|Home | About | Journals | Submit | Contact Us | Français|
A 65-year-old woman presented with a 2-month history of postmenopausal bleeding. Her past medical history was significant for hypertension, type 2 diabetes, and a remote history of pulmonary embolism, and her surgical history was significant for a thyroidectomy for benign disease and a hip replacement. On physical examination, she was found to have a mass protruding through the cervix. Biopsy revealed a poorly differentiated grade 2 endometrioid cancer of the uterus, with a suspected sarcomatous component. Subsequent imaging also identified a pancreatic mass (Figure (Figure11).
The patient underwent surgical exploration, beginning with a modified radical abdominal hysterectomy, bilateral salpingo-oophorectomy, and left pelvic lymph node sampling. The patient's uterus was approximately the size of a 12- to 14-week gravid and boggy uterus with necrotic friable tissue at the fundus and in the left parametrial region. There was also a necrotic left pelvic external iliac lymph node. The patient had a 3 4-cm vaginal mass on the anterior vaginal wall. Since resection of the vaginal mass would have required an extensive dissection of the entire bladder and the near-entire removal of the anterior vagina, the vaginal cuff was closed with a plan to locally irradiate this focus of disease.
In the upper abdomen, the patient was found to have a mass along the margin of the right lobe of her liver, which was locally resected. Pathologically, this lesion was consistent with a neuroendocrine tumor. This mass was believed to be related to the pancreatic lesion, and an aggressive surgical approach was used (1, 2), given that the endometrial disease was controlled. Surgical treatment of these lesions required a distal pancreatectomy and splenectomy with resection of adjacent nodes and resection of an additional focus in the liver. Total gross resection of the neuroendocrine disease was achieved. The patient tolerated these surgical procedures without significant complications and was discharged from the hospital 7 days later.
Pathological findings of the permanent fixed sections revealed a carcinosarcoma (previously called malignant mixed Mullerian tumor, or MMMT) in the uterus with heterologous sarcomatous elements and a carcinoma consisting primarily of an undifferentiated high-grade neuroendocrine malignancy with extensive lymphovascular invasion and deep myometrial invasion (Figure (Figure22). The biopsy of the 3 4-cm vaginal mass was composed entirely of undifferentiated high-grade neuroendocrine tumor (Figure (Figure33). The left pelvic lymph node sampling revealed metastatic undifferentiated high-grade neuroendocrine carcinoma with extensive necrosis (Figure (Figure44). However, the pancreatic tumor was a well-differentiated neuroendocrine carcinoma consistent with a pancreatic origin (Figure (Figure55), metastatic to 12 of 24 regional lymph nodes and 1 of 3 celiac nodes (Figure (Figure66). In addition, the right hepatic lobe contained metastatic well-differentiated neuroendocrine carcinoma morphologically consistent with the pancreatic primary tumor (Figure (Figure77). The diagnoses for the neoplasms were stage IIIC uterine carcinosarcoma with local (uterine) and metastatic (left pelvic lymph node, vaginal involvement) undifferentiated high-grade neuroendocrine tumor, and a concomitant metastatic well-differentiated pancreatic neuroendocrine tumor (PNET). These diagnoses were supported by neuroendocrine immunohistochemical stains: positive stains for CD56, synaptophysin, chromogranin, and neurofilament in the poorly differentiated tumor cells in the uterus (Figure Figure88) and positive stains for chromogranin and CD56 in the pancreas (Figure (Figure99). There were no clinical signs that the neuroendocrine tumors were functional.
The patient was discharged in stable condition on postoperative day 7. Postoperatively, she had some minor bleeding from her vaginal tumor, for which she received external beam radiotherapy. Low pelvic fields measuring approximately 10 10 cm in a parallel opposed fashion (anterior to posterior/posterior to anterior) were utilized to deliver a total dose of 3000 cGr in 10 fractions. The patient tolerated the treatment well and her vaginal bleeding subsided. The patient developed pulmonary and hepatic metastases 2 months later and declined additional chemotherapy. She succumbed to progressive metastatic disease, and her family declined an autopsy.
