The term primitive neuroectodermal tumor (PNET) was used to describe a group of tumors that were thought to be derived from neuroectodermal cells. They are composed of small round cells with different degrees of neural, glial, and ependymal differentiation. The World Health Organization recognizes central- and peripheral-type PNETs. Central PNETs usually involve the brain and the spinal cord, whereas the peripheral PNET involves the sympathetic nervous system, the skeleton, and soft tissues.1
Peripheral PNETs are classically described as small round blue cell tumors of putative neuroectodermal origin. Although they are commonly described as sarcomas that occur in childhood, adolescence, and early adulthood, primary cases have also been reported in visceral sites, such as the kidney, bladder, pancreas, and testis.2 The tumor may occur anywhere in the body and in any age group. The precise diagnosis of such tumors is challenging by routine microscopy because of frequent nonspecific histologic features and requires thorough histopathologic examination, immunohistochemistry, and cytogenetic analysis.
Peripheral PNETs of the female genital tract are very rare. To date, few cases of peripheral PNET have been reported in the English-language literature, and data on long-term follow-up are not available.3–6 The deterrent factor of clinical outcome for patients is still elusive. Here, we report the clinicopathologic profile, management, and follow-up of 11 patients with peripheral PNET arising in the female genital tract, mainly focusing on its clinical characteristics, treatment, and clinical outcomes.
MATERIALS AND METHODS
Eleven patients with PNET were treated at Peking Union Medical College Hospital from April 2001 to May 2013. All cases were confirmed as pure PNETs by histologic and immunohistochemical examination. Eight patients received initial treatment at our hospital, whereas 3 patients received their initial treatment at other hospitals but subsequently came to our institution for reoperation after diagnosis. The location of 11 cases of PNET in the female genital tract included vulva (2 patients), cervix (2 patients), uterus and its ligament (5 patients), and the ovaries (2 patients).
Clinical information was obtained from a review of the patients’ clinical records, and follow-up information was obtained during reexamination at the hospital or telephone conversations with the patients.
Pathologic specimens were centrally reviewed by 2 pathologists at Peking Union Medical College Hospital to confirm the diagnosis.
A total of 13,137 patients with malignant tumors in the female genital tract were treated at our hospital during the same period. Primitive neuroectodermal tumors accounted for 0.08% (11/13,137 patients) of all malignant tumors.
The clinical characteristics of the 11 patients with PNET are summarized in Table 1. Their ages at presentation ranged from 18 to 59 years with a median of 31 years. Their clinical manifestations also varied, depending on where the tumors originated. Both of the vulvar PNETs presented with a rapidly increasing mass and vulvar pain. Although 1 of the patients with cervical PNETs presented with abdominal distension and pain that had lasted 15 days, another patient presented with vaginal bleeding that was associated with a mass prolapsed from the vagina. Of the 5 patients with PNETs involving the uterus and its ligaments, 3 patients presented with irregular vaginal bleeding, 2 patients presented with abdominal distension and pain, and 1 patient had a diagnosis during an operation for a different reason. Both ovarian PNETs presented with pelvic solid cystic masses. All of the patients can find the mass by either physical examination or imaging examination. After surgical evaluation or imaging studies, the International Federation of Gynecology and Obstetrics stage was determined as follows: stage I (1 patient), stage II (3 patients), stage III (3 patients), and stage IV (2 patients). In 2 patients, information regarding stage was unavailable because they had received their initial treatment at another hospital.
Pathologic and Immunohistochemical Findings
The sizes of the tumors were varied, with the maximum diameters ranging from 2 to 20 cm. They were mainly solid (7/11 patients) without capsules. One consisted of a solid part and a cystic portion, and the others were cystic with pseudocapsules. On cross-sections, the tumors showed a solid yellowish white matter with hemorrhage and necrosis. Microscopic examination revealed a malignant pattern of a monomorphic population of small round blue cells with poorly to well-formed rosettes.
On immunohistochemical staining, all of the patients (11 patients) were CD99 positive. Seven patients were evaluated for synaptophysin expression, of which 6 patients had demonstrable synaptophysin expression with 1 weakly positive. The remaining 1 patient was negative. Of the 6 patients stained with neuron-specific enolase (NSE), all patients had expression of NSE with 1 patient staining particularly strong. Vimentin was performed on 4 patients. In addition, S100 was used in 3 patients, which were found to be negative. The neuroectodermal component had no expression of cytokeratin in 7 of 9 patients stained for cytokeratin (AE1/AE3). In 2 patients, there was very weak focal cytokeratin AE1/AE3 expression in neuroectodermal cells. Immunoperoxidase results of the patients in this article are summarized in Table 2.
