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Malignant mixed Müllerian tumor of the fimbriated end of the fallopian tube: origin as an intraepithelial carcinoma
Gynecologic Oncology 97 (2005) 219 – 222 www.elsevier.com/locate/ygyno
Case Report
Malignant mixed Mqllerian tumor of the fimbriated end of the fallopian tube: origin as an intraepithelial carcinoma Jean-Pierre Gagner, Khush Mittal* Department of Pathology, Bellevue Hospital Center, New York University School of Medicine, 462 First Avenue, Room 4W35, New York, NY 10016, USA Received 27 January 2004 Available online 20 January 2005
Abstract Background. A paucity of examples of malignant mixed Mqllerian tumors (MMMT) of the fimbriated end of the fallopian tube has been reported. Case. We report a first case of FIGO Stage IV primary MMMT, heterologous type, in the right fimbria of a 77-year-old woman associated with symptomatic pleural spread who succumbed with recurrent disease 12 months after resection and postoperative paclitaxel and carboplatin chemotherapy. Conclusions. The identification of intraepithelial carcinoma in this tumor lends support to a role of the epithelial component in fimbrial MMMT histogenesis as seen for MMMT at other anatomic sites. Comparison of the clinical management of these tumors shows prolonged survival of patients whose treatment included postoperative pelvic external radiotherapy. D 2004 Elsevier Inc. All rights reserved. Keywords: Malignant mixed Mqllerian tumor; Fallopian tube; Fimbria
Introduction Fallopian tube tumors that arise in the fimbriae are rare occurrences that range from benign (adenofibroma, cystadenoma), to borderline (serous papillary cystic tumor, endometrioid adenofibroma), to malignant (serous, endometrioid, undifferentiated, and a-fetoprotein-producing (hepatoid) carcinomas, malignant mixed Mqllerian tumors) [1–3]. Compared to tumors located elsewhere in the tube, fimbrial tumors are exposed to the peritoneal cavity without invasion of the tubal wall. Recognizing that fimbrial tumors may be associated with an increased risk of peritoneal spread and apparently worse prognosis, the suggestion [1] was made to extend the fallopian tube tumor staging classification to include Stage I(F). To our knowledge, only four cases of malignant mixed Mqllerian tumors (MMMT) of the tubal fimbriae have been Abbreviations: MMMT, malignant mixed Mqllerian tumor. * Corresponding author. Fax: +1 212 263 2041. E-mail address: [email protected] (K. Mittal). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.11.053
clearly described in the medical literature worldwide [4–7]. No cases of MMMT were part of the largest collection of fimbrial tumors reported to date [1]. We report a first case of Stage IV primary MMMT of the fimbria, heterologous type.
Case report The patient is a 77-year-old para 3 Caucasian female who presented with dyspnea and chest tightness for 5 days. Her history was significant for a recent benign mammogram, a negative Papanicolaou smear 6 months earlier, a rectal tubular adenoma, and osteoporosis (treated with alendronate and calcium supplement). She denied any history of pelvic pain, atypical vaginal bleeding, or tobacco use. On physical exam, the patient had diminished breath sounds and dullness to percussion at the right base. Her chest X-ray demonstrated a moderate right pleural effusion and a 2 2 cm right anterior chest wall/pleural base density. Thoracocentesis yielded 1.2 L of serosanguinous fluid; cytologic examination of that fluid was consistent with adenocarci-
220
J.-P. Gagner, K. Mittal / Gynecologic Oncology 97 (2005) 219–222
Fig. 1. Identification of malignant mixed Mqllerian tumor at the fimbriated end of the right fallopian tube (hematoxylin and eosin, original magnification 200).
