The surgical treatment of thoracic metastases in ovarian cancer

Ovarian cancer still represents one of the most aggressive malignancies aff ecting women worldwide. Unfortunately many patients are still diagnosed in an advanced stage of the disease when distal metastases are already present. When it comes to thoracic involvement in advanced stage ovarian cancer, this may develop via peritoneal, hematogenous and lymphatic route. This is a literature review of the most commonly seen involvements in ovarian cancer and of the most appropriate surgical procedures which might be performed in order to increase the rate of complete cytoreduction.


INTRODUCTION
Ovarian cancer is one of the most lethal diseases, representi ng 2% of all malignancies and 4% of malignancies in women. (1) Majority of cases are diagnosed in advanced stages of the disease, up to 50% of pati ents being diagnosed in FIGO stage III and 13% in stage IV. In pati ents diagnosed with metastati c ovarian cancer the 5 year survival rate varies between 28-33%. (2) Advanced ovarian cancer usually presents with peritoneal seeding, distant metastasis, mainly hepati c and pulmonary, multi ple adenopathy, neoplasti c pleuriti s.

Peritonectomy and diaphragmatic resections
Many pati ents have diaphragmati c involvement. In these cases, in order to increase the rate of complete cytoreducti on and secondarily to improve the overall survival, various surgical procedures have been imagined. Nowadays there are three types of surgical procedures managing diaphragmati c disease: the fi rst one is a superfi cial destructi on or ablati on (SD) which consists of coagulati on of very small and ti ny nodules (≤ 2-3 mm), the second procedure is diaphragmati c peritonectomy (stripping, DS) defi ned as dissecti on and resecti on of the peritoneum presenti ng tumoral seeding while the third type is the full thickness diaphragm resecti on (FTDR) which means diaphragm muscle resecti on or central tendon resecti on including the overlying peritoneum and pleura. Aft er pleurectomy and before performing a full-thickness suture a catheter is placed in the pleural cavity. The last procedure in associated with pneumothorax and a higher rate of pleural eff usion. (3) In most cases diaphragmati c peritonec-tomy is associated with full thickness diaphragm resecti on. (4) Depending on the local diaphragmati c extension of the metastases the adequate type of surgery is selected. (1) As presented before advanced ovarian cancer is usually associated with residual tumor and diaphragm metastasis (5) and an important percent of these pati ents are submitt ed to cytoreducti ve surgery due to the fact that residual disease remains the most important independent prognosti c factor. (6) In some cases the metastases are located not only in the diaphragam but also in the liver. New modern techniques such as roboti c resecti on of liver and full-thickness diaphragm are menti oned. (7) Traditi onally, opti mal cytoreducti on of ovarian cancer has been limited to abdominal disease. While there is an increase in morbidity and mortality with upper abdominal surgery, the outcomes appear to justi fy the risks. (6) While liver and diaphragmati c resecti on are becoming more common, lung disease pose unique challenges.

