In the 21st century medicine is characterized by population problem, the great impact of computer and information technology, the contribution of genetics development to disease prevention and treatment, and the reform of health care system. By 2025, there will be 274 million people over 60 years old and cancer may be the primary killer as well in China. The incidences of cancers of the lung, intestine, and breast are on the rise; the incidence of cervical cancer is decreasing in developed countries while increasing in developing ones. Whether oral contraceptives (OCs) add the risk of breast cancer remains unconfirmed, but its protection against ovarian cancer and uterine endometrial cancer has been proved. The risk of hormone replacement treatment (HRT) for uterine endometrial cancer and breast cancer continues to be a focus of investigation. Screening plays a significant role in reducing the prevalence rate and mortality of cervical and breast cancer. Human papilloma virus (HPV) test is the major approach for cervical cancer screening, and the development of HPV vaccine opens a new era of cancer prevention.
Treatment of gynecological tumors varies in concepts including (1) microinvasive treatment: endoscopic surgery, trans-vaginal and interventional surgery (ultrasound, radiology, high intensity focused ultrasound surgery (HIFUS)); (2) individual and humane treatment: emphasis on the quality of life, respect for the patients' will, limitation of surgical scope, preservation of physiological function and fertility; and (3) multiple treatment: multiple methods, multiple routes, combination treatment, supportive treatment, and psychiatric-psychological treatment.
Strategies for the treatment of gynecological tumors focus on the following: (1) screening; (2) treatment of pre-malignant lesions and borderline tumors; (3) preservation of physiological function and fertility; (4) treatment of persistent and recurrent tumors; and (5) training of gynecological oncologists and decision-making of diagnosis and therapy.
Construction of screening model for gynecological tumors compatible with China's socio-economic situation
The construction of the screening model should meet the following three elemental criteria: sustainable development of economy; concepts acceptable by the general population; equality to all women. With this model, the prevalence of gynecological tumors in China is expected to decrease greatly in the early half of the 21st century.
The proposals of the China Cancer Research Foundation and the Cervical Cancer Prevention Cooperation Group suggest the initial age to be conducted the screening of cervical cancer should be: 24–30 years old in economically developed areas and 35–40 years old in under-developed areas. For the high-risk population, the earlier screening the better. The end age can be over 65 years old. The screening interval is a year; if normal results are obtained twice consecutively the interval can be prolonged to 3 years. If HPV remains negative twice consecutively, the interval can be prolonged to 5–8 years. More attention should be paid to the high-risk population rather than to times of screening. For specific purposes, there are optimal method (thin-layer cytology test (TCT), HPV test), popular method (pap smear, HPV test), and basic method (naked eye inspection: visual inspection with 3%-5% acetic acid (VIA), visual inspection with Lugol's iodine (VILI)). In one word, that is “see and treat”.1
The prevalence of uterine endometrial cancer is rising, while the on-set age is declining. Populations with triplets (obesity, hypertension and diabetes) are usually at a high risk of cancer involvement. Diagnostic curettage, hysteroscopy and ultrasound scanning are the three major methods for the detection of the cancer. Uterine cavity cytology screening is still at trial stage.
Screening for ovarian cancer is most difficult. Pelvic examination, B ultrasound scanning and serum CA125 can be used to rule out dormant ovarian cancer, but they are not ideal for screening. Identifying the high-risk population will improve the efficacy of screening. The risk of developing ovarian cancer among average population is 1.4%, and among the population with one first-degree relative is 5%, with two first-degree relatives is 7%, with hereditary ovarian cancer syndrome (HOCS) is 50%. So it is still demanding for more effective tumor markers and screening methods.
Pre-malignant lesions and borderline tumors
Pre-malignant lesion is a running process with somehow a continuing period. Borderline tumor is a definite status and could be persistent. So far, it is hard to evaluate whether cancer could regress and even vanish all by itself. Intervention (or treatment) for pre-malignant lesions and borderline tumors is a vital method (or stage) for cancer prevention and also a crucial opportunity for achieving fortunate prognosis.
In 1967, Richart brought about the concept of cervical intraepithelial neoplasia (CIN), which comprises atypical hyperplasia (cancerization potential, pre-malignant lesion) and cancer in situ (CIS).“Three steps” CIN diagnosis has been advocated, i.e. cytology-colposcopy-histology (CCH). Cytology is liquid-based, classification is the Bethesda system (TBS), and HPV virology is hybrid capture (hC).