noma positive for cytokeratin 20 and focally positive for cytokeratin 7 and progesterone receptor. Tumor cells were negative for estrogen receptor, HER-2/Neu, S-100, thyroid transcription factor 1, and mucin. An ultrasound and a computerized tomogram showed the presence of an atrophic uterus, an enlarged right ovary (5 4 3 cm) and adnexa with dominant cystic component, and pelvic ascites with multiple nodules suggestive of peritoneal tumoral implant. Her serum CA125, carcinoembryogenic antigen, and CA153 levels were all within normal limits. Three days after her imaging studies, the patient underwent exploratory laparotomy with hysterectomy and bilateral salpingo-oophorectomy, including removal of a cul-desac implant and an omentum biopsy. A tumor mass measuring 2.5 1.8 0.7 cm was identified, the major portion of which was at the fimbriated end of the right fallopian tube and protruding out from the fimbriated end. The right ovary appeared normal but adherent to the tumor
Fig. 3. Immunostain for p53 antigen showing transition from normal epithelium to intraepithelial carcinoma. Normal epithelium is negative, while the intraepithelial carcinoma is strongly positive for p53 (original magnification 400).
Fig. 2. Areas of chondroid differentiation in the sarcomatous elements of the fimbrial MMMT (hematoxylin and eosin, original magnification 400).
mass. A 2-cm in diameter nodule attached to the peritoneum was identified in the cul-de-sac. Approximately 100 mL of pelvic ascites was collected and read as positive for adenocarcinoma. Exploration of the upper abdomen and para-aortic and pelvic lymph nodes was negative. The final pathological diagnosis was malignant mixed Mqllerian tumor at the fimbriated end of the right fallopian tube (Fig. 1). The epithelial component of this tumor was adenocarcinoma, in part papillary serous type, whereas the sarcomatous element was poorly differentiated with some chondroid areas (Fig. 2). Foci of intraepithelial carcinoma were identified (Fig. 3). Immunohistochemical analysis of the tumor was positive for p53 antigen in both the carcinoma and the sarcoma components (Fig. 4). Expression of the proliferation-associated marker Ki-67 detected by monoclonal antibody MIB-1 was also increased. The tumor also involved the cul-de-sac (predominantly sarcomatous elements) and the left para-ovarian soft tissue focally. The right ovary had inclusion cysts, the uterine corpus had an inactive endometrium, and an omentum biopsy had meso-
Fig. 4. Immunostain for p53 antigen showing diffuse expression in both the epithelial and sarcomatous elements (original magnification 400).
J.-P. Gagner, K. Mittal / Gynecologic Oncology 97 (2005) 219–222
thelial hyperplasia but no tumor was identified. The left adnexa showed no pathological alteration. Given the patient’s AJCC (2002) pathologic stage being pT2bNxM1, her tumor was classified as FIGO Stage IV. Within the first postoperative week, the patient underwent a repeat right thoracocentesis that yielded another 1.1 L of serosanguinous fluid and was started on a chemotherapeutic protocol. The protocol included premedication with dexamethasone and diphenhydramine and consisted of a total of five cycles of paclitaxel (Taxol, 175 mg/m2 3-h infusion) followed by carboplatin (Paraplatin, area under the concentration-time curve (AUC) of 5 1-h infusion) administered at 3- to 4-week intervals. At three and five and a half months postoperatively, computerized tomography showed resolution of pelvic peritoneal fluid and no evidence of new pelvic or peritoneal implant. However, 8 months postoperatively, the patient returned with a malignant right-sided pleural effusion and a complex cystic pelvic mass (15 10 cm), for which she received bleomycin pleurodesis followed by three cycles of chemotherapy. She was admitted the last time 3 months later, when CT and US showed marked progression of disease with a large multicystic mass extending from the pelvic floor with omental, peritoneal, and thoracic metastasis and complex collection of serosanguinous ascites. After receiving bilateral percutaneous nephrostomy for hydronephrosis from obstruction from the pelvic tumor, the patient refused further interventions and expired 5 days later, 12 months after her initial diagnosis. No autopsy was performed.
