No patients in this group Non-pulmonary visceral metastases AFP >10 000 ng/ml HCG >50 000 iu/ml LDH >10 normal 16% of teratomas: 5-year survival 48% Management of Stage I seminoma (cid:2) 20% seminomas recur after orchidectomy (cid:2) 90% of relapse is in para-aortic nod es (cid:2) Radiotherapy to para-aortic/pelvic nodes reduces relapse to 4% (cid:2) Current trials for chemotherapy in Stage 1 seminoma (cid:2) Radiotherapy to para-ao rtic nodes in all stages (T10 \200\223S1) (cid:2) Risk factors for pelvic node involvement \200\224previous inguino-scrotal surgery \200\224maldescent If risk factor is present giv e pelvic node radiotherapy (cid:2) OHO-22(389-416) 11/18/02 8:33 AM Page 414 GENITOURINARY CANCERS 414 IVU to identify kidney position \200\224limit radiation to kidney \200\224horseshoe kidne y is contraindication to radiotherapy (cid:2) (cid:2) Standard dose of radiotherapy is 30 Gy in 15 fractions over 3 weeks (cid:2) Side-ef fects of radiotherapy \200\224nausea \200\224tiredness Stage 2a and 2b seminoma (cid:2) Radiotherapy \200\22430 Gy in 15 fractions over 3 weeks Stage 2c, 3, and 4 seminoma (cid:2) Chemotherapy (cid:2) Toxic in older patient (cid:2) Bleomycin pneumonitis common Stage 1 teratoma (cid:2) Relapse rate after orchidectomy alone \200\22425% (cid:2) Vascular or lymphatic inv asion relapse rate \200\22450% If vascular or lymphatic invasion \200\2242 courses of BEP reduce relapse rate to 1% (cid:2) (cid:2) No vascular or lymphatic invasion \200\224surveillance (90% cure rate) (cid:2) Surv eillance is \200\230active \200\231 \200\224monthly clinic visits for \201rst year \200\2243 CT scans \201rst year \200 \22480% who relapse do so in \201rst year Stage 2, 3, and 4 teratoma (cid:2) Standard treatment for metastases \200\224Bleomycin \200\224Etoposide \200\224Cis platin (cid:2) Cure rates \200\224good prognostic group (90%) \200\224intermittent group (75%) \200\224poor prognosis (50%) (cid:2) Role of high-dose chemotherapy, marrow or stem cell transplanta- tion \200\224not clear (cid:2) Chemotherapy side-effects common \200\224nephropathy \200\224neuropathy \200\224ototoxiciy \200\224myelosupression \200 \224Bleomycin pneumonitis (fatal in 10%) (cid:2) Results better in specialized centers (cid:2) Monitor response \200\224scans, tumor markers OHO-22(389-416) 11/18/02 8:33 AM Page 415 TESTICULAR CANCER 415 Post-chemotherapy surgery or residual masses Where residual masses are present after chemot herapy for metastatic testicular teratoma, surgery should be performed to resect these. The majority of these will be in the retroperitoneum, and extensive and dif \201cult surgery is often necessary for a complete resection. The resid- ual masses may contain differentiat ed teratoma, \201brosis, or indeed viable tumor, and further chemotherapy may be indicate d. Surgery should usually only be undertaken when markers have normalized. Residual pulmonary masses should also be resected where possible. The problem of surgical t echnique and anesthetic risk, particularly as most patients will have been exposed to Bleom ycin, again demand that patients are seen and operated on in a center experienced in this s urgery. Following primary management of metastatic disease, fairly intens- ive follow-up is necessa ry as in those patients who relapse, salvage therapy can be effective in about 25% of cases . Non-germ cell testicular tumors. These represent a very small proportion of testicular tumo rs. Stromal tumors such as those arising from Leydig cells are generally thought to be beni gn, but metastases have been reported in approxi- mately 10% of cases. Unfortunately, patho logical examination of the primary tumor does not give a good indication of the propensity to metastasize, making management dif \201cult. It is reasonable to perform normal staging investigations and monitor such patients for about two years. Testicular lymphomas are the commonest testicular cancer in elderly men and should be treated along the same principles as lymphomas arising at other sites. Psychological issues There is undoubtedly a signi \201cant psychological morbidity associa ted with diagnosis and subsequent management of men with germ cell tumors. The loss of a te sticle alone in many patients is considered mutilating, and a testicular prosthesis should be inserted when possi- ble. The optimal support for these patients is not clear, but psych olog- ical help should be available. OHO-22(389-416) 11/18/02 8:33 AM Page 416 GENITOURINARY CANCERS 416 Further reading Atzpodien, J. et al. (1990) Home therapy with recombinant interleukin-2 and interferon (cid :2)- 2b in advanced human malignancies. Lancet 353, 1509 \200\22312. Cookson, M.S., Herr, H.W., Zhang, Z.F., et al. (1997) The treated natural history of high risk super \201cial bladder cancer: 15 year outcome. J Urol 158, 62 \200 \2237. MRC Renal Cancer Collaborators. (1999) Interferon-(cid:2) and survival in