(BQ) Part 2 book “Principles and practice of gynecologic oncology” has contents: Vaginal cancer, cervix uteri, epithelial ovarian cancer, ovarian germ cell tumors, ovarian sex cord – stromal tumors, breast cancer, palliative and supportive care,… and other contents.
SECTION III D ISEASE S ITES 832 CHAPTER 18 Vulva Emily Penick, Sushil Beriwal, Edward J Wilkinson and John W Moroney* INTRODUCTION Malignant tumors of the vulva are rare and account for less than 5% of all cancers of the female genital tract In 2015, there were an estimated 5,150 new cases of and 1,080 deaths from invasive vulvar carcinoma in the United States (1) Because of its low incidence, most primary care providers will never encounter a patient with vulvar cancer Although a rare patient with vulvar cancer will present without symptoms, most women with vulvar cancer initially present with complaints such as vulvar irritation, pruritus, pain, or a mass that does not resolve The interval between the onset of symptoms and the diagnosis of cancer can be protracted if a woman who is embarrassed by new vulvar symptoms delays seeking care, or if a physician prescribes empiric topical therapies without a proper physical examination or tissue biopsy confirmation Jones and Joura (2) evaluated the clinical events preceding the diagnosis of squamous cell carcinoma of the vulva and found that 88% of patients had experienced symptoms for more than months, 31% of women had three or more medical consultations before the diagnosis of vulvar carcinoma, and 27% had applied topical estrogen or corticosteroids to the vulva The vulva is covered by keratinized squamous epithelium; accordingly, most malignant vulvar tumors are squamous cell carcinomas (SCCs) Consequently, our current understanding of the epidemiology, spread patterns, prognostic factors, and survival data for vulvar cancer is largely derived from experience with SCCs Malignant melanoma is the second most common cancer of the vulva Although there is some consensus regarding the behavior and treatment of vulvar melanoma, its rarity has thus far precluded robust, prospective clinical trials A number of other malignant tumors, both epithelial and stromal in origin, arise from normal vulvar tissue and are discussed in detail later in this chapter Finally, the vulva may be secondarily involved with malignant disease originating in the cervix, bladder, anorectum, colon, breast, or other organs The traditional therapeutic approach to vulvar cancer has been radical surgical excision of the primary tumor and inguinofemoral lymphadenectomy Experience has shown that survival is improved with the administration of postoperative radiation therapy (RT) to selected patients deemed to be at high risk for locoregional failure More recently, the use of neoadjuvant radiotherapy (RT) with concomitant radiosensitizing chemotherapy (CT) has proven to be effective in treating vulvar cancer patients for whom radical surgery would be either too morbid or technically not feasible New surgical techniques, including sentinel lymph node (SLN) biopsy, hold the promise of better outcomes for patients with early disease An individualized approach to vulvar cancer management, often employing multiple modalities in an effort to achieve disease control with better cosmetic results and sexual function, is now the norm This chapter deals with these and other topics pertinent to the principles of management of women with vulvar cancer ANATOMY 833 The vulva consists of the external genital organs—including the mons pubis, labia minora and majora, clitoris, vaginal vestibule, and perineal body—and their supporting subcutaneous tissues The vulva is bordered superiorly by the anterior abdominal wall, laterally by the labiocrural fold at the medial thigh, and inferiorly by the anus The vagina and urethra open onto the vulva The mons pubis is a prominent mound of hair-bearing skin and subcutaneous adipose and connective tissue that is located anterior to the pubic symphysis The labia majora are two elongated skin folds that course posterior from the mons pubis and blend into the perineal body The labia minora are a smaller pair of skin folds medial and parallel to the labia majora that extend inferiorly to form the margin of the vaginal vestibule Superiorly, the labia minora separate into two components that course above and below the clitoris, fusing with those of the opposite side to form the prepuce and frenulum, respectively The skin of the labia minora contains sebaceous glands near its junction with the labia majora, but it is not hair-bearing