Discussion To our knowledge, only four other cases of MMMT of the fimbriae have been clearly documented [4–7]. All patients including ours developed or presented with pelvic metastatic disease (Table 1), which is consistent with the notion of peritoneal spread of fimbrial tumors. The patients were pre- to postmenopausal (age 35–77), without race predilection (2 Caucasians, 1 African-American, 1 Asian), and had a history of parity (P1-1 case, P2-1 case, P3-2 cases). They presented
221
with pelvic or thoracic (present case) symptoms and positive ascites (2 cases including ours). With the exception of one bilateral tumor [5], these fimbrial tumors were unilateral with no side predilection and reached up to 10 cm in greatest dimension. Microscopically, the tumor consisted of unique combinations of carcinomatous (adenomatous, clear cell, endometrioid, or papillary serous type) and sarcomatous components. The latter was heterogeneous (chondrosarcoma, chondroid, or mucoid) in most cases, with areas of necrosis and many mitotic figures present. The tumors infiltrated the lymphatics and metastases of the carcinomatous component were identified at pelvic and pleural sites. As previously observed in one other case at autopsy [4], this patient’s metastases included sarcomatous elements and reached distant sites. Although rare cases of extragenital primary MMMT have been reported, the present fimbrial MMMT is unlikely to have a peritoneal origin because of the fimbrial in situ component identified and the limited peritoneal involvement. Likewise, the notion of a uterine origin is not supported due to the lack of involvement by tumor. Features of MMMT of the fimbria share some homology with those previously reported for MMMT located elsewhere in the fallopian tube [2,6]. Approximately 64 patients with tubal MMMT not originating in the fimbriae are nearly all postmenopausal, with a mean age of 61 years (range 38– 79). They usually present with a watery or bloody vaginal discharge, abdominal pain, or both. Grossly the tumors distend the tube and typically spread to the pelvis, abdomen, or both. The lumen of the tube is usually filled with solid neoplastic tissue that contains areas of hemorrhage and necrosis. Microscopically distinct carcinomatous and sarcomatous components resemble those of similar tumors found elsewhere in the female genital tract. Both the transformation-associated marker p53 and the proliferation-associated marker Ki-67 were expressed in the carcinomatous and sarcomatous elements of the present MMMT of the fimbria. Similar immunoreactivity for p53 protein in both carcinomatous and sarcomatous components suggests, as has been reported for MMMT in the uterus, ovaries, and fallopian tubes [8,9], a monoclonal epithelial origin and an epithelial-to-mesenchymal transformation
Table 1 Summary of reported cases of malignant mixed Mqllerian tumor of the fimbriated end of the fallopian tube Cases
Ref. [4] Ref. [5] Ref. [6] Ref. [7] Present
Age at diagnosis (years)
Symptoms
35 45 60 56 77
VB AP VB AP, VB D
Carcinoma
Tumor components Sarcoma
Metastatic sites (cell types)
Stage at diagnosis
Therapies after surgery
Follow-up (months)
A A A (CC, E) A (CIS) A (PS)
HE (C) HE (CS) HO HE (M) HE (C)
PP, LL (A, S) LN (A) PP (A), AS (A) O (A), LN (A) PP (S), PE (A)
IA IIIC IIC IIIC IV
ERT n.d. CAP ERT, AP PC
DWD (54) AWD (9) AOD (19) AOD (58) DWD (12)
Abbreviations: AP, lower abdominal pain; D, dyspnea; VB, atypical vaginal bleeding; A, adenocarcinoma; CC, clear cell type; CIS, carcinoma in situ; E, endometrioid type; PS, papillary serous type; HO, homologous type; HE, heterologous type; C, chondroid area; CS, chondrosarcoma; M, myxoid area; S, sarcoma/stromal; AS, ascites; LL, lung and liver; LN, pelvic/retroperitoneal lymph nodes; O, ovary; PE, pleura effusion; PP, pelvic peritoneum; AP, doxorubicin (Adriamycin) + cis-platinum; CAP, cyclophosphamide + doxorubicin + cis-platinum; PC, paclitaxel + carboplatin; ERT, external radiation therapy; n.d., not described; AWD, alive with disease; AOD, alive without disease; DWD, deceased with disease.