metastatic renal carcinoma: early results of a randomized controlled trial. Lancet 353, 14 \200\22317. Raghavan, D., Shipley, W.U., Garnick, M.B., Russell, P.J., and Richie, J.P. (1990) Biology and management of bladder cancer. N Eng J Med 322, 1129 \200\22338. Scottish Intercollegiate Guidelines Network (2000). Management of adult testicular germ cell tumors: a national clinical guideline. OHO-23(417-442) 11/18/02 8:34 AM Page 417 Chapter 23 Gynecological cancer Ovarian cancer 418 Cancer of the uterine corpus 422 Cancer of the cervix 426 Vaginal and vu lval cancer 432 Trophoblastic tumors 436 OHO-23(417-442) 11/18/02 8:34 AM Page 418 gynecological CANCER 418 Ovarian cancer Introduction Ovarian cancer is the \201fth commonest cancer in women with nearly 6000 cas es diagnosed and over 4000 women dying of the disease each year. The majority of cases occu r over the age of 55 years with the peak in the 65 \200\22375 age group. Treatment consists of surgery, followed for most patients by chemotherapy which, for over 20 years, has consi sted of platinum-based regimens. Etiology The risk of ovarian cancer appears to relate to the number of ovula- tory cycles i n a woman \200\231s lifetime and multiple pregnancies. Use of the oral contraceptive pill s eems to offer protection, infertility raises the risk. Less than 5% are clearly hereditary \200\224associated with BRCA1 or BRCA2 or Lynch II families. Pathology More than 80% of ovarian malignancies are epithelial, the rest com- prise germ ce ll and stromal tumors. Epithelial cancers are classi \201ed by their cell type (serous, mu cinous, endometrioid, Brenner, mixed) and by their grade. CA125 80% of women with advanced ovarian cancer have elevated serum CA125 and this marker i s valuable in monitoring response to therapy and in the detection of early relapse. However , it is not speci \201c for ovarian cancer and is elevated in association with other perit oneal pathologies. Presentation and staging The vast majority of women present with disease that has spread be yond the ovary to involve the peritoneum and other abdomino- pelvic organs. The most common symptoms are of abdominal dis- comfort and swelling; vaginal bleeding and gastrointestinal and urinary symptoms also occur. The two main prognostic factors in ovarian cancer are stage and the amount of residual dise ase after surgery. Five-year survival rates according to stage are as follows: 75% (cid:2) Stage I 45% (cid:2) Stage II 20% (cid:2) Stage III OHO-23(417-442) 11/18/02 8:34 AM Page 419 OVARIAN CANCER 419 Table 23.1 Staging of ovarian cancer Stage Description Ia Tumor con \201ned to one ovary Ib Tumor con \201ned to both ovaries Ic Tumor Stage I but with capsule ruptured or malignant ascites II Tumor with pelvic extension III Tumor with peritoneal implants outwith the pelvis or involved small bowel; retroperitoneal or inguinal nodes IV Distant metastases (cid:2) Stage IV Less than 5% The majority of patients present with advanced disease (Stage II \200\223IV) with a corresponding poor prognosis. The three-year survival rate for patie nts with advanced ovarian cancer but no residual disease after surgery is 75%, and for thos e with maximum residuum less than 1 cm, 50%. Patients who have greater than 2 cm disease af ter their initial surgery have a poor prognosis with only 20% of patients sur- viving three years. Median survival times for patients with subopti- mally debulked disease (greater th an 1 \200\2232 cm) range from 16 to 29 months and from 26 to 96 months for patients with op timally debulked disease. Surgery Patients must undergo full surgical staging \200\224generally early ovarian cancer of good prognosis (Stage Ia \200\223b, well differentiated) does not require adjuvant chemo therapy. A surgical staging procedure consists of: (cid:2) A midline incision (cid:2) Total abdominal hysterectomy (cid:2) Bilateral salpingo-oophorectomy (cid:2) Omentectomy (cid:2) Multiple peritoneal biopsies and washings (cid:2) Lymph node sampling of the para-aortic a nd pelvic regions (cid:2) Careful assessment of the subdiaphragmatic areas There is uncerta inty as to which patients with Stage I disease require adjuvant chemotherapy and there are three trials (MRC, EORTC, and Scandinavian) currently addressing this issue. Radical surgery plays an important role in the treatment of ovarian cancer. In addition, a randomized trial has shown that for patients who cannot be optimally debulked at initial la parotomy, interval debulking surgery after three cycles of chemotherapy confers a signi \201cant survival bene \201t. It is reasonable to treat with chemo- therapy and plan inter val debulking surgery if clinical and imaging OHO-23(417-442) 11/18/02 8:34 AM Page 420 gynecological CANCER 420 assessment show that optimal debulking will not be possible. A small proportion of patients of child-bearing age who wish to preserve fer- tility may be treated by