Pulmonary resections for ovarian cancer metastases
There are few studies referring to pulmonary metastasectomy in ovarian cancer. A substanti al number of studies refer to gynecologic cancerthis review takes in considerati on only those where ovarian cancer is included. (8) Although in ti me the indicati on and the adequate type of resecti on during pulmonary metastasectomy from diff erent types of cancers has been debated some questi ons sti ll remain. (9) This is also the case of pulmonary mestastasis from ovarian cancer. (8) In order to help the practi ti oner guidelines have been published for the management of pulmonary metastasectomy from diff erent cancers. Specifi cally guidelines for pulmonary metastsectomy from ovarian cancer haven't been published yet, but there are studies conducted on this subject which are similar with those presented for breast and colonic cancers. Generally, pulmonary metastasectomy originati ng from gynecologic malignancies should be taken in considerati on in pati ents (1) with no evidence of recurrent disease at their primary, (2) with isolated pulmonary metastases, (3) in pati ents with adequate pulmonary reserve, and (4) in the absence of uncontrollable extrathoracic metastati c disease. (8) Pulmonary metastasectomy is a controversial subject in the oncology fi eld. (10) For some histophatological subtypes such as epithelial cancer signifi cant survival benefi t aft er the resecti on of metastases was proven, but clear inclusion criteria in this group could not be specifi ed. (11) The most common type of pulmonary metastasectomy in diff erent cancers includes anatomical pulmonary resecti ons, wedge resecti ons and laser excisions. (12) The procedure of choice for treatment of pulmonary metastati c disease is pulmonary wedge excision. Extensive pulmonary resecti on, such as pneumonectomy, should be discouraged in these pati ents with poor prognosti c factors. (8) Segmentectomy for pulmonary metastases is a new technique that seems promising. It is less invasive than lobectomy, negati ve margins can be achieved to ensure complete resecti on of lesions and an adequate pulmonary functi on is easier to be preserved, but large studies regarding segmentectomy in ovarian cancer pulmonary metastases haven't been published yet. (12) Even in cases submitt ed to complete primary cytoreducti on, recurrent ovarian tumors might develop and a secondary cytoreducti on might be needed. Koichi et al reported the case of a pati ent diagnosed with liver and diaphragmati c metastases originati ng from an ovarian clear cell tumor which were successfully resected; after a year she developed pulmonary metastases and right lower lobectomy was performed. (8) Few cases of direct extension of the diaphragm metastasis into the lung are presented; in these cases en bloc full-thickness diaphragmati c resecti on including a porti on of lung ti ssue is considered opti mal soluti on. (13) In rare cases aft er several debulking procedure metastases are found in the liver with direct extension into diaphragm and lung. In these cases the tumor is resected en bloc with atypical hepatectomy full thickness diaphragm resecti on and lung resecti on. A right lower lobe wedge resecti on of the tumor mass en bloc is menti oned. (14) Right pulmonary metastasectomy is more frequently performed than left one because usually pulmonary metastases are found in the right lung, but are some case reports that menti on metastases from ovarian granulosa cell tumor in the left lung in which a parti al resecti on of the left lung was performed. (15) Distant metastases in multi ple organs can be found in ovarian cancer. This is the case of a pati ent with immature teratoma of the ovary that developed lung, liver and brain metastases. The management of the case was sequenti al resecti ons of all three metastati c areas which led to a ten year survival (16).
Thoracic metastases of ovarian cancer are common, the thorax being the third site of disseminati on aft er liver and diaphragm. Although noninvasive techniques as positron emission tomography with 18F-fl uorodeoxyglucose -(18F) FDG-PET -have been developed to investi gate this area, someti mes is diffi cult to establish the exact pathology of pleural or lung nodules. Thoracoscopy is a technique performed when the suspicion of metastasis exists and when nodules on visceral pleura are found are resected. Metastases from ovarian granulosa cell tumor have been diagnosed in visceral pleura by this method. (17)