Level of CA125
In all patients, serum CA125 levels were measured before and after the operations; the basic levels of which were summarized in Table 1. In 8 patients, the levels were elevated before the operations, in addition to the 2 vulvar PNETs and 1 cervical PNET (case 3), and the levels decreased markedly to normal when the disease was controlled. CA125 levels increased when the tumors progressed. The CA125 level of 1 patient (case 3) was normal, but the level increased when the tumor recurred, and this patient died only 1 month after recurrence. The other patient with uterine PNET had elevated levels before the initial operation, which decreased to a normal level after the operation and remained normal throughout the tumor recurrence and even now 5 years after the second operation. The 2 uncontrolled patients, 1 of whom had a normal CA125 level with vulvar PNET and the other 1 with a CA125 level of more than 700 U/mL, died rapidly after diagnosis. It is worth that the CA125 levels in both vulvar PNETs were normal.
Treatment and Follow-up
Ten of the 11 patients who presented with primary PNET in the female genital tract underwent surgical resection 1 to 2 times as summarized in Table 1, whereas the remaining patient had only underwent a vulvar biopsy (case 1). Nine patients underwent preoperative or/and postoperative combination chemotherapy. The regimens of chemotherapy were dependent on the origin of the tumor and included cisplatin, epirubicin, and ifosfamide (PEI), cisplatin, epirubicin, and cyclophosphamide (PAC), and bleomycin, etoposide, and cisplatin (BEP).
Three patients experienced recurrence (cases 2, 3, and 9). One patient (case 9) only had pelvic recurrence 60 months after the first treatment and received surgical treatment and chemotherapy again. She currently shows no signs of recurrence or metastasis for 79 months. The other patient (case 2) had lung metastasis 8 months after primary treatment, which was local radical vulvectomy and chemotherapy (PEI, 4 courses), and she received chemotherapy (PAC, 5 courses) and died 5 months later. The last one (case 3) had recurrence 6 months after initial operation and chemotherapy (cisplatin, vincristine, and bleomycin, 2 courses) and died of widespread disseminated tumor 3 months later.
The follow-up in these patients ranged from 1 to 145 months (median, 30.5 months). Six patients died within 1 to 15 months with 2 patients dying only 1 month after the diagnosis was made, and 3 patients are alive with no evidence of disease 30 to 145 months after the diagnosis. One patient is under combination chemotherapy treatment now, and 1 patient was lost to follow-up.
Peripheral PNET constitutes very rare malignancies and aggressive of the female genital tract. It had reported that the most common site of origin were the ovaries,7 followed by the uterine body,8 and less commonly the cervix,6,9 vagina, and vulva.3 As previously reported, the main presenting symptoms of PNET in the female genital tract are lower abdominal distension and pain, irregular vaginal bleeding, uterine enlargement, and increasing mass.8 The incidence is difficult to ascertain because these tumors are rare and diagnosis is difficult. We found that PNETs accounted for only 0.08% (11/13,137 patients) of all female genital tract malignant tumors during the same period in our hospital. Therefore, more data are required to confirm the incidence.