and it has little or no underlying adipose tissue The clitoris is supported externally by the fusion of the labia minora (prepuce and frenulum) and is approximately to cm anterior to the urethral meatus It is composed of erectile tissue organized into the glans, body, and two crura Two loosely fused corpora cavernosa form the body of the clitoris and extend superiorly from the glans, ultimately dividing into the two crura The crura course laterally beneath the ischiocavernosus muscles and attach to the ischial rami The vaginal vestibule is situated in the center of the vulva and is homologous to the male distal urethra It has squamous mucosal epithelium that is demarcated bilaterally and posteriorly by the junction with the keratinized epithelium at Hart’s line, located on the medial labia minora and inferiorly on the perineal body The vagina, urethra, periurethral glands, minor vestibular glands, and the Bartholin’s glands open onto the vestibule Anteriorly, the minor small vestibular glands are located beneath the vestibular mucosa and open onto its surface, predominantly on the more anterior vestibule The vestibular bulbs, a loose collection of bilateral erectile tissue covered superficially by the bulbocavernosus muscle, are located laterally The Bartholin glands, two small, mucus-secreting glands situated within the subcutaneous tissue of the posterior labia majora, have ducts opening onto the posterolateral portion of the vestibule The perineal body is a to cm band of skin and subcutaneous tissue located between the posterior extensions of the labia majora It separates the vaginal vestibule from the anus and forms the posterior margin of the vulva Vascular Anatomy and Neurologic Innervation The vulva has a rich blood supply derived primarily from the internal pudendal artery, which arises from the anterior division of the internal iliac (hypogastric) artery, and the superficial and deep external pudendal arteries, which arise from the femoral artery The internal pudendal artery exits the pelvis and passes behind the ischial spine to reach the posterolateral vulva, where it divides into several small branches to the ischiocavernosus and bulbocavernosus muscles, the perineal artery, artery of the bulb, urethral artery, and dorsal and deep arteries of the clitoris Both external pudendal arteries travel medially to supply the labia majora and their deep structures These vessels anastomose freely with branches from the internal pudendal artery Innervation of the vulva is derived from multiple sources and spinal cord levels The mons pubis and upper labia majora are innervated by the ilioinguinal nerve (L1) and the genital branch of the genitofemoral nerve (L1–2) Either of these nerves may be easily injured during pelvic lymph node dissection, with resulting paresthesias The pudendal nerve (S2–4) enters the vulva parallel to the internal pudendal artery and gives rise to several branches that innervate the lower vagina, labia, clitoris, perineal body, and their supporting structures Groin Anatomy and Lymphatic Drainage Vulvar lymphatics run anteriorly through the labia majora, turn laterally at the mons pubis, and drain primarily into the superficial inguinal LNs Dye studies by Parry-Jones demonstrated that vulvar lymphatic channels not extend laterally to the labiocrural folds and not cross the midline, unless the site of dye injection is at the clitoris or perineal body (3) The vulvar lymphatics drain to the superficial inguinal LNs located within the femoral triangle formed by the inguinal ligament superiorly, the border of the sartorius muscle laterally, and the border of the adductor longus muscle medially 834 There are to 10 inguinal LNs lying along the saphenous vein and its branches between Camper’s fascia and fascia overlying the femoral vessels (Fig 18.1A–C) (3) The first draining LN is the SLN and can be identified using various lymphatic mapping techniques The SLN is frequently found medial to the femoral vein just above the adductor muscle Second echelon LNs may be in the groin or pelvis The Cloquet’s node, or the most superior inguinal LN, is located under the inguinal ligament Lymphatic drainage from the SLN is sequential to the external iliac, common iliac, and aortic LNs (Fig 18.1A–C) 835 836 Figure 18.1 These historic figures illustrate some of the problems depicting the lymphatic anatomy of the groin accurately A, B: Vessels, muscles, and nerves A: Sentinel nodes; however, this is based on location rather than a mapping procedure, which is misleading B: Nodes between the femoral artery and the