In histological types of uterine leiomyoma, three could be thought as borderline leiomyomas. They include cellular leiomyoma (CL), bizarre nuclei leiomyoma (BL)and mitotically active leiomyoma (mAL). Smooth muscle tumors of uncertain malignant potential (STUMP) is defined as 2–4/10HPF atypical cells and mitoses; >15/HPF mitoses, without condensed and atypical cells; or fewer mitoses but with necrotic tumor cells.
Uterine endometrial hyperplasia can be regarded as pre-malignant lesions, in which the rates of canceration are as follows: 1%-3% for simple hyperplasia (SH), with a mean follow-up of 15 years; 3%-4% for complex hyperplasia (CH), with a mean follow-up of 13 years; 23% for atypical hyperplasia (AH), with a mean follow-up of 11 years. The rates of canceration for mild AH, moderate AH and severe AH, are 15%, 24% and 45% respectively. As for the treatment of endometrial hyperplasia in young SH, CH, ovulation inducing medication could be administrated to maintain regular menstruation cycle; for young AH, the following 3 steps should be taken: progesterone treatment (luteum, MPA, diagnostic curettage after 3–6 months treatment), ovulation induction (CC, HMG, FSH, GnRHa), and assisted reproductive technique (ART-COH/AIH, IVF-ET).
Treatment of ovarian borderline tumors has been controversial. The consensus is that surgery is the most important, basic treatment by now. For those who are of stage Ia, young and desiring for pregnancy, unilateral salpingo-oophorectomy or cystectomy, peritoneal cytologic examination and multiple biopsy of peritoneal sites can be performed. For those who are of stage Ia, older, not desiring for child, and stage Ib, Ic, TAH+BSO, omentumectomy, appendectomy and lymphadenectomy (staging surgery) should be carried out. Stage II, III, IV patients should be treated with cytoreductive surgery (CRS). Chemotherapy is not necessary for stage I. As for stage II-IV, chemotherapy is highly controversial. Some insist on that peritoneal implantation and aneuploid DNA should be followed by chemotherapy, but no evidence shows any beneficial effect on survival rate, and others claim that chemotherapy brings severe side-effects rather than benefits. For late stage cancer, with surgical residual, extensive implantation or invasion, chemotherapy is the same as the formula for epithelial cancer.2,3
Endometriosis is a common benign disease, but could transform into cancer. Its canceration rate is 1%. In 1925, Sampson first described the canceration of endometriosis; his three diagnostic criteria for canceration of endometriosis include (1) endometriosis coexisting with cancer in the same ovary; (2) endometriosis similar to cancer tissue in histological features; and (3) exclusion of metastatic malignant tumors. One criterion was added by Scott in 1953, with the transition form between endometriosis and malignant tissue.4
In 1988, La Grenade and Silverberg first put forward the concept of ovarian atypical endometriosis. Morphologically, it is characterized by atypical endometriosis glands. Signs of atypical hyperplasic epithelium transforming to malignant epithelium may play a major role in endometriosis combined with ovarian malignant tumors. To be alert for malignant transformation the following clinical situations should be observed: (1) over-sized ovarian endometriosis cyst with a diameter over 10 cm or growing significantly; (2) recurrence after menopause; (3) change of episodes of abdominal pain, aggravation of dysmenorrhea or persistent abdominal pain; (4) radiological examination showing a solid mass or papilla-like structure in the cyst or lesions rich in blood flow; and (5) unreasonable high serum CA125 (>200 kIU/L). Additionally, routine test should be given to surgical specimens.5,6
Preservation of physiological function (PF) and fertile function (FF)
This preservation of PF and FF is the most humanitarian and challenging issue in treatment of cancer patients, and also one of the progresses in gynecological tumor treatment. For instance, the preservation of PF and FF has been achieved in invasive mole, choriocarcinoma, ovarian malignant germ cell tumors (OMGCT), early stage ovarian epithelial cancer (stage Ia), early stage cervical invasive cancer (stage Ia1, Ia2, Ib1), and some early stage uterine endometrioid cancer (stage Ia, G1). Preservation of ovarian physiological function and vaginal prolongation have been possible in patients with late stage cervical invasive cancer.
