs and symptoms Pelvic mass Abnormal vaginal bleeding Nonspecific pelvic pain Gastrointestinal symptoms Preoperative diagnosis Adnexal massa Endometrial cancer Cervical cancer Colon cancer or rectal cancer Tubal cancer Preoperative serum CA-125, median FIGO stage I II III IV Histologic grade 1/2 3 Histologic subtypes Serous Undifferentiated 1 (6.3) 14 (87.5) 3 5 6 2 (18.8) (31.2) (37.5) (12.5) 11 (68.6) 1 (6.3) 1 (6.3) 2 (12.5) 1 (6.3) 133 U/mL 3 2 9 2 (18.8) (12.5) (56.2) (12.5) 10 (62.5) 6 (37.5) 12 (75) 4 (25) CA ¼ carbohydrate antigen; FIGO ¼ International Federation for Obstetrics and Gynecology. a Any adnexal mass of unknown origin, whether benign or malignant, on imaging study. nulliparous. None of the included patients had undergone either hysterectomies or tubal sterilization, and 14 (87.5%) were postmenopausal (i.e., cessation of menstruation for at least 1 year). The most common clinical presentation was nonspecific pelvic pain (37.5%), followed by abnormal vaginal bleeding (31.2%), pelvic mass (18.8%), and gastrointestinal symptoms (12.5%). One patient was accurately diagnosed with PFTC preoperatively. The majority of preoperative diagnoses were adnexal mass of an unknown location (68.6%), but mainly involved the ovary. The serous type was histologically predominant (75%), and six patients were high grade (37.5%). Details of management are summarized in Table 2. Fifteen patients underwent adjuvant therapy after initial surgery with or without evidence of recurrence. The preoperative serum carbohydrate antigen (CA)-125 (enzyme immunoradiometric assay) levels of all patients were evaluated. Antigen levels were < 35 U/mL in four patients only: three patients with Stage I/II disease and one with Stage III disease. For the entire cohort, the 5-year DFS rate was 73.3%. The mean OS was 95 months [95% confidence interval (CI) 81e109], but the median OS was not reached. The mean DFS was 70 months (95% CI 49e91), and the median DFS was 87 months (95% CI 48e126; Fig. 1). The differences in survival according to age, tumor stage, histology type, differentiation, and residual tumor size using Kaplan-Meier analysis are listed in Table 3. The DFS was H.-Y. Lau et al. / Journal of the Chinese Medical Association 76 (2013) 583e587 Table 2 Types of management. 585 Table 3 Survival of patients with primary fallopian tube cancer in univariate analysis. No. of patients Surgical procedures Complete staging 15 Incomplete staging 1 Positive pelvic lymph node 3 Positive para-aortic lymph node 3 Complete resection Yes (residual tumor <1 cm) 14 No (residual tumor 1 cm 2 First-line chemotherapy 15 Paclitaxel þ cisplatin 8 Paclitaxel þ carboplatin 6 Cyclophosphamide þ cisplatin 1 No. of courses in first-line chemotherapy cycle <6 1 6 14 % 93.7 6.3 18.8 18.8 87.5 12.5 93.8 53.3 40 6.7 6.7 93.3 significantly related to residual tumor size ( p ¼ 0.045); OS was also related to residual tumor size, but without statistical significance ( p ¼ 0.055). In this series, the mean follow-up from the time of initial surgery was 39.8 months (range, 4e102.8 months). Five patients (31.3%) had experienced recurrence at the time of the review. One patient (6.3%) died due to the disease. 4. Discussion PFTC is an uncommon gynecologic malignancy, and is generally recognized as a disease of menopausal women.10 In the present study, 87.5% of the patients were in menopausal status. Unlike ovarian cancer, fallopian tube cancer is Fig. 1. Disease-free survival for all patients with primary fallopian tube carcinoma (median 87 months, 95% confidence interval, 48e126). OS (mo) Age 50 y >50 y Stage I/II III/IV Histology Serous Nonserous Differentiation Grade I/II Grade III Residual tumor <1 cm 1 cm DFS (mo) Mean 95% CI p Mean 95% CI p 53 40 0e112 21e59 0.596 59 71 22e97 47e85 0.843 38 47 15e62 21e72 0.420 56 75 28e85 50e100 0.678 30 75 12e49 64e87 0.113 55 87 26e84 87e87 0.216 34 55 size 47 12 12e56 28e82 0.388 50 87 21e80 87e87 0.137 29e66 0e24 0.055 75 18 55e96 18e18 0.045 CI ¼ confidence interval; DFS ¼ disease-free survival; OS ¼ overall survival. not routinely suspected in a patient with a complex pelvic mass. Because of the low incidence of PFTC, only about 4% (0.3e15%) are diagnosed preoperatively,11 and up to 50% are missed intraoperatively.12 In our study, one (6.3%) patient was diagnosed with PFTC preoperatively, and 14 (93.7%) patients were diagnosed with another cancer intraoperatively. Of these other cancers, 10 were ovarian cancer, with the others including colon cancer, rectal cancer, cervical cancer, and endometrial cancer. One patient underwent incomplete surgery with initial misdiagnosis. Eleven patients (68.7%) were diagnosed at Stage III/IV postoperatively. Because of the rarity of the disease, it is difficult to accurately diagnose, especially in patients who are early stage and symptom-free. Therefore, careful intraoperative assessment of the adnexa is necessary. Moreover, symptoms and the serum CA-125 level may be helpful indicators. The Latzko’s triad of typical symptoms consists of intermittent profuse serosanguinous vaginal bleeding, colicky pain relieved by discharge, and an abdominal or pelvic mass. However, none of these symptoms are specific, and this triad was reported in only 15% of PFTC cases.11 In addition, numerous studies have described the correlation of CA-125 level with FIGO stage, but not with a PFTC prognosis.13 In our study, the circulating CA-125 level was increased by >35 U/mL in 75% of the population. It was also increased in 33%, 50%, 89%, and 100% of patients with Stage I, II, III, or IV disease, with mean levels of 58.0 U/mL, 94.1 U/mL, 1357.6 U/mL, and 2712.5 U/mL, respectively. The etiology of PFTC remains unclear. Some factors have been postulated to increase the risk of this cancer, i.e., infertility, chronic tubal inflammation, endometriosis, nulliparity, smoking, and genetic predisposition.14 Although some investigators have suggested that PFTC shares several biological and clinical features with ovarian carcinoma,15,16 we did not find an increased number of nulliparous women or a higher incidence of tubo-ovarian abscess in our patient cohort. Because of the relatively small number of patients in the 586 H.