vein Lymph nodes between the vessels are common in the pelvis but not in the groin C: Direct drainage from the clitoral area of the vulva to pelvic lymph nodes This drainage pattern is not observed with preoperative or intraoperative lymphatic mapping studies The fossa ovalis is a crescent-shaped terminus of the fascia lata and the site where vascular and lymphatic structures meet with the femoral vessels The cribriform fascia is a term widely used in the literature describing the anatomy of the groin and is said to cover the fossa ovalis The cribriform fascia is hard to identify and is more of a “lamina” than an actual fascia SLN biopsy with lymphatic mapping deemphasizes the need to identify the cribriform structure and focuses the surgeon’s attention on functional in vivo surgical anatomy rather than textbook descriptions of LN locations (3) EPIDEMIOLOGY An estimated 5,150 women were diagnosed with vulvar cancer in the United States in 2015, and approximately 1,050 died of the disease Vulvar SCC accounts for approximately 3% to 5% of all gynecologic malignancies and 1% of all carcinomas in women, with an incidence rate of to per 100,000 women (1) Most vulvar cancers occur in postmenopausal women in the seventh decade, although more recent reports have identified a trend toward younger age at diagnosis (4,5) Earlier observational studies suggested associations between hypertension, diabetes mellitus, and obesity 837 and vulvar carcinoma; however, subsequent analyses have not confirmed the prognostic significance of these diagnoses (5) NATURAL HISTORY (PATTERNS OF SPREAD) Several infectious agents have been proposed as possible etiologic agents in vulvar carcinoma, including granulomatous infections, herpes simplex virus, and, most notably, human papillomavirus (HPV) HPV infection is present in virtually 100% of women with cervical cancer The relationship between HPV infection and vulvar cancer is much less straightforward This is likely due to the different etiologic pathways that are believed to be responsible for vulvar cancer These different etiologic pathways are discussed in detail in the chapter on preinvasive disease; however, because of subject matter overlap, some of the data related to HPV and invasive squamous cell carcinoma of the vulva are discussed here Vulvar condyloma acuminata have a well-described relationship with HPV as the causal agent, most commonly HPV-6 or -11, and strong associations between vulvar condylomas and the later development of vulvar cancer have been identified (6) The role of HPV in the development of premalignant and malignant lesions of the vulva has become clearer as molecular techniques for HPV detection and mutational analyses have improved Earlier studies identified HPV DNA in both invasive and carcinoma in situ lesions via immunohistochemistry More recent studies have used DNA detection methods such as polymerase chain reaction and in situ hybridization to detect high-risk serotypes (7) Among HPV serotypes, HPV16 is the most common; however, many other serotypes, including -18, -33, and -52, have been reported HPV DNA can be identified in approximately 85% to 97% of intraepithelial lesions (HSIL/VIN 2–3), but is seen in 10% to 69% of invasive lesions (8) Such a wide range of associated HPV is seen in association with HSIL/vulvar intraepithelial neoplasia (VIN) and invasive vulvar carcinoma primarily because of differences in detection methods, with newer molecular methods having greater sensitivity and specificity There are also differences between studies regarding the distribution of HSIL/VIN subtypes (usual or differentiated) and histologic types of carcinomas This work continues in clinical investigations In a recent clinical trial of 12,021 women using a 9-valent HPV vaccine, the number of HPV-related external genital biopsies was reduced by 92.3% for follow-up to 54 months (9) Although HPV DNA is associated with most intraepithelial lesions (85% to 97%), it is much less commonly seen in association with invasive lesions (~27% to 50%) (8,10) Marked differences between HPV positivity in VIN and vulvar cancers are also seen with respect to age Basta et al (11) conducted a retrospective case control study examining the coexistence of HPV and the incidence of both VIN and stage I vulvar cancer HPV infection was present in 61.5% of cases of VIN and vulvar cancer in women aged 45 years or less, and in 17.5% of women older than 45 years In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) proposed a modified terminology for VIN as two distinct processes: the “usual