222
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mechanism in the histogenesis of MMMT of the fimbriated end. Genetic progression and diversion parallel the development of divergent phenotypes in MMMT [10]. The detection of p53 protein immunoreactivity was not a predictor of disease-free survival, even when other prognostic factors were held constant [11]. On the other hand, high expression level of Ki-67 antigen, detected with antibody MIB-1, correlated very highly with a decreased survival in patients with uterine MMMT [12]. The short survival of our patient with high MIB-1 expression is congruent with this observation. Similar to the 3rd and 4th cases in Table 1, the present patient underwent surgical resection and platinum-based chemotherapy. This approach with surgery and combination paclitaxel-platinum chemotherapy has been used successfully in a majority of patients with clinical Stage I–IVovarian MMMT, including complete clinical response [13]. However, the two patients in Table 1 who survived by far the longest (up to 58 months) received postoperative pelvic external radiation therapy. This latter approach in patients with clinical Stage I–III uterine MMMT was recently shown to produce a lower rate of local recurrence as compared to surgery alone, as well as a 9% improvement trend in survival rate [14].
Acknowledgments The authors thank Karina Ventura, MD, and Jian-Jun Wei, MD, PhD, for their critique of the manuscript. Conflict of interest: The authors received no financial support from commercial companies for the research reported.
References [1] Alvarado-Cabrero I, Navani SS, Young RH, Scully RE. Tumors of the fimbriated end of the fallopian tube: a clinicopathologic analysis
[2] [3]
[4] [5]
[6]
[7] [8]
[9]
[10]
[11]
[12]
[13]
[14]
of 20 cases, including nine carcinomas. Int J Gynecol Pathol 1997;16: 189 – 96. Hellstrfm AC. Primary fallopian tube cancer: a review of the literature. Med Oncol 1998;15:6 – 14. Aoyama T, Mizuno T, Andoh K, Takagi T, Mizuno T, Eimoto T. Alpha-fetoprotein-producing (hepatoid) carcinoma of the fallopian tube. Gynecol Oncol 1996;63:261 – 6. Williams TJ, Woodruff JD. Malignant mixed mesenchymal tumor of the uterine tube. Report of a case. Obstet Gynecol 1963;21:618 – 21. van Dijk CM, Kooijman CD, van Lindert ACM. Malignant mixed mqllerian tumour of the fallopian tube. Histopathology 1989;16: 300 – 2. Imachi M, Tsukamoto N, Shigematsu T, Watanabe T, Uehira K, Amada S, et al. Malignant mixed mqllerian tumor of the fallopian tube: report of two cases and review of the literature. Gynecol Oncol 1992;47:114 – 24. Carlson Jr JA, Ackerman BL, Wheeler JE. Malignant mixed mqllerian tumor of the fallopian tube. Cancer 1993;71:187 – 92. Guarino M, Giordano F, Palloti F, Polizzotti G, Tricomi P, Cristofori E. Malignant mixed mqllerian tumor of the uterus. Features favoring its origin from a common cell clone and an epithelial-to-mesenchymal transformation mechanism of histogenesis. Tumori 1998;84: 391 – 7. Kounelis S, Jones MW, Papadaki H, Bakker A, Swalsky P, Finkelstein SD. Carcinosarcomas (malignant mixed mqllerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components. Hum Pathol 1998;29:82 – 7. Fujii H, Yoshida M, Gong ZX, Matsumoto T, Hamano Y, Fukunaga M, et al. Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity. Cancer Res 2000;60:114 – 20. Costa MJ, Vogelsan J, Young LJ. p53 gene mutation in female genital tract carcinosarcomas (malignant mixed mqllerian tumors): a clinicopathologic study of 74 cases. Mod Path 1994;7:619 – 27. Swisher EM, Gown AM, Skelly M, Ek M, Tamimi HK, Cain JM, et al. The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma. Gynecol Oncol 1996;60:81 – 8. Duska LR, Garrett A, Eltabbakh GH, Oliva E, Penson R, Fuller AF. Paclitaxel and platinum chemotherapy for malignant mixed mqllerian tumors of the ovary. Gynecol Oncol 2002;85:459 – 63. Callister M, Ramondetta LM, Jhingran A, Burke TW, Eifel PJ. Malignant mixed Mullerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome. Int J Radiat Oncol Biol Phys 2004;58:786 – 96.