Supradiaphragmatic lymph node involvement in ovarian cancer
At this moment the enlargement of supradiaphragmati c lymph nodes is not always associated with malignancy and even if they are positi ve the prognosti c signifi cance and staging indicator isn't known. (18) Because of these fi ndings several techniques to explore the cardiophrenic space have been developed. A new method to biopsy these lymph nodes is transabdominal cardiophrenic lymph node dissecti on (CPLND). (19) It is considered more useful than video-assisted thoracic surgery (VATS) in advanced ovarian cancers with cardiophrenic involvement in which biopsy can be performed at the same ti me with cytoreducti ve surgery.
Usually cardiophrenic lymph nodes are associated with advanced, extensive intrathoracic disease represented by right-sided pulmonary and pleural disseminati on. (20) Isolated adenopathy of the mediasti num is rare while isolated bilateral adenopathies have been never described before in associati on with ovarian cancer. A few studies noted the fi ndings of isolated abnormal cardiophrenic lymph nodes in diff erent types of ovarian cancer. (18,19) Two cases of isolated adenopathy without lung or pleural involvement from papillary ovarian cancer are presented which were removed completely through the help of video-assisted thoracic surgery. (18,19) Mediasti nal cyst with benign aspect without pleuro-pulmonary pathological fi ndings on CT evaluati on was identi fi ed at a woman with personal history of ovarian cystadenocarcinoma which was identi fi ed aft er en-block resecti on with free margins as mediasti nal recurrence of the ovarian cancer. (20) In general when lymph nodes are identi fi ed with metastases from ovarian cancer the pati ent is already diagnosed with the primary disease. In this way even though clinical malignancy characters can't be found on the modifi ed lymph nodes the suspicion of the disseminati on is put into questi on. Isolated metastati c papillary patt ern lymph nodes without personal history of cancer were identi fi ed on immunohistochemistry aft er surgical biopsy before the intraabdominal ovarian serous carcinoma manifests. (21) Mediasti nal metastases from high-grade serous ovarian carcinoma are menti oned in diff erent case reports. (22) Video-assisted thoracoscopic surgery performed for an irregularly-shaped calcifi ed chest mass along the right cardiac border (identi fi ed as low-grade papillary serous carcinoma from ovary), multi ple pulmonary nodules identi fi ed on CT at a woman with pelvic mass measuring 6×7 cm found an unresectable mediasti nal mass because of her involvement in the phrenic nerve and the superior vena cava that compresses the ti ght atrium. A right middle lobe wedge resecti on was performed for pulmonary metastases and mediasti nal mass was treated with Cyberknife radiosurgery. (23) Systemati c mediasti nal lymph dissecti on is accepted to be performed for complete resecti on in non-small cell lung cancer. (24) In other types of cancers with lung metastases when pulmonary metastasectomy is performed systemic mediasti nal lymphadenectomy is not a practi ce. When modifi ed mediasti nal lymph are found in preoperati ve (thoracic CT, PET) investigati ons and when the suspicion of malignancy appears a series of procedure including mediasti noscopy are performed although positi ve results are rare. At this moment the prognosti c signifi cance of positi ve lymph nodes with pulmonary metastasectomy has not been established. (25) It appears that the presence of lymph node metastases infl uences the survival and tumor recurrence. Due to these factors some authors sustain the benefi ts of systemati c lymph node dissecti on at the ti me of pulmonary metastasectomy for metastati c ovarian carcinoma but sti ll a standard therapeuti c protocol has not been established. (26) Mediasti nal involvement in pati ents with ovarian cancer is rare (27) and is associated with advanced disease stage and poor prognosis. Prevascular mediasti nal lymph node biopsy showed metastati c ovarian adenocarcinoma from serous papillary ovarian adenocarcinoma. (28) Malignant pleural eff usion from metastati c ovarian cancer usually necessitates the initi ati on of chemotherapy. Symptomati c pati ents may require thoracocentesis. Other invasive methods used for pleural eff usion used are tube thoracostomy, small-bore catheters (pigtail catheters), both of them with the advantage of drainage and pleurodesis.
Pati ents with suspected advanced ovarian cancer and moderate to large pleural eff usions may be evaluated through video-assisted thoracic surgery. Video-assisted thoracic surgery has an important role in the management of these cases. Depending on the fi ndings at video-assisted thoracic surgery multi ple types of procedure as pleural cytology, chest tube drainage, adheolysis, directed biopsies can pe performed. Pleural nodes greater than 1 cm are resected as part of intrathoracic cytoreducti on with the help of this procedure. (24,29) Thoracic metastasis in ovarian cancer represents an open problem for oncology. Pulmonary metastasectomy can improve survival in selected pati ents, but litt le informati on exists regarding this group of pati ents. Although general practi ce is menti oned: pati ents (1) with no evidence of recurrent disease at the primary site, (2) with pulmonary metastases that are limited in number, (3) with the pati ent who has adequate pulmonary reserve, and (4) when no evi-dence of extrathoracic metastati c disease exists or can be controlled, informati on about the cell type of the primary tumor, the exact number and localizati on of metastases does not exist. Also the surgical technique used for pulmonary resecti on poses questi ons in some cases: wedge resecti ons, lobectomy or segmentectomy? Informati on about regional lymph nodes are even scarcer. Recommendati ons regarding the indicati ons and potenti al therapeuti c role of mediastinal lymphadenectomy or sampling have not been defi ned.
Several prognosti c indicators have been identi fi ed such as short interval between resecti on of the primary tumor and the fi rst pulmonary metastasesectomy and the fi nding of metastases in mediasti nal lymph nodes.

CONCLUSIONS
Although a standard therapeuti c protocol has not yet been established complete macroscopic resecti on of thoracic lesions originati ng from ovarian cancer seems to be the most efficient opti on in order to improve survival. However more studies are sti ll needed in order to assess the most important prognosti c factors and to decide in which cases these resecti ons might provide a more signifi cant improvement of long term outcomes.