conservative surge ry, but these patients need careful selection and counseling. First-line chemotherapy Cisplatin was introduced in the 1970s and the main controversy dur- ing the 1980s was whether patients required single-agent or platinum- based combination th erapy. A meta-analysis published in 1991 suggested a survival bene \201t for platinum-base d combinations but sin- gle-agent carboplatin remained standard treatment in the UK. In 199 6, the Gynaecologic Oncology Group published the results of a pivotal study (GOG 111) which demonstrated a signi \201cant survival advantage for cisplatin \200\223paclitaxel over ci splatin \200\223cyclophosphamide (the gold standard therapy in the US and most of Europe). Median survival was improved by over one year in this study and cisplatin \200\223 paclitax el became standard therapy in the US. In 1998, the Intergroup published con \201rmatory da ta from a similar study. Cisplatin \200\223paclitaxel causes signi \201cant neuro-toxicity particularly with shorte r infusions of paclitaxel (the Intergroup used a three-hour, GOG 24-hour infusion), althoug h these do reduce the risk of neutro- penia. Phase II data of carboplatin \200\223paclitaxe l demonstrate similar response rates to cisplatin \200\223paclitaxel, with less toxicity. T hese regi- mens are now being compared directly in Phase III studies. Treatment at relapse Patients who relapse after \201rst-line therapy are incurable. The m ajority of patients relapse within 12 months and the length of the treatment- free interval before relapse is an important factor in predicting response to second-line therapy. Peopl e with a treatment-free interval of greater than 12 months should be re-challenged with a p latinum- containing regimen. Other indicators of response are the bulk of disease, previous response to treatment, and the number of disease sites. A number of new agents including topotecan, liposomal doxo- rubicin, etoposide, gemcitabine , and altretamine have response rates of 15 \200\22325% in this setting. Follow-up Clinical dilemmas arise after \201rst-line therapy \200\224what follow-up pro- tocol is appropriate and when should second-line therapy be insti- tuted? All patients have serial CA125 estimations but as soon as the marker rises, much anxiety is caused and many patients expect treat- ment. There is no evidence that treating simply because of a rising CA125 is of bene \201t, and because second-line therapy is not very effec- tive within 12 months of previous treatment, there is good reason to OHO-23(417-442) 11/18/02 8:34 AM Page 421 OVARIAN CANCER 421 try and withhold chemotherapy until patients are either symptomatic or have measurably prog ressive disease on imaging or clinical exami- nation. An MRC \200\223EORTC study is address ing this important issue, randomizing patients with a rising CA 125 to immediate second-lin e therapy or delayed treatment. New approaches The overall response rate to platinum \200\223paclitaxel therapy is 70 \200 \22375% with 30 \200\22350% of patients achieving a complete clinical remission. The questi on has been raised whether some form of consolidation or maintenance therapy should be inve stigated. Possible approaches include: Intra-peritoneal chemotherapy (cid:2) High-dose systemic chemotherapy (cid:2) Biological re sponse modi \201ers (cid:2) Metalloprotinease inhibitors (cid:2) Anti-angiogenic agents (cid:2) OHO-23(417-442) 11/18/02 8:34 AM Page 422 gynecological CANCER 422 Cancer of the uterine corpus Introduction By far the commonest cancer of the corpus is carcinoma of the endometrium, whi ch accounts for over 80% of tumors; less common are the uterine sarcomas. Of the latter, so me have a glandular element, the so-called Mixed Mesodermal Mullerian Tumors (MMMT) or carc inosarcomas, and some are \201brosarcomas. In some respects endometrial cancer has been unjustly regarded as the \200\230Cinderella \200\231 of gynecological cancers, as it often appears straight- forward to manage. In fact , it requires as much attention to detail as other cancers and the death rate, stage for st age, is no different from cervical or ovarian cancer. Endometrial adenocarcinoma Epidemiology Endometrial cancer occurs principally in post-menopausal women and the inciden ce rises with age. Its etiology has not been determined but it occurs more commonly in wome n who take unopposed oestro- gen as hormone replacement therapy, and also in women with bre ast cancer taking tamoxifen, which exerts oestrogenic agonist effects on the endometrium. I t is also commoner in obese women in whom estrogen is peripherally produced in fat. These d ata suggest not so much a hormone \200\224dependent tumor but one in which oestrogenic effe cts in \202uence cell growth or perhaps inhibit apoptosis. Because it commonly presents ea rly with post-menopausal bleeding, advanced disease at presentation is uncommon compared wi th other gynaeco- logical