Case Report
Malignant mixed Mqllerian tumor of the fimbriated end of the fallopian tube: origin as an intraepithelial carcinoma Jean-Pierre Gagner, Khush Mittal* Department of Pathology, Bellevue Hospital Center, New York University School of Medicine, 462 First Avenue, Room 4W35, New York, NY 10016, USA Received 27 January 2004 Available online 20 January 2005
Abstract Background. A paucity of examples of malignant mixed Mqllerian tumors (MMMT) of the fimbriated end of the fallopian tube has been reported. Case. We report a first case of FIGO Stage IV primary MMMT, heterologous type, in the right fimbria of a 77-year-old woman associated with symptomatic pleural spread who succumbed with recurrent disease 12 months after resection and postoperative paclitaxel and carboplatin chemotherapy. Conclusions. The identification of intraepithelial carcinoma in this tumor lends support to a role of the epithelial component in fimbrial MMMT histogenesis as seen for MMMT at other anatomic sites. Comparison of the clinical management of these tumors shows prolonged survival of patients whose treatment included postoperative pelvic external radiotherapy. D 2004 Elsevier Inc. All rights reserved. Keywords: Malignant mixed Mqllerian tumor; Fallopian tube; Fimbria
Introduction Fallopian tube tumors that arise in the fimbriae are rare occurrences that range from benign (adenofibroma, cystadenoma), to borderline (serous papillary cystic tumor, endometrioid adenofibroma), to malignant (serous, endometrioid, undifferentiated, and a-fetoprotein-producing (hepatoid) carcinomas, malignant mixed Mqllerian tumors) [1–3]. Compared to tumors located elsewhere in the tube, fimbrial tumors are exposed to the peritoneal cavity without invasion of the tubal wall. Recognizing that fimbrial tumors may be associated with an increased risk of peritoneal spread and apparently worse prognosis, the suggestion [1] was made to extend the fallopian tube tumor staging classification to include Stage I(F). To our knowledge, only four cases of malignant mixed Mqllerian tumors (MMMT) of the tubal fimbriae have been Abbreviations: MMMT, malignant mixed Mqllerian tumor. * Corresponding author. Fax: +1 212 263 2041. E-mail address: [email protected] (K. Mittal). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.11.053
clearly described in the medical literature worldwide [4–7]. No cases of MMMT were part of the largest collection of fimbrial tumors reported to date [1]. We report a first case of Stage IV primary MMMT of the fimbria, heterologous type.
Case report The patient is a 77-year-old para 3 Caucasian female who presented with dyspnea and chest tightness for 5 days. Her history was significant for a recent benign mammogram, a negative Papanicolaou smear 6 months earlier, a rectal tubular adenoma, and osteoporosis (treated with alendronate and calcium supplement). She denied any history of pelvic pain, atypical vaginal bleeding, or tobacco use. On physical exam, the patient had diminished breath sounds and dullness to percussion at the right base. Her chest X-ray demonstrated a moderate right pleural effusion and a 2 2 cm right anterior chest wall/pleural base density. Thoracocentesis yielded 1.2 L of serosanguinous fluid; cytologic examination of that fluid was consistent with adenocarci-
220
J.-P. Gagner, K. Mittal / Gynecologic Oncology 97 (2005) 219–222
Fig. 1. Identification of malignant mixed Mqllerian tumor at the fimbriated end of the right fallopian tube (hematoxylin and eosin, original magnification 200).
noma positive for cytokeratin 20 and focally positive for cytokeratin 7 and progesterone receptor. Tumor cells were negative for estrogen receptor, HER-2/Neu, S-100, thyroid transcription factor 1, and mucin. An ultrasound and a computerized tomogram showed the presence of an atrophic uterus, an enlarged right ovary (5 4 3 cm) and adnexa with dominant cystic component, and pelvic ascites with multiple nodules suggestive of peritoneal tumoral implant. Her serum CA125, carcinoembryogenic antigen, and CA153 levels were all within normal limits. Three days after her imaging studies, the patient underwent exploratory laparotomy with hysterectomy and bilateral salpingo-oophorectomy, including removal of a cul-desac implant and an omentum biopsy. A tumor mass measuring 2.5 1.8 0.7 cm was identified, the major portion of which was at the fimbriated end of the right fallopian tube and protruding out from the fimbriated end. The right ovary appeared normal but adherent to the tumor
Fig. 3. Immunostain for p53 antigen showing transition from normal epithelium to intraepithelial carcinoma. Normal epithelium is negative, while the intraepithelial carcinoma is strongly positive for p53 (original magnification 400).