type (uVIN) encompasses high-grade lesions (VIN and 3) and are caused by HPV (12) The differentiated type of VIN (dVIN) is not caused by HPV VIN1 lesions are considered to be condyloma and should be managed accordingly as discussed by the 2011 American College of Obstetrician Gynecologists (ACOG)– American Society for Colposcopy and Cervical Pathology (ASCCP) (13) The most common VIN type occurs more frequently in younger women, tends to be multifocal, and has association with HPV serotypes 16, 33, and 18 In contrast, dVIN is less common (2% to 10% of all VIN), generally not related to HPV, and is shown to be unifocal and associated with other vulvar dermatoses such as lichen sclerosus and lichen planus (10,14) The incidence of HPV-associated VIN has been increasing over the past 20 years, particularly in women of reproductive age, with the highest frequency reported in women aged 20 to 35 (15) The development of condyloma acuminatum/genital warts is attributed to infection with HPV-6 or -11, with the median time between infection and development of lesions at to months In patients with a history of cervical or vaginal cancer, the vulva should be examined as part of a surveillance exam In those patients with a history of VIN or lichen sclerosus, self-examination with a mirror should be taught (16) 838 Chronic immunosuppression and tobacco smoking have also been linked as cofactors for the development of invasive vulvar cancer Vulvar cancer incidence is increased in female renal transplant patients, as well as women with HIV and AIDS (17,18) Smoking is an independent risk factor for the development of SCC of the vulva, although the reason for this is unclear One hypothesis is that genetic variations in T-cell-mediated IL-2 responses among smokers may explain differential susceptibility to the development of squamous vulvar carcinomas (19) Chronic vulvar inflammatory lesions, such as vulvar dermatoses, including lichen sclerosus (LS), lichen planus, lichen simplex chronicus (including squamous cell hyperplasia), and vulvar intraepithelial neoplasia (HSIL/VIN 2–3 (usual as well as differentiated types), particularly dVIN, have been suggested as precursors of invasive squamous cancers (15) Carli et al (16) suggested a possible role of LS as a precursor to vulvar cancer, based on their observation that 32% of vulvar cancer cases not related to HPV were associated with LS More recently, in a pathologic reevaluation of patients with a diagnosis of LS who were followed clinically for a minimum of 10 years, van de Nieuwenhof and colleagues identified concordant diagnoses of LS in 58/61 patients who did not progress to cancer, and concordant diagnoses of LS in only 29/60 patients who were identified with a subsequent diagnosis of vulvar cancer Most patients reclassified as having something other than LS were considered to have dVIN (25/31 patients) This study highlights dVIN as a uniquely at-risk histology that deserves prompt treatment and close follow-up Differentiated VIN is often found in lesions, previously diagnosed as LS, that have progressed to vulvar SCC (15) In a more recent long-term follow-up study of women with LS, those identified with LS had a progressively increased frequency of vulvar SCC with increasing duration of the disease In this study, most squamous carcinomas were superficially invasive At 24 months of follow-up, 1.2% had carcinoma, whereas at 300 months, 36.8% had carcinoma (20) Despite this association, however, LS is not considered a true premalignant condition like HSIL/VIN 2–3 Standard clinical management of LS, including chronic, as-needed topical steroid use, periodic surveillance examinations, and selective biopsies of discrete lesions, has been reported to reduce the risk of vulvar carcinoma (21) Vulvar lichen planus (LP), like LS, is also recognized as being associated with an increased risk of a subsequent diagnosis of vulvar SCC In a long-term Finnish study (follow-up >43 years) evaluating more than 12,144 women with LS and 9,030 women with LP, both diagnoses were associated with an increased risk of vulvar carcinoma Among women with LS, many of those who subsequently presented with vulvar carcinoma presented within years of the beginning of the study, with 993 (8%) women subsequently having carcinoma Among women with LP, 919 (10%) subsequently developed carcinoma (22) In a study of 405 patients noted to have VIN 2–3, Jones et al (23) found that 3.8% of patients had developed invasive cancer despite therapy, and 10 untreated patients developed invasive cancer between 1.1 and 7.3 years (mean, 3.9 years) from the time of initial observation In a recent retrospective study of 240 women with vulvar squamous lesions, 213 with HSIL/VIN 2–3 were treated with surgical excision Among these patients, 21 (9.8%) were found to have an associated invasive squamous carcinoma within the surgical specimen Most tumors were superficial, varying in size from 0.1 to cm On follow-up, 25% of the patients with positive margins had local recurrence of HSIL, whereas 16.6% of those with negative surgical margins were identified with a recurrence (22) Although some intraepithelial lesions regress spontaneously, it appears that a significant number persist or progress to invasive cancer Differentiated VIN is recognized as a precursor of vulvar SCC and is associated with LS in many cases In a retrospective study involving 240 patients with vulvar squamous lesions, 27 were found to be dVIN, and 19 of these cases (70.4%) had associated SCC (22) In a retrospective study of 18 dVIN cases, 14 were found to have associated SCC, and of these, 12 had associated vulvar LS (24) Trimble et al (25) postulated that SCC of the vulva may represent a final common endpoint of heterogeneous etiologic pathways According to their studies, two histologic subtypes, those with basaloid or warty features, are associated with HPV, whereas keratinizing squamous carcinomas are not Furthermore, basaloid or warty carcinomas are associated with classic risk factors for cervical carcinoma, including age at first intercourse, lifetime number of sexual partners, prior abnormal Pap smears, smoking, and lower socioeconomic status Keratinizing squamous carcinomas are weakly linked to these factors, and in some cases not at all Mitchell et al evaluated 169 women with invasive vulvar cancers and noted that second genital squamous neoplasms 839 occurred in 13% of cases The risk of a second primary tumor was significantly increased in cancer cases with HPV DNA, intraepithelioid growth pattern, or adjacent dysplasia (26) These observations support the concept that some squamous lesions may be initiated by neoplastic etiologies that produce change within the entire field of the lower genital tract (field effect) The obvious clinical implication of this observation is that a patient with an established squamous lesion of the vulva, vagina, or cervix needs to be evaluated and monitored for new or coexistent lesions at other genital sites Vulvar cancers metastasize in three ways: (a) local growth and extension into adjacent organs, (b) lymphatic embolization to regional lymph nodes in the groin, and (c) hematogenous dissemination to distant sites Inguinal node metastasis can be predicted by the presence of multiple risk factors, including tumor diameter, higher histologic grade, depth of stromal invasion, and lymph-vascular space invasion (27) Clinically important observations regarding nodal metastases include the following: (a) Inguinal nodes are the most frequent site of lymphatic metastasis; (b) In-transit metastases within vulvar epithelium and deep tissues are exceedingly rare, suggesting that most initial lymphatic metastases represent embolic phenomena; (c) Metastasis to the contralateral groin or deep pelvic nodes are unusual in the absence of ipsilateral groin metastases; (d) Nodal involvement generally proceeds in a stepwise fashion from the superficial inguinal to the deep inguinal and then to the pelvic nodes (27) Spread beyond the inguinal lymph nodes is considered distant metastasis (stage IVB) The occurrence of such metastases are due to either sequential lymphatic spread to secondary and tertiary nodal groups or as a result of hematogenous dissemination to more distant sites, such as bone, lung, or liver Distant metastases are uncommon at initial presentation and are usually seen in the setting of recurrent disease CLINICAL PRESENTATION Most women with vulvar cancer present with pruritus or vulvar discomfort and a recognizable, exophytic or endophytic ulcerated lesion Selecting the most appropriate site for biopsy in women with condyloma, chronic vulvar LS, multifocal high-grade squamous intraepithelial lesions (VIN 3), or Paget’s disease can be difficult, and multiple biopsies may be required Optimal management for any patient presenting with a suspicious lesion is to proceed directly to biopsy under local analgesia Tissue biopsies should include the cutaneous lesion in question and representative contiguous underlying stroma, so that the presence and depth of invasion (DOI) can be accurately assessed Because DOI is a central issue in the management