cancers. Pathology The natural history of endometrial adenocarcinoma is not well understood. Precurs or lesions in the form of atypical hyperplasia are recognized but it is not known whether t hese changes always precede cancer development. Endometrial adenocarcinoma exhibits a spectrum of differentiation from well-differentiated lesions with acinar or glandular morphology to poor differentiation with none. Lymph node m etastases and prog- nosis are strongly associated with the degree of differentiation. Adenosquamous lesions, clear cell, and serous papillary tumors all carry a worse prognosis. The other major prognostic factor is the depth of invasion of the myometrium and this is r e \202ected in the FIGO staging classi \201cation. OHO-23(417-442) 11/18/02 8:34 AM Page 423 CANCER OF THE UTERINE CORPUS 423 Diagnosis Table 23.2 Revised FIGO staging for endometrial cancer Stage De \201nition Ia Tumor limited to endometrium Ib Invasion to <1/2 myometrium Ic Invasion to >1/2 myometrium IIa Endocervical glandular involvement only IIb Cervical stromal invasion IIIa Tumor invades serosa and/or adnexa and/or positive peritoneal cytology IIIb Metastases to pelvic and/or para-aortic lymph nodes IVa Tumor invasion of bladder and/or bowel mucosa IVb Distant metastases including intra-abdominal and/or inguinal lymph nodes. Treatment The mainstay of treatment for Stage I disease is hysterectomy and bilateral salpi ngo-oophorectomy. This should be performed through a vertical incision and peritoneal washi ngs should be taken at the start of the operation. The role of lymphadenectomy remains to b e de \201ned. In North America, lymphadenectomy is preferred to stage the disease and, if the nodes are free of disease, adjuvant radiotherapy is avoided. In the UK, the traditional approach has been to determine the level of risk of nodal metastasis by uterine pathology and, in high-risk cases, to prescribe adjuvant radiation. The MRC is conducting a random- i zed trial of lymphadenectomy in endometrial cancer. If the cervix is known to be involved pre-operatively, a radical hysterectomy should be per formed. Occasionally the patient will pre- sent with a frozen pelvis that requires a non-su rgical approach. Some surgeons are advocating laparoscopic lymphadenectomy together with a laparoscopically-assisted vaginal hysterectomy but, as yet, this is an unproven procedure. Radiotherapy Radiotherapy has two roles in endometrial cancer. The usual indication is adju vant therapy following hysterectomy but, less commonly it may be required as primary treatm ent for women un \201t to undergo surgery, usually through a combination of co-morbidity a nd marked obesity. It may also be required for advanced disease where residual tumor remain s following surgery or where the tumor was inoperable from the outset or for local recurren ce. Adjuvant radiotherapy is generally delivered with external-beam irradiation of a planned vo lume (usually four \201elds) to around 50 Gy OHO-23(417-442) 11/18/02 8:34 AM Page 424 gynecological CANCER 424 over four weeks. Vault brachytherapy reduces the risk of vault recur- rence in Stage II dis ease. Although currently given to 40 \200\22350% of cases treated in the UK, the value of adjuvan t radiotherapy is not certain. While early trials have demonstrated that loco-regional cont rol is improved by irradiation, there is no evidence that radiotherapy improves survival, a nd it does carry a risk of radiation damage to bowel and bladder. The current MRC trial ran domizes women with regards to adjuvant radiotherapy for high-risk disease, with the aim of answering this question. Chemotherapy Chemotherapy alone has relatively little to offer in endometrial carcinoma. Co mbinations such as cisplatin and doxo- rubicin have some activity but response rates are lo w. Progestagens, which have been widely prescribed in the past, have never been shown to be of signi \201cant bene \201t and should not be prescribed as adjuvant long-term therapy. Prognosis Overall, endometrial cancer has the best survival rate of the gynaeco- logical ca ncers, with a 70 \200\22375% \201ve-year survival. Low-risk Stage I disease carries a \201ve-year survival in excess of 90%, but in high-risk Stage I disease this may drop to ne arer 50%. In Stage II, III, and IV dis- ease the \201ve-year survival falls to 50%, 30%, and 10% respectively. Sarcomas The epidemiology of these tumors is less well-de \201ned than endome- trial carci noma, although cases of mixed Mullerian tumor have been reported following tamoxifen therap y. The mixed Mullerian tumors (MMTs) are divided into homologous and heterologous. Homologous MMTs are composed of tissues native to the uterus, whereas heterologous MMTs inv olve tissue from outside the uterus. The tumors vary also in the frequency of mitoses seen on pathology sections, and this predicts prognosis. Tumors with fewer than 5 mitoses per 10 