Fig. 2. Areas of chondroid differentiation in the sarcomatous elements of the fimbrial MMMT (hematoxylin and eosin, original magnification 400).
mass. A 2-cm in diameter nodule attached to the peritoneum was identified in the cul-de-sac. Approximately 100 mL of pelvic ascites was collected and read as positive for adenocarcinoma. Exploration of the upper abdomen and para-aortic and pelvic lymph nodes was negative. The final pathological diagnosis was malignant mixed Mqllerian tumor at the fimbriated end of the right fallopian tube (Fig. 1). The epithelial component of this tumor was adenocarcinoma, in part papillary serous type, whereas the sarcomatous element was poorly differentiated with some chondroid areas (Fig. 2). Foci of intraepithelial carcinoma were identified (Fig. 3). Immunohistochemical analysis of the tumor was positive for p53 antigen in both the carcinoma and the sarcoma components (Fig. 4). Expression of the proliferation-associated marker Ki-67 detected by monoclonal antibody MIB-1 was also increased. The tumor also involved the cul-de-sac (predominantly sarcomatous elements) and the left para-ovarian soft tissue focally. The right ovary had inclusion cysts, the uterine corpus had an inactive endometrium, and an omentum biopsy had meso-
Fig. 4. Immunostain for p53 antigen showing diffuse expression in both the epithelial and sarcomatous elements (original magnification 400).
J.-P. Gagner, K. Mittal / Gynecologic Oncology 97 (2005) 219–222
thelial hyperplasia but no tumor was identified. The left adnexa showed no pathological alteration. Given the patient’s AJCC (2002) pathologic stage being pT2bNxM1, her tumor was classified as FIGO Stage IV. Within the first postoperative week, the patient underwent a repeat right thoracocentesis that yielded another 1.1 L of serosanguinous fluid and was started on a chemotherapeutic protocol. The protocol included premedication with dexamethasone and diphenhydramine and consisted of a total of five cycles of paclitaxel (Taxol, 175 mg/m2 3-h infusion) followed by carboplatin (Paraplatin, area under the concentration-time curve (AUC) of 5 1-h infusion) administered at 3- to 4-week intervals. At three and five and a half months postoperatively, computerized tomography showed resolution of pelvic peritoneal fluid and no evidence of new pelvic or peritoneal implant. However, 8 months postoperatively, the patient returned with a malignant right-sided pleural effusion and a complex cystic pelvic mass (15 10 cm), for which she received bleomycin pleurodesis followed by three cycles of chemotherapy. She was admitted the last time 3 months later, when CT and US showed marked progression of disease with a large multicystic mass extending from the pelvic floor with omental, peritoneal, and thoracic metastasis and complex collection of serosanguinous ascites. After receiving bilateral percutaneous nephrostomy for hydronephrosis from obstruction from the pelvic tumor, the patient refused further interventions and expired 5 days later, 12 months after her initial diagnosis. No autopsy was performed.