-Y. Lau et al. / Journal of the Chinese Medical Association 76 (2013) 583e587 Table 4 Review of the literature. Authors 24 Patient no. Age, y: Median (range) Stage I II III IV Unknown 5-year survival Stage I II I/II III IV III/IV All patients Heintz et al Kosary and Trimble25 Gadducci et al16 Baekelandt et al13 1576 64 176 416 88 58.5 (36e78) 151 61 (35e82) 553 (35) 186 (12) 393 (25) 392 (25) 52 (3) 51 (29.1) 40 (22.9) 67 (38.9) 12 (6.9) 5 (2.9) 102 (24.5) 29 (7.0) 52 (12.5) 151 (36.3) 82 (19.7) 21 (23.9) 21 (23.9) 43 (48.8) 3 (3.4) 0 49 33 52 17 0 81 65 81 67 95 75 73 37 64 36 41 33 69 45 29 12 Rosen et al Wethington et al 143 5 10 (32) (27) (34.5) (11.5) 59 19 56 57 44 Data are presented as % or n (%), unless otherwise indicated. present study, it is unclear whether PFTC and epithelial ovarian carcinomas share the same etiological factors. Some studies have reported that pelvic serous carcinoma could follow a defined precursor of the distal fallopian tube that has been present for some time.17,18 Imaging studies such as ultrasound, computed tomography, or magnetic resonance imaging may aid in diagnosing PFTC. Although the imaging findings of tubal carcinoma are nonspecific, and mimic other pelvic diseases such as tubo-ovarian abscess or ovarian tumor, several findings may provide a diagnostic clue preoperatively. A sausage-shaped mass or a multilobular mass with a cog-and-wheel appearance on ultrasound,19 or low-impedance vascular flow within the solid components on ultrasound with color Doppler might lead to a suspicion of tubal malignancy.20 Magnetic resonance imaging is considered a better method than computed tomography or ultrasound for detecting tumor infiltration of extratubal organs.21 The gold-standard treatment for managing PFTC is similar to that for ovarian carcinomadcytoreductive surgery with the removal of as much of the tumor as possible.21 However, which chemotherapy regimen is optimum to address PFTC remains unclear. More recently, paclitaxel-based chemotherapy has been used for PFTC based on the propensity to use the same therapy for epithelial ovarian cancer. With the introduction of cisplatin-containing chemotherapy regimens, an objective response rate of about 80% can be achieved in patients with advanced disease.22,23 In this study, the complete response rate and partial response rate of the patients with advanced disease were 60% and 90%, respectively. Age, tumor stage, histology type, and grading were not significantly related to survival. Only the residual tumor size was significantly related to DFS ( p ¼ 0.045). The lack of correlation of prognosis with tumor stage maybe due to the small sample size; a large multicenter study would help establish the prognostic risk factors. A review of the literature with stage, survival, and demographic data is provided (Table 4). In conclusion, PFTC is a challenge to surgeons. It is very difficult to diagnose intraoperatively or preoperatively due to its rarity. Therefore, surgeons perform an additional staging surgery after the initial incomplete surgery, which seems to increase the morbidity of the patients. Therefore, PFTC should be considered in patients complaining of lower abdominal pain in association with vaginal bleedings/watery discharge; a hydrosalpinx or adnexal mass of unknown location is shown on imaging, especially in postmenopausal women. Moreover, careful intraoperative assessment of the adnexa is necessary. Further studies are warranted to increase understanding of the correct diagnosis of PFTC, and a multicenter randomized clinical trial is necessary determine the most favorable medical management protocols to be applied. References 1. Semrad N, Watring W, Fu YS, Hallatt J, Ryoo M, Lagasse L. Fallopian tube adenocarcinoma: common extraperitoneal recurrence. Gynecol Oncol 1986;24:230e5. 2. Rosenblatt KA, Weiss NS, Schwartz SM. Incidence of malignant fallopian tube tumors. Gynecol Oncol 1989;35:236e9. 3. Riska A, Leminen A. 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Combination chemotherapy for advanced carcinoma of the fallopian tube. Obstet Gynecol 1980;56:530e2. 23. Peters 3rd WA, Andersen WA, Hopkins MP. Results of chemotherapy in advanced carcinoma of the fallopian tube. Cancer 1989;63:836e8. 24. Rosen AC, Ausch C, Hafner E, Klein M, Lahousen M, Graf AH, et al. A 15-year overview of management and prognosis in primary fallopian tube carcinoma. Austrian Cooperative Study Group for Fallopian Tube Carcinoma. Eur J Cancer 1998;34:1725e9. 25. Kosary C, Trimble EL. Treatment and survival for women with fallopian tube carcinoma: a population-based study. Gynecol Oncol 2002;86:190e1.