high-power \201elds are regarded as low-grade and carry a good prognosis, whereas those with a mitotic rate of over 20 per 10 high-power \201elds often have a more aggressive co urse with a high risk of nodal and systemic metastasis. Even low-grade tumors can behave un predictably and if there is any residual disease it tends to be very unresponsive to non-su rgical treatment. Fibrosarcomas may arise de novo or rarely are found in a \201broid uterus. These tumors a lso exhibit a spectrum of mitotic activity that determines prognosis. Successful treatment depends very much on surgery for loca- ized disease. Residual disease or tumors with nodal or distant metastases are usually incurable. Hysterectomy and bilatera l salpingo- oophorectomy should be performed, together with pelvic and para- OHO-23(417-442) 11/18/02 8:34 AM Page 425 CANCER OF THE UTERINE CORPUS 425 aortic lymphadenectomy to stage the disease. Residual disease can be treated with radiation . Adjuvant radiation may improve pelvic control but does not confer a survival bene \201t. Chemotherapy (e.g. doxorubicin and ifosfamide) can be prescribed for metastatic disease, e specially outside the pelvis, but long-term survival is very poor under these cir- cumstanc es. The future Endometrial cancer will probably continue to increase in incidence as more women live longer. Long-term tamoxifen treatment for breast cancer may merit endometrial screeni ng to identify early change, but screening on a population basis is not currently regarded as an effec- tive strategy. OHO-23(417-442) 11/18/02 8:34 AM Page 426 gynecological CANCER 426 Cancer of the cervix Etiology (cid:2) Sexual intercourse (cid:2) Human papillomavirus (HPV) (cid:2) HPV types 16, 18 \200 \224USA and Europe (cid:2) Vaccination program in development Epidemiology The epidemiology of this disease has been extensively studied and strong assoc iations demonstrated with: (cid:2) Low social class (cid:2) Multiparity (cid:2) Cigarette s moking (cid:2) Early onset of sexual intercourse (before 17) (cid:2) Non-barrier forms of c ontraception More recent studies have focused attention speci \201cally on papillo- maviru s transmission and the increased susceptibility of the cervical epithelium of the sexually active teenage female. This disease has dramatic variations in incidence around the world. In the developing count ries of South-East Asia, Africa, and South America, it is the commonest female cancer. Limi ted regional studies in South America have revealed massive incidences up to 96/100 000 (ag ainst 14.5/100 000 in the UK and only 2/100 000 in Israel). The UK saw signi \201cant incidence changes during the different decades of the twentieth century. High rates occurred in the cohorts of women who were aged 20 \200\22330 years duri ng the First and Second World Wars when they entered their 50s and 60s. More recently, a ri se in inci- dence occurred in the late 1970s and early 1980s in women aged 30 \200\22350 ye ars. The UK incidence is now falling for the \201rst time in a century. This is attribute d to the success of the population-based screening program, which was introduced following success in Finland and British Columbia. Pathology When the disease is con \201ned to the cervix, patient management depends on the cytology and/or histology specimens. These can reveal a spectrum of changes in the epithel ium of the cervix: (cid:2) Slight dysplastic changes to the cell architecture (cid:2) Viral cytoplasmic changes OHO-23(417-442) 11/18/02 8:34 AM Page 427 CANCER OF THE CERVIX 427 Intra-epithelial neoplasia (CIN 1, 2, or 3) (cid:2) (cid:2) Micro-invasive carcinoma (cid:2) Frank invasive carcinoma A number of changes may b e present in the same patient at one time. The changes are often maximal at the junction zo ne where the squa- mous epithelium of the ectocervix meets the cuboidal epithelium of the e ndocervix close to, or at, the external os. The changes can be a single focus, multiple foc i, or con \202uent change extending up the endocervical canal. These early changes may \201rst be identi \201ed by examination of a smear of cells, col lected by a special wooden (Ayers) spatula or a brush, from the vaginal surface of the cerv ix. The specimen is a sample of the cells that are being shed from the ectocervix along, so metimes, with cells that are being shed from the endocervix and the endome- trium. They are examined on a slide after staining with Papanicolou stain and an impression of the health of the epithelium can be formed. To accurately map changes in the cervical epithelium patie nts require colposcopy where the cervix is examined by binocular microscopy at ten times no rmal magni \201cation. A skilled operator can discriminate between different grades of cha nge identi \201able histolog- ically, map the abnormalities, and biopsy the most abnormal areas. If changes extend up the cervical canal the operator will proceed to