Discussion To our knowledge, only four other cases of MMMT of the fimbriae have been clearly documented [4–7]. All patients including ours developed or presented with pelvic metastatic disease (Table 1), which is consistent with the notion of peritoneal spread of fimbrial tumors. The patients were pre- to postmenopausal (age 35–77), without race predilection (2 Caucasians, 1 African-American, 1 Asian), and had a history of parity (P1-1 case, P2-1 case, P3-2 cases). They presented
221
with pelvic or thoracic (present case) symptoms and positive ascites (2 cases including ours). With the exception of one bilateral tumor [5], these fimbrial tumors were unilateral with no side predilection and reached up to 10 cm in greatest dimension. Microscopically, the tumor consisted of unique combinations of carcinomatous (adenomatous, clear cell, endometrioid, or papillary serous type) and sarcomatous components. The latter was heterogeneous (chondrosarcoma, chondroid, or mucoid) in most cases, with areas of necrosis and many mitotic figures present. The tumors infiltrated the lymphatics and metastases of the carcinomatous component were identified at pelvic and pleural sites. As previously observed in one other case at autopsy [4], this patient’s metastases included sarcomatous elements and reached distant sites. Although rare cases of extragenital primary MMMT have been reported, the present fimbrial MMMT is unlikely to have a peritoneal origin because of the fimbrial in situ component identified and the limited peritoneal involvement. Likewise, the notion of a uterine origin is not supported due to the lack of involvement by tumor. Features of MMMT of the fimbria share some homology with those previously reported for MMMT located elsewhere in the fallopian tube [2,6]. Approximately 64 patients with tubal MMMT not originating in the fimbriae are nearly all postmenopausal, with a mean age of 61 years (range 38– 79). They usually present with a watery or bloody vaginal discharge, abdominal pain, or both. Grossly the tumors distend the tube and typically spread to the pelvis, abdomen, or both. The lumen of the tube is usually filled with solid neoplastic tissue that contains areas of hemorrhage and necrosis. Microscopically distinct carcinomatous and sarcomatous components resemble those of similar tumors found elsewhere in the female genital tract. Both the transformation-associated marker p53 and the proliferation-associated marker Ki-67 were expressed in the carcinomatous and sarcomatous elements of the present MMMT of the fimbria. Similar immunoreactivity for p53 protein in both carcinomatous and sarcomatous components suggests, as has been reported for MMMT in the uterus, ovaries, and fallopian tubes [8,9], a monoclonal epithelial origin and an epithelial-to-mesenchymal transformation
Table 1 Summary of reported cases of malignant mixed Mqllerian tumor of the fimbriated end of the fallopian tube Cases
Ref. [4] Ref. [5] Ref. [6] Ref. [7] Present
Age at diagnosis (years)
Symptoms
35 45 60 56 77
VB AP VB AP, VB D
Carcinoma
Tumor components Sarcoma
Metastatic sites (cell types)
Stage at diagnosis
Therapies after surgery
Follow-up (months)
A A A (CC, E) A (CIS) A (PS)
HE (C) HE (CS) HO HE (M) HE (C)
PP, LL (A, S) LN (A) PP (A), AS (A) O (A), LN (A) PP (S), PE (A)
IA IIIC IIC IIIC IV
ERT n.d. CAP ERT, AP PC
DWD (54) AWD (9) AOD (19) AOD (58) DWD (12)
Abbreviations: AP, lower abdominal pain; D, dyspnea; VB, atypical vaginal bleeding; A, adenocarcinoma; CC, clear cell type; CIS, carcinoma in situ; E, endometrioid type; PS, papillary serous type; HO, homologous type; HE, heterologous type; C, chondroid area; CS, chondrosarcoma; M, myxoid area; S, sarcoma/stromal; AS, ascites; LL, lung and liver; LN, pelvic/retroperitoneal lymph nodes; O, ovary; PE, pleura effusion; PP, pelvic peritoneum; AP, doxorubicin (Adriamycin) + cis-platinum; CAP, cyclophosphamide + doxorubicin + cis-platinum; PC, paclitaxel + carboplatin; ERT, external radiation therapy; n.d., not described; AWD, alive with disease; AOD, alive without disease; DWD, deceased with disease.