This patient had two rare primary tumors, both aggressive and carrying a poor prognosis. For uterine carcinosarcoma, the incidence is 7 per 100,000 women, comprising only 3% of uterine neoplasms (3), and the median survival in one study of 1697 patients was 40 months (4). For PNET, the incidence is 0.52 per 100,000 women aged 60 to 69, and a recent review of 1483 cases noted an overall survival of 28 months (5). In addition, our patient had several negative prognostic factors for both primary tumors, including metastatic spread and age. Not surprisingly, the uterine cancer was found first, based on its traditional clinical symptom of bleeding. It is not unusual for patients with nonfunctional PNETs to remain symptom free for years, as evident in the 10% incidence of PNETs found at autopsy and the fact that 19% of pancreatic lesions incidentally detected by computed tomography are PNETs (6).
Fendrich et al (7) found that multiple primary malignancies are much more common in patients with PNETs than in the general population. In their group of 115 patients, 15 (13%) had at least one other malignant tumor—compared with general rates of multiple malignancies of 2.3% in surgical cases and 8.1% in autopsies. Specifically, in those with nonfunctioning PNETs, the risk of developing multiple cancers was 20.5%. Despite varying hypotheses for development of additional tumors—such as decreased immunity, familial cancer syndromes, hormone secretion, radiotherapy, and environmental effects—the authors concluded that coincidental cancer clusters probably accounted for most of their cases (7). The most common tumor type presenting with multiple primaries is gastrinoma, followed by nonfunctioning PNETs. The prognosis for functioning PNETs is better than that for nonfunctioning, and the prognosis for PNETs in general is better than that for pancreatic adenocarcinoma.
In selected patients with uterine carcinosarcoma alone, aggressive management may be offered after surgery, including both chemotherapy and radiation (8, 9). Brachytherapy has also been used (10). These treatments address the risk of recurrence, which is both high, at 60%, and early, usually occurring within 12 months of treatment (8); treatment is also used for palliative purposes. Most studies have shown better outcomes with chemotherapy than with radiation, and one study showed improved survival with chemotherapy in a group of 49 patients: 3-year overall survival of 66% with chemotherapy (with or without radiation) versus 34% for radiation alone (11). A variety of chemotherapy regimens have been used. The Gynecologic Oncology Group supports the use of iphosphamide and paclitaxel (12), but cisplatin-based regimens are favored (13).
Treatment for patients with PNETs focuses on aggressive surgical resection, including metastatic sites. There is evidence that debulking PNETs may improve survival and debulking/resection of symptomatic functional PNETs is recommended for palliation of symptoms (i.e., symptoms of hormone excess, such as Zollinger-Ellison syndrome, carcinoid syndrome). However, recurrence may be as high as 76% even after complete resection, including resection of hepatic metastases (6). Other methods utilized to control metastatic PNETs include embolization, particularly for hepatic metastases, and ablation of disease with radiofrequency or stereotactic radiosurgery (14).
Biotherapy options include somatostatin analogs when somatostatin receptor scintigraphy (SRS) results are positive and interferon-alpha when SRS results are negative. If biotherapy fails, chemotherapy with streptozotocin, 5-fluorouracil, and doxorubicin can be considered (6). As Ehehalt et al summarized (6), experimental approaches still to be validated include internal radiation therapy (15), polypeptide radionuclide receptor therapy (16), antiangiogenic therapy (17), and targeted chemotherapy regimens (18–20).
For our patient with both types of cancer, the goal of treatment after surgery was palliative. Locoregional radiation was instituted in an attempt to provide symptomatic relief of her vaginal bleeding. Because of the aggressive nature of her cancers, her metastatic disease progressed shortly after she recovered from surgery. Palliative chemotherapy can be considered in such cases, but such patients should be counseled that there would be little benefit with the inherent risks of systemic therapy.
Among the unique features of this case are that the patient presented with multiple primaries simultaneously, both with neuroendocrine differentiation. The neuroendocrine component of the MMMT was undifferentiated, whereas the morphology was less aggressive (well-differentiated) in the pancreas. Further, the metastases for each respective region mimicked the histology for the neuroendocrine component of the tumor in the region (i.e., well-differentiated for abdomen, undifferentiated for pelvis).
The authors thank Cynthia Orticio, MA, ELS, for editorial contributions.