of vulvar cancer, punch biopsies are encouraged and shave biopsies are generally discouraged in the diagnosis of vulvar lesions If invasion is suspected and a punch biopsy fails to confirm the clinical suspicion, then an incisional or excisional biopsy should be performed Primary care physicians should be encouraged not to excise an entire lesion if avoidable, in order to facilitate a subsequent sentinel node procedure by a gynecologic oncologist Figure 18.2 illustrates an early-stage vulvar cancer 840 Figure 18.2 Early-stage vulvar cancer DIAGNOSTIC EVALUATION The evaluation of a patient with vulvar cancer must consider the clinical extent of disease and the presence of coexisting medical illnesses Initial evaluation should include a detailed physical examination with measurements of the primary tumor, assessment for extension to adjacent mucosal or bony structures, and clinical evaluation of the inguinal LNs It is helpful to record the distance from vital structures such as the clitoris, urethral meatus, and anus, since these structures limit the ability to obtain adequate surgical margins Diagnostic imaging is not required in women with small primary lesions and normal body habitus In obese women, the inguinal nodes are difficult to palpate, and imaging may help identify the presence of lymphadenopathy Patients with large or fixed tumors, and those who are difficult to examine in the clinic, may benefit from an exam under anesthesia with cystourethroscopy and proctosigmoidoscopy Figure 18.3 illustrates an advanced tumor, for which such an approach can help determine resectability Radiographic studies that have been described as beneficial are computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasound, and single photon emission CT While newer imaging modalities can benefit treatment planning, it is also important to note that published series are small, and no individual modality has been shown to be superior to others in terms of detecting metastatic or recurrent disease (28–31) The best modality might differ depending on the practice situation and skills of the diagnostic imaging consultants Suspicious lymph nodes should be biopsied if the findings would alter the surgical plan Because neoplasia of the female genital tract is often multifocal, evaluation of the vagina and cervix, including cervical cytologic screening, should always be performed in women with vulvar neoplasms (32) Lymphoscintigraphy (LSG) is discussed later in this chapter 841 developmental chemotherapy adaptations to traditional, 296–297, 296t FDA approval, 297 phase trials, 296–297 phase trials, 296–297 phase trials, 296–297 postmarketing studies, 297 eligibility criteria, 365–366 hypothesis test, 370 p value, 370 incorporating tumor marker into, 85t monoclonal antibodies, 352–353 with monoclonal antibodies, 352–353 ovarian cancer, results, reporting, 373–375 targeted therapies, involving, 375–377 therapeutic intervention trials phase trials, 366–367 phase trials, 367 phase trials, 367–370 translational research, 370–373 biomarker development process, 371–373 biospecimen collection, 371 studies, developing, 373–375 uterine cancer, clinical validation biomarker, 371 Clinoril (sulindac), 837t clitoris, 398–399 cloacogenic carcinoma, 415f clonal evolution, 24t clonidine, 841, 842t clonogenic assay, 215 clonogenic survival curves, 216f Cloquet’s node, 399 clostridial myonecrosis (gas gangrene), 815–816 Clostridium difficile, 294, 815–816 Clostridium species, 808 1545 CMA (cost-minimization analyses), 382 CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), 784 CML (chronic myelogenous leukemia), 275, 718 CMS (Centers for Medicare and Medicaid Services), 385, 874 CMV (controlled mechanical ventilation), 149 CO (cardiac output), 146–148, 149, 157, 159 cobalt 60 (60Co), 221t Cockroft–Gault (CG) formula, 287t, 309 codeine, 838t, 839 coffee consumption, cognitive behavioral therapy (CBT), 869–870 cognitive pain management approaches, 845 cold knife conization during pregnancy, 486 collagens, 69 College of American Pathologists (CAP) Guidelines, 650 colon cancer, definition of, 627t colorectal surgery, 142–143, 144–145, 151, 811 colpectomy, 434 colposcopy, 470–471, 486 colpostats, 229, 233, 237, 247, 249, 574 columnar cell hyperplasia, 773f combination chemotherapy, 74 combination therapy, 75–76, 590t combined modality chemotherapy, 496–497 related adverse events, 498–499 comedo-type ductal carcinoma in situ, 773f comedocarcinoma, 773 Common Terminology Criteria for Adverse Events (CTCAE), 292 communication, 139, 183 in primary palliative