a formal cone b iopsy in which the abnormal ectocervix along with the endocervical canal up to the internal os of the cervix is removed in one piece and examined histologically. Viral changes, dysplasia, CIN 1 and 2 are common in the sexually active adult female, parti cularly among those in their 20s when multi- ple partners and non-barrier contraception are involved. They can all revert to normal without treatment and are monitored by regular sme ars. CIN 3 changes are more commonly part of a process that can progress over months or yea rs to invasive carcinoma. Invasive cancer can also develop de novo. Most patients have chan ges to the squamous cell population, some have pure adenomatous cell changes, and others ha ve mixtures of the two cell types. Papillary or small cell carcinomas are seen occasionally . The pathology report should indicate the cell type(s), the level it has reached relative to the basement membrane, the maximum depth of any invasion below the membrane, and the width of invasion. These last two points are particularly important when invasion is only a few millimeters as this determines whether the problem is micro-invasion (less than 5 mm in dep th or 7 mm in width) or invasive carcinoma. Staging The FIGO staging system is based predominantly on the extent of the primary tumor. Metastatic spread is normally by the lymphatic system and tends to be sequential \200\224to the parametrial nodes, the obturator OHO-23(417-442) 11/18/02 8:34 AM Page 428 gynecological CANCER 428 Table 23.3 FIGO staging system for cervical cancer Stage De \201nition Ia Micro-invasive disease (max depth 5 mm, max width 7 mm) Ib Clinical disease con \201ned to the cervix IIa Disease involves upper 1/3 vagina but not parametrium IIb Disease involves parametrium but does not extend to pelvic wall III Disease involves lower 2/3 vagina and/or pelvic wall IV Involvement of bladder, rectum, or distant organs group, the internal then common iliacs, and on through the para-aortics to the left neck. S ystemic metastases are rare outside the chest. Presentation Patients with CIN and micro-invasive carcinoma have no symptoms. The diagnosis typically follows an abnormal cervical smear or colpo- scopic examination. Symptomatic pat ients should not be investigated by cervical smear alone. The earliest symptoms of invasive carcinoma are: Increased vaginal discharge (cid:2) (cid:2) Post-coital bleeding Inter-menstrual or post-menopausal bleeding (cid:2) Increasing tumor bulk and pelvic in \201ltration leads to pressure on the bladder (frequen cy), rectum (altered bowel habit), or ureters (often asymptomatic until uraemia appears). D eep lateral pelvic pain can be due to direct extension of nodal disease. This can progress to lympho- edema, venous thrombosis of a lower limb, and even sciatic nerve palsy. Rarely i n Western countries patients may present with a vesico- vaginal or recto-vaginal \201stul a. Investigation Asymptomatic patients with CIN 1, 2, or 3 or micro-invasive car- cinoma do no t require any further investigation prior to treatment. Symptomatic patients should have an examination under anesthetic to complete FIGO staging, cystoscopy or sigmoidoscopy if thes e organs appear to be involved, and an IVU in Stage 2 \200\2234. CT or MRI scanning of the pelvis and abdomen de \201ne more fully the size of the primary tumor and any lymphadenopa thy. Treatment Surgery (cid:2) CIN 3 disease localized to ectocervix \200\224colposcopy and loop diathermy, cryoprobe or laser OHO-23(417-442) 11/18/02 8:34 AM Page 429 CANCER OF THE CERVIX 429 (cid:2) CIN 3 disease extending into endocervical canal or micro- invasion \200\224cone biopsy (cid:2) Complete excision still requires follow-up or if patient wants no more children \200\224hysterectomy and surveillance for vaginal vault Invasive carcinoma (less than 4 cm, con \201ned to cervix) \200\224Wertheim \200\231s hysterectomy removes parametrium and pe lvic nodes (cid:2) (cid:2) Radiotherapy if \200\224incomplete excision of tumor \200\224poor tumor differentiation \200\224vascular invasion \200\224node involvement \200\224all other stages/medically un \201t Radiotherapy (cid:2) External-beam irradiation followed by intra-cavitary brachy- therapy (ICT) (cid:2) 40 \200\22345 Gy \200\224pelvis over 4 weeks (cid:2) Sterilizes pre-menopausal pati ents ICT gamma sources (137Cs on 192Ir) in uterus/upper vagina (GA) \200\224left for minutes (h igh dose rate) \200\224left for days (low dose rate) ICT \200\224dose to central pelvic st ructures (cid:2) (cid:2) \200\22480 Gy to 2 cm lateral and superior to external os \200\224dose to bladder and rec tum below 70 Gy (cid:2) Pelvic radiotherapy for advanced cancer \200\2245% late morbidity (bowel and urinary tract) \200\224bleeding \200\224stricture \200\224ulceration \200\224 \201stula \200\224vaginal shortening/dryness Chemotherapy Despite a considerable number of studies, chemotherapy