Conservative surgery is feasible for OMGCT which is (1) most common in young women or girls (17–21 years old); (2) usually unilateral(the bilateral occurrence rate of dysgerminoma is 10%-20%, that of the rest is less than 5%); (3) highly sensitive to chemotherapy (PVB & PEB regimens); (4) usually not involved with the uterus and bilateral adnexa after recurrence; (5) subjected to contralateral oophorectomy and hysterectomy; (6) shown by definite tumor markers (AFP,HCG); and (7) shown as an immature teratoma changing to a mature one.7,8 High cautions should be taken in conservative surgery for ovarian epithelial cancer, which must meet the following requirements: (1) young woman, desiring for pregnancy; (2) stage Ia; (3) G1; (4) contralateral ovary: normal to naked eyes, negative on biopsy; (5) negative in “high-risk” regions (Douglas pouch, paracolic gutters, intestinal mesenteries, omentum, retro-peritoneal lymph nodes) by surgical exploration and on biopsy; and (6) patients who could be followed up. In addition, it is suggested that hysterectomy and salpingo-opphorectomy be performed after child birth.
Conservative surgery is feasible for uterine endometrial cancer (endometrioid cancer)since the following criteria can be met: (1) high prevalence and younger on-set age (2%-4%, <40 years old; (2) highly estrogen-dependent, good response to a high-dose progesterone treatment in young patients; (3) stage Ia, G1, excluding myometrium invasion shown by MRI; (4) progesterone receptor (PR) positive; (5) patients with a desire to preserve fertility; and (6) no contradiction to progesterone treatment (normal liver function).
Radical trachelectomy initiated by Dargent (French) is an epoch-making advancement of conservative surgery for early stage cervical invasive cancer (stage Ia2, Ib1). The feasibility is based on:(1) young women with a strong desire for pregnancy; (2) no evidence for other damage to fertility; (3) stage Ia2, Ib1 (FIGO); (4) tumor diameter less than 2 cm; (5) no para-cervical or para-corpus invasion; (6) tumor limited to cervical external os and not extended to the cervical canal or internal os; (7) no evident lymphatic metastasis; and (8) cautious about cervical adenocarcinoma. The following four steps should be taken for the surgery: (1) laparoscopic pelvic lymphadenectomy for first frozen pathology: lymph node (-); (2) radical trachelectomy for second frozen pathology: border (-); (3) uterine cervical cerclage; and (4) closure of new cervical external os and vaginal mucosa. This surgery does not increase the chance of recurrence and 60% of cases after the surgery can get pregnancy, while the rates of abortion and early birth are relatively high.9
Treatment of persistent and recurrent tumors
Treatment of persistent and recurrent tumors is also a tough problem, since it is the combination of surgery, medicine, radiation and biological therapy. The treatment should be individualized and standardized or evidence-based. Clinical practice guidelines (CPGs) and good practice guidelines (GPGs) should be based on the above concepts and principles so that the quality of life and psychological treatment can be emphasized. Gynecological tumor is more than merely a biological problem, and the introduction of quality of life evaluation could help preview prognosis on a more objective basis. Economic evaluation is also an important part. Economic problem could interfere with a patient's access to certain treatment; an effective but expensive method is not an optimal choice. Psychological care could greatly improve the whole therapeutic process for patients. Gynecological oncologists should help not only the patients but also their spouses and children. Young gynecological oncologists should be specially trained on social psychology, while the psychologists should join in the forces of research and clinical practice of gynecological oncology.10
Humanism and decision-making
Humanism involve philosophy, decision-making, changes of surgical concepts, and doctor-patient relationship and communication. Philosophical concepts should be present in clinical diagnosis and treatment. Right or wrong diagnosis and treatment involve responsibility, technique, experience, thoughts and methods, the latter refers to philosophy. Decision-making accounts for 75% and technique for 25% for a perfect surgery. Decision-making is to judge and design.
Great changes have taken place in surgical concepts. With the development of techniques, endosopic surgery, neoadjuvant chemotherapy, interventional surgery, radiology and chemotherapy, selection of surgery, modus operandi and surgical scope should be individualized and humanized. Microinvasive treatment,preservation of physiological function and fertility and the improvement of life quality have been greatly emphasized during Dargent surgery, pelvic nerve sparing radical hysterectomy, “tri-incisions” for vulval carcinoma, and endoscopic surgery for malignant tumor.
Ethics should be emphasized in decision-making for diagnosis and therapy of gynecological tumor, This includes respect for patients' will, mercy, harmlessness, equity and honesty. Meanwhile, professional principles, science integrity, dignity and honor, conflict of interests should be kept in mind. In the present era with a changing medical science model, a doctor-patient relationship is an important factor for a harmony society. Communication skills, especially respect and listening, reservation and acceptation, open and soft in communication, assurance and clarification, and guidance and conclusion should be stressed. In short, gynecological oncologists in the 21st century should keep in mind what they can do for patients and their disease is sometimes to cure, often to help, but always to console.