care advance care planning, 871–872 breaking bad news, 871 family meetings, 872 impact on outcomes, 872–873 prognosis, 871 styles of, 872t teaching, 872 1546 comparative effectiveness research (CER), 380 comparative genomic hybridization (CGH), 39, 738 complement-dependent cytotoxicity (CDC), 346 complementary pain management approaches, 845 complete debulking surgery, 635t complete hydatidiform moles (CHMs), 744, 747, 749f complex atypical hyperplasia (CAH), 527, 528–529 complex hyperplasia (CH), 527, 528 Compton effect, 212, 219f computed tomography See CT (computed tomography) computer-aided detection (CAD), 768, 769 computerized dosimetry, 225–226 concealment, 369 concurrent chemotherapy, 283 condom use and risk of genital HPV infection, 14 confidence intervals, 368f confluent glandular invasion pattern, 661 Confusion Assessment Method, 868 congestive heart failure (CHF), 148 conization, 471, 479, 486 conjugates See vaccines connective tissue–activating protein III (CTAP III), 89 consolidative chemotherapy, 682–683 consolidative radiotherapy, 682 constipation, 842, 867–868 continent urinary diversion, 181, 182f continual reassessment method (CRM), 366 continuous home care, 865 continuous infusion, 841 contraceptives See OCPs (oral contraceptives) contralateral breast cancer, 790 controlled mechanical ventilation (CMV), 149 conventional (two-and three-dimensional) radiotherapy, 421, 422f conventional cytotoxic agents, in gynecologic malignancies, 275–279, 275–278t Cooper’s ligaments, 767 COPD (chronic obstructive pulmonary disease), 133 core biopsy, 778, 780 1547 MRI-guided, 771 coronary ligaments, 169 coronary vascular disease (CVD), 130–131, 132t, 138, 154 corpus See uterine cancer corpus luteum cyst, 625t corticosteroids, 137, 161t, 842t, 843 Corynebacterium parvum, 479 Corynebacterium species, 804 Cosmegen (dactinomycin), 313, 711 cost-effective and value-based gynecologic cancer care cost and comparative effectiveness, 380 cost-effectiveness of therapeutics cervical cancer, 392 endometrial cancer, 392–394 ovarian cancer, 390–392 cost, quality, and value in, 380 health economic analyses, principles of cost-effectiveness analyses, 382 cost-minimization analyses, 382 cost-utility analyses, 382 methods for development, 382–385 health economic models, input development for costs, estimation of, 385 modeling effectiveness, 385–386 modeling quality of life, 386–387 screening for cancer, natural history of, 387–388 cervical cancer, 388–389 ovarian cancer, 389–390 simulation, 388 value in ASCO value framework, 381 methods for measurement, 381–382 Porter value framework, 381 status quo measurement, 382–383 cost-effectiveness analyses (CEA), 382 cost-minimization analyses (CMA), 382 1548 cost-utility analyses (CUA), 382 costs, estimation of, 385 Council of Graduate Medical Education, 875 counseling dietary, 856 endometrial cancer, 516 genetic, 617–618 preoperative, 130, 133, 144 Cowden syndrome, 62 COX-1, 836 COX-2, 569, 571, 836, 837t CPM See cyclophosphamide (Cytoxan, Neosar, CTX, CPM, Endoxan) CPT-11 (irinotecan), 277t, 288t, 329, 688 CRBED (cumulative rectal biologically effective dose), 233 creatinine clearance, 287t cribriform ductal carcinoma in situ, 773f cribriform fascia, 399 CRISPR-Cas9 system, 33–34 critical care management cardiovascular issues acute postoperative myocardial infarction, 147–148 arrhythmias, 148 congestive heart failure, 148 inotropes, 148 monitoring issues, 146–147 valvular disease, 148 vasopressors, 148 end of life consideration, 161–162 fluid and electrolyte issues acid-base disturbances, 153–154 calcium derangements, 153 magnesium derangements, 153 metabolic acidosis, 154, 154t metabolic alkalosis, 154, 154t potassium derangements, 152–153 respiratory acidosis, 154, 154t respiratory alkalosis, 154, 154t 1549 sodium derangements, 152 infectious disease issues abdominal compartment syndrome, 159 abdominal infections, 158 fungal infections, 158 multiple organ dysfunction syndrome, 159 nosocomial infections, 157–158 sepsis, 158–159 systemic inflammatory response syndrome (SIRS), 158–159 neurologic issues analgesia, 160 delirium, 161 ICU syndrome, 161 neuromuscular blockade, 161 sedation, 160 pulmonary issues acute respiratory distress syndrome, 150 deep venous thrombosis prophylaxis, 150 modes, 149–150 oxygenation, 149 pneumonia, 150 pulmonary embolism, 150 setting ventilator, 149 ventilator management, 148 weaning from ventilator, 150 work of breathing, 149 shock cardiogenic, 157 definition, 157 hemorrhagic, 157 septic, 157 CRM (continual reassessment method), 366 cross-sectional studies, 