has no established role in the radical treatment of any stage of this cancer. Patients with recurrent pelvic or sy stemic metastatic disease may bene \201t from palliative chemotherapy. The principal activ e agents are (cid:2) Cisplatin (cid:2) Mitomycin C Ifosfamide (cid:2) Methotrexate (cid:2) 5- \202uorouracil (cid:2) Bleomycin (cid:2) OHO-23(417-442) 11/18/02 8:34 AM Page 430 gynecological CANCER 430 Combined therapy Modern management of advanced cancer regularly involves the use of concurr ent or sequential chemotherapy and radiotherapy. Results Survival at \201ve years is typically \200\224Stage 1a, 100%; Stage 1b, 70 \200 \22390%; Stage 2, 50 \200\22370%; Stage 3, 25 \200\22360%; Stage 4, 10 \200\22320%. The wid e ranges re \202ect the large variation in disease volume seen within the present staging system that is based on tissue involvement rather than volume of disease. Relapse after \201ve years is unusual. OHO-23(417-442) 11/18/02 8:34 AM Page 431 CANCER OF THE CERVIX 431 OHO-23(417-442) 11/18/02 8:34 AM Page 432 gynecological CANCER 432 Vaginal and vulval cancer Vaginal cancer Primary vaginal cancer is uncommon, constituting only 1 \200\2232% of malign ant female genital tract malignancies. Most vaginal maligancies are metastatic, from primar ies in the cervix, vulva, endometrium, or trophoblast (choriocarcinoma). The most common hi stological types of primary cancer are squamous (80%) and adenocarcinoma (10%). Etiology The cause of primary squamous carcinoma is uncertain. The recog- nized association with squamous intra-epithelial and invasive neo- plasia at other anogential mucosal and cu taneous sites such as the cervix, vulva, and anus suggests a common aetiological agent. Onc ogenic human papillomavirus (HPV) subtypes 16 and 18 and/or primary p53 polymorphisms are l ikely to be important in this tumor \200\231s biology. Symptoms and signs (cid:2) Symptoms \200\224abnormal vaginal bleeding \200\224vaginal discharge \200\224bladder, rectal symptoms (cid:2) Signs \200\224vaginal examination: best method of detection \200\224speculum examination \200\224most lesions in upper 1/3 and are exophytic Staging and investigations The staging is clinical but may include results of invasive inve stiga- tions such as cystoscopy, protoscopy, and appropriate radiography in order to detect local and distant spread. MRI is the preferred investi- gation for evaluating local spread , particularly if body or transvaginal coils are used. The negative predictive values of CT and MRI for regional nodal involvement remain unsatisfactory. Treatment Radical radiotherapy with a combination of pelvic external-beam and utero-vaginal intra-cavitary brachytherapy is the treatment of choice. The literature is unclear regardi ng optimum dosimetry and \201eld design. Lower vaginal involvement should prompt consider ation of either additional groin node dissection or irradiation. Para-aortic irradiation (e xtended \201eld) is associated with high morbidity and is of uncertain value. OHO-23(417-442) 11/18/02 8:34 AM Page 433 VAGINAL AND VULVAL CANCER 433 Overall \201ve-year survival is 40%, and salvage after \201rst relapse is uncommon. Bad prognostic features are primary adenocarcinoma, large tumor bulk, tumor site (lower vagina l lesions fare worse), and posterior vaginal wall involvement. One in \201ve long-term su rvivors will suffer from serious radiotherapy-related complications. If the uterus is intact, the tumor involves the upper posterior vagina, and there is small volume disease (highly selected Stage I disease), then a radical hysterectomy, partial vagi nectomy, and bilateral pelvic lymphadenectomy may be performed. Treatment of vaginal cancer should be limited to centers with exper- tise in gynaecologic oncology. Vulval cancer Primary invasive vulval cancer occurs as commonly as cervical cancer in women over 60 years. One in four tumors occur in women under the age of 65 years. The majority ( 85%) are squamous carcinoma. Other types include basal carcinoma (10%) and malignant melano ma (4%). Etiology The known associations with oncogenic HPV DNA (types 16 and 18), p53 mutations, an d pre-existing abnormal vulval skin conditions such as a thickened epidermis (squamous hype rplasia), lichen sclerosis, and intra-epithelial atypia, suggest a complex etiology. Little prospective data exist to clarify the etiology further. Women with these skin dis- orders should be kept under regular review by experienced clinicians and advised to report persist ent symptoms or new skin changes that might herald malignant change. Symptoms and signs Many tumors are preceded by chronic vulval skin symptoms such as pruritu s and irritation, which probably re \202ect pre-existing skin dis- orders. Patients compla in of the sensation of a painful lump. Abnormal genital tract bleeding or haematuria may oc cur. A simple, thorough examination of the external genitalia will