The diagnosis of PNET is difficult by routine hematoxylin and eosin staining alone because of overlapping clinical, imaging, histologic, and immunophenotypic features with other small round cell tumors, such as primary small cell tumor, rhabdomyosarcoma, osteosarcoma, non–Hodgkin lymphoma, malignant melanoma, and metastasis.3 The diagnosis of peripheral PNET is made based on a combination of morphologic and immunohistochemical features and electron microscopy examinations. In many cases, rosettes are formed from the cell’s cytoplasmic extensions. CD99 (a cell surface product of the MIC2 gene) represents the specific immunohistochemical marker for the diagnosis of PNET and is present in more than 97% of the cases.10 In our cases, it was intensely and diffusely expressed on tumor cell membranes. Some tumor cells are positive for vimentin and may focally express NSE, chromogranin, synaptophysin, and S100.11 Markers that were not expressed include CD20 (B-cell lymphoma) and CD15 (Hodgkin disease, some B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, and most acute nonlymphocytic leukemia), which further supported the histopathologic diagnosis.3 Genetic techniques in molecular pathology can identify translocations that help distinguish peripheral PNETs from other round cell tumors. Approximately 85% of peripheral PNETs reported cases have a balanced t(11;22)(q24;q12) translocation that results in formation of a chimerical fusion of the EWS-FLI1 gene.12
To date, there are no standard guidelines for treatment of peripheral PNET because of the small number of cases in different body sites.13 Extraskeletal PNETs had more aggressive behavior and a worse prognosis than bone PNET (Ewing sarcoma); therefore, they require multimodal treatment strategies. Current treatment strategies for PNET include surgical resection, which is preferred whenever feasible,14 and adjuvant chemotherapy, which was thought to play an important role in the management of these tumors because these tumors had a 80% to 90% relapse rate with surgery alone15 and disseminated in the regional lymph nodes, lung, and bones.6 The overall survival has dramatically improved through adjuvant systemic chemotherapy.16 To avoid the risk of radiation-induced sarcomas, radiation therapy is usually not recommended for patients receiving complete resection. It is used for patients with inoperable tumors and/or positive surgical margins or with a poor histologic response.16 However, the latest population-based study showed that adding preoperative or postoperative radiation therapy to a surgical resection with at least a marginal margin did not improve outcome.17 In our cases, 10 patients underwent local surgical resection including total hysterectomy with bilateral salpingo-oophorectomy with or without pelvic lymphadenectomy. Multiple chemotherapy regimens for treatment of PNETs have been reported, most of them based on trials of bone PNETs.18 Primary PNET of the ovary is generally considered a variant of germ cell tumors, and the treatment modality is also considered to be the same.7 Chemotherapy agents used include cisplatin, doxorubicin, ifosfamide, vincristine, cyclophosphamide, dactinomycin, and VP-16, but the consensus of optimal chemotherapy treatment still needs to be determined.
Similar to the skeletal Ewing sarcoma/PNET, the most unfavorable prognostic factor is the presence of distant metastasis at the time of diagnosis.19 In our cases, 6 (6/11) patients died of the disease within 1 to 15 months. Of these, 3 patients died in less than 1 month after diagnosis or recurrence, 1 patient with widespread disease of the abdominopelvic cavity, and the other 2 patients with pulmonary metastasis. Other unfavorable prognostic factors of the PNET tumors include the tumor late stage, insufficient surgical resection, larger size, central lesions (as in the pelvis or spine), and poor response to chemotherapy.19 However, Serlo et al17 reported that younger patients and patients with peripheral primary tumors have a better prognosis, and chemotherapy before local treatment and high-dose chemotherapy with autologous stem cell rescue seemed to improve prognosis. Three of our patients with early stage of the disease are still alive with no evidence of disease 30 to 145 months after diagnosis. It is worth noting that CA125 may be an important marker for prognosis and follow-up, especially for the PNET of the female internal genital tract. CA125 tests are just as routine tests for all patients with suspicious tumor. In our 11 cases, the CA125 levels of 8 patients were elevated before treatment and fell markedly to the normal when the disease was controlled. Although the level of CA125 does not correlate with the severity of the disease, it increases when the tumor progresses. There are only few cases that report the CAl25 level,20 and the CA125 levels in 2 of the patients with vulvar PNETs were normal before treatment. One of the patients with uterine PNET had a CA125 level of 918 U/mL that decreased to normal.20 Therefore, the correlation between CA125 and peripheral PNET needs to be investigated further.
In conclusion, peripheral PNET is a very rare disease with fast and infiltrating growth in the female genital tract. It requires early detection, correct diagnosis, and appropriate treatment. Multimodal treatment strategies include total excision, adjuvant chemotherapy, and/or radiotherapy. Because peripheral PNETs in general are aggressive tumors, close follow-up is necessary. CA125 level may be an important marker for prognosis and monitoring of PNET in the female internal genital tract. Studies of more cases of primary peripheral PNET with longer follow-up periods are needed to estimate the clinical characteristics and treatment of PNET in the female genital tract.
The authors thank all the personnel of the medical record library of Peking Union Medical College Hospital for data collection.
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