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J.-P. Gagner, K. Mittal / Gynecologic Oncology 97 (2005) 219–222
mechanism in the histogenesis of MMMT of the fimbriated end. Genetic progression and diversion parallel the development of divergent phenotypes in MMMT [10]. The detection of p53 protein immunoreactivity was not a predictor of disease-free survival, even when other prognostic factors were held constant [11]. On the other hand, high expression level of Ki-67 antigen, detected with antibody MIB-1, correlated very highly with a decreased survival in patients with uterine MMMT [12]. The short survival of our patient with high MIB-1 expression is congruent with this observation. Similar to the 3rd and 4th cases in Table 1, the present patient underwent surgical resection and platinum-based chemotherapy. This approach with surgery and combination paclitaxel-platinum chemotherapy has been used successfully in a majority of patients with clinical Stage I–IVovarian MMMT, including complete clinical response [13]. However, the two patients in Table 1 who survived by far the longest (up to 58 months) received postoperative pelvic external radiation therapy. This latter approach in patients with clinical Stage I–III uterine MMMT was recently shown to produce a lower rate of local recurrence as compared to surgery alone, as well as a 9% improvement trend in survival rate [14].
Acknowledgments The authors thank Karina Ventura, MD, and Jian-Jun Wei, MD, PhD, for their critique of the manuscript. Conflict of interest: The authors received no financial support from commercial companies for the research reported.
References [1] Alvarado-Cabrero I, Navani SS, Young RH, Scully RE. Tumors of the fimbriated end of the fallopian tube: a clinicopathologic analysis
[2] [3]
[4] [5]
[6]
[7] [8]
[9]
[10]
[11]
[12]
[13]
[14]
of 20 cases, including nine carcinomas. Int J Gynecol Pathol 1997;16: 189 – 96. Hellstrfm AC. Primary fallopian tube cancer: a review of the literature. Med Oncol 1998;15:6 – 14. Aoyama T, Mizuno T, Andoh K, Takagi T, Mizuno T, Eimoto T. Alpha-fetoprotein-producing (hepatoid) carcinoma of the fallopian tube. Gynecol Oncol 1996;63:261 – 6. Williams TJ, Woodruff JD. Malignant mixed mesenchymal tumor of the uterine tube. Report of a case. Obstet Gynecol 1963;21:618 – 21. van Dijk CM, Kooijman CD, van Lindert ACM. Malignant mixed mqllerian tumour of the fallopian tube. Histopathology 1989;16: 300 – 2. Imachi M, Tsukamoto N, Shigematsu T, Watanabe T, Uehira K, Amada S, et al. Malignant mixed mqllerian tumor of the fallopian tube: report of two cases and review of the literature. Gynecol Oncol 1992;47:114 – 24. Carlson Jr JA, Ackerman BL, Wheeler JE. Malignant mixed mqllerian tumor of the fallopian tube. Cancer 1993;71:187 – 92. Guarino M, Giordano F, Palloti F, Polizzotti G, Tricomi P, Cristofori E. Malignant mixed mqllerian tumor of the uterus. Features favoring its origin from a common cell clone and an epithelial-to-mesenchymal transformation mechanism of histogenesis. Tumori 1998;84: 391 – 7. Kounelis S, Jones MW, Papadaki H, Bakker A, Swalsky P, Finkelstein SD. Carcinosarcomas (malignant mixed mqllerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components. Hum Pathol 1998;29:82 – 7. Fujii H, Yoshida M, Gong ZX, Matsumoto T, Hamano Y, Fukunaga M, et al. Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity. Cancer Res 2000;60:114 – 20. Costa MJ, Vogelsan J, Young LJ. p53 gene mutation in female genital tract carcinosarcomas (malignant mixed mqllerian tumors): a clinicopathologic study of 74 cases. Mod Path 1994;7:619 – 27. Swisher EM, Gown AM, Skelly M, Ek M, Tamimi HK, Cain JM, et al. The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma. Gynecol Oncol 1996;60:81 – 8. Duska LR, Garrett A, Eltabbakh GH, Oliva E, Penson R, Fuller AF. Paclitaxel and platinum chemotherapy for malignant mixed mqllerian tumors of the ovary. Gynecol Oncol 2002;85:459 – 63. Callister M, Ramondetta LM, Jhingran A, Burke TW, Eifel PJ. Malignant mixed Mullerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome. Int J Radiat Oncol Biol Phys 2004;58:786 – 96.