iden- tify the majority of tu mors. Persistent erythematous areas that are raised or tender should be suspected as invasi ve disease and a con \201rmatory full thickness skin biopsy should be performed. Staging and investigations Staging requires a combination of surgical and histopathological investigations. The incidence of nodal metastases rises from less than 1% for tumors with less than 1 mm depth of invasion to over 10% for tumors over 3 mm in depth. The con \201rm ation of groin lymph node status is therefore mandatory in all but early stage I disease. N on-invasive modalities such as ultrasound, CT, or MRI are of OHO-23(417-442) 11/18/02 8:34 AM Page 434 gynecological CANCER 434 insuf \201cient negative predictive value for regional (groin) node metas- tases. The rout ine dissection of groin nodes therefore remains import- ant for most stages of this disease . Treatment (cid:2) Surgical excision with clear margins and removal of groin nodes (cid:2) Care if tum or involves distal urethra, anal mucosa (preserve function) (cid:2) Extensive disease may require complex reconstruction (cid:2) Psychosexual dysfuncti on, body image problems frequent (cid:2) Chemo-irradiation for advanced disease: 5 FU and m itomycin C combined with radiotherapy \200\224encouraging results (cid:2) 5-year survival \200\22485% if node-negative (cid:2) Bad prognosis if \200\224>3 re gional nodes involved \200\224Stage III, IV disease \200\224large tumor bulk \200\224node metastases \200\224 poor performance status \200\224tumor type (melanoma) (cid:2) Treatment in specialized centers OHO-23(417-442) 11/18/02 8:34 AM Page 435 VAGINAL AND VULVAL CANCER 435 OHO-23(417-442) 11/18/02 8:34 AM Page 436 gynecological CANCER 436 Trophoblastic tumors Introduction Gestational trophoblastic disease (GTD) includes a spectrum of dis- orders ran ging from the pre-malignant complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM), to the malignant invasive mole, gestational choriocarcinoma, and the highly malignan t placental-site trophoblastic tumor (PSTT). Both CHM and PHM can develop into invasive mol es. However, it is thought that only CHM may progress to the highly malignant choriocarcino ma and the rare PSTT. Dif \201culty in diagnosis occurs most frequently with choriocarcino- mas and PSTT, which can arise after any type of pregnancy and may not present until many years later with wides pread metastases. GTD remains an important group of disorders for the clinician to recog- n ize, because they are nearly always curable if appropriately managed and, in most cases, fe rtility can be preserved. What is trophoblast? Within a few days following conception a ball of cells is formed calle d the blastocyst and the outer layer of this ball differentiates into trophoblast. This con sists of an inner layer of cytotrophoblast cells that migrate outwards and fuse to form lar ge multinucleate syn- cytiotrophoblast cells. The latter produce the pregnancy-associated h ormone, human chorionic gonadotrophin (HCG), and invade the myometrium, triggering the form ation of new maternal blood vessels which are leaky and supply nutrition to the growing fet us. Trophoblast tissue frequently invades these blood vessels, both in normal and molar pre gnancies, and circulates in the blood. Hydatidiform moles Epidemiology (cid:2) 1/1000 pregnancies in UK (cid:2) Two-fold frequency in South-East Asia (cid:2) More common after pregnancy when aged <16 years or >40 years Pathology (cid:2) Ovum lacking maternal nucleus DNA fertilized by one or two sperm \200\224duplicate its chromosomes (cid:2) Conceptus is androgenetic (cid:2) Proliferate to give abnormal trophoblastic tissue OHO-23(417-442) 11/18/02 8:34 AM Page 437 TROPHOBLASTIC tumors 437 (cid:2) Partial mole \200\224arises when two sperm fertilize an ovum that has retained nuclear DNA \200\224triploid conceptus proliferation, to give abnormal trophoblas t and variable fetal tissue \200\224abnormal trophoblast forms hydropic villi which resemble grapes Histology (cid:2) Dilated villi of hyperplastic syncytiotrophoblast and cytotro- phoblast (cid:2) Later, cisterns form (cid:2) Large AV shunts form \200\224facilitates spread Presentation and staging (cid:2) Bleeding in early pregnancy (cid:2) Anemia (cid:2) Toxemia, hyperemesis, hyperthyro idism About 15-20% of complete moles and 0.5% of partial moles will require chemotherapy. S taging of the disease involves ultrasound of the pelvis, serum HCG, and chest X-ray. In mos t instances the CXR will be normal but metastatic disease can present with: (cid:2) Cannonb all secondaries (cid:2) Pleural effusions (cid:2) Wedge infarcts (cid:2) Oligaemic areas (c id:2) Cavitating lesions (cid:2) Miliary appearance If there are chest lesions then a CT or preferably MRI brain scan is indicated prior to lumbar puncture for HCG analysis of the CS F (an HCG ratio of >1:60 (CSF: blood) indicates CNS involvement). Diagnosis