363, 364 CRS (cytoreductive surgery), 204, 674 ovarian cancer, complications, 824–828 for patients with extrauterine disease at initial diagnosis, 579 cryotherapy, 480 1550 crystals of Reinke, 734 CT (computed tomography), 189, 192, 197, 204–205, 421, 437 adnexal mass, 631 based simulators (“CTSims”), 225 cervical cancer, 472 cone beam, 222 gestational trophoblastic neoplasia, low-risk, 756–757 ovarian cancer, 631–632 postoperative adynamic ileus, 824 CT (cancer testis) antigens, 345, 348, 348t CTAP III (connective tissue–activating protein III), 89 CTCAE (Common Terminology Criteria for Adverse Events), 292 CTCF, 37t, 40, 41 CTEP (Cancer Therapy Evaluation Program), 292 CTLA-4 (cytotoxic T-lymphocyte antigen 4), 219, 347–351 CTNNB1 (β-catenin), 32, 41, 43t, 46, 369t, 545t CTP (Child-Turcotte-Pugh), 139, 140t “CTSims” (CT-based simulators), 225 CTV (clinical target volume), 212, 212f, 217, 226, 450, 455 CTX See cyclophosphamide (Cytoxan, Neosar, CTX, CPM, Endoxan) CUA (cost-utility analyses), 382 cumulative rectal biologically effective dose (CRBED), 233 curie, 220t cutaneous Paget’s disease, 408 CVD (coronary vascular disease), 130–131, 132t, 138, 154 CVP (central venous pressure), 146 CXCL12 ligand, 72 CXCR4 receptor, 72 cyclic hematologic toxicity, 275 cyclin-dependent kinases (CDK), 265–266 cyclin E, 745t cyclin E1 (CCNE1) amplification, 42, 45 cyclophosphamide (Cytoxan, Neosar, CTX, CPM, Endoxan), 276t, 288t, 289, 294, 295, 312–313, 390, 449, 485, 543, 585t, 590t, 592t, 595t, 596t, 681t, 687, 687t, 689, 714, 758, 758t, 759t, 783t, 784, 785, 786t, 796 activation, 322 biotransformation, 286 1551 CMF, 784 VAC, 711 cyclophosphamide, doxorubicin, and cisplatin (CHAP, CAP), 539 cyclophosphamide, hydroxyurea, actinomycin D, methotrexate with folinic acid, vincristine, and doxorubicin (CHAMOCA), 758 cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), 784 CYFRA 21-1, 92, 93t, 94 cylinders, 237f CYP (cytochrome P450) isozymes, 285, 290t, 297 CYP3A4 isozyme, 285, 288–289, 289t, 328 cystadenomas, 653 cystosarcoma phyllodes (phyllodes tumors), 778 cystoscopy, 437 cytarabine, 304 cytochrome P450 (CYP) isozymes, 285, 290t, 297 cytokeratins, 92, 745t cytokine inhibitors, 857, 857t cytokines, 92, 346, 350–351, 352, 852 cytology, cervical cancer and, 388 cytoreductive surgery See CRS (cytoreductive surgery) cytosolic hydrolase, 306 cytotoxic agents See also cisplatin; cyclophosphamide (Cytoxan, Neosar, CTX, CPM, Endoxan); doxorubicin (Adriamycin); paclitaxel (Taxol) 5-fluorouracil, 319–321, 544 altretamine, 305–306 bleomycin, 306–307, 312, 327, 713t, 715 capecitabine, 286, 307–308 carboplatin, 295, 308–310, 544 dactinomycin, 313–314, 711 docetaxel, 314–315 epothilones, 544–545 eribulin, 318 etoposide, 318–319, 713, 713t, 718, 758–760 floxuridine, 319–321 gemcitabine, 252, 254, 321–322, 689 ifosfamide, 286, 322–323, 583t, 589t, 590t, 688, 715 irinotecan, 688 1552 ixabepilone, 323–324 liposomal doxorubicin, 688–689 liposomal encapsulated doxorubicin, 324 melphalan, 304f methotrexate, 304, 324–326, 753, 756–760 mitomycin, 326–327, 588 oxaliplatin, 295 paclitaxel, 327–328, 547 pemetrexed, 328 taxanes, 688 topotecan, 298t, 329, 544, 679, 689 vincristine, 544 vinorelbine, 329–330 cytotoxic chemotherapy, 423 endometrial cancer and, 543–545 cytotoxic T-lymphocyte antigen (CTLA-4), 219, 347–351 cytotoxicity, enhanced chemotherapy, 496 after neoadjuvant chemotherapy before radiochemotherapy, 496–497 before surgery, 496 radiochemotherapy, 496 for second-line chemotherapy, 497 cytotrophoblast cells, 707, 748 Cytoxan See cyclophosphamide (Cytoxan, Neosar, CTX, CPM, Endoxan) D dacarbazine (DTIC), 276, 322, 414, 585t, 587, 588, 590t, 592t, 593t, 594t, 595t, 596t dacarbazine, doxorubicin, mitomycin, and cisplatin (DAMP), 588 DACH (diaminocyclohexane) platinum (oxaliplatin), 288t, 294, 295, 305t, 677, 715 daclizumab, 350 dactinomycin (actinomycin D, ACT-D, Cosmegen), 276t, 294, 313–314, 711, 753–754, 756, 757, 758t DAMP (dacarbazine, doxorubicin, mitomycin, and cisplatin), 588 Danish Breast Cancer Cooperative Group (DBCCG), 790 1553 daptomycin, 813, 814 Data Safety Monitoring Board (DSMB), 693 Datril (acetaminophen), 160, 834, 836, 837t, 838t, 839, 843 Daypro (oxaprozin), 837t DBCCG (Danish Breast Cancer Cooperative Group), 790 DCE-MRI (dynamic contrast-enhanced-magnetic resonance imaging), 479 DCIS (ductal carcinoma in situ), 333, 768 breast cancer, 772–774 comedo-type, 773 cribriform ductal, 771f micropapillary, 771f surgical management, 780 DCs (dendritic cells), 115, 345, 347 activation, 348–349 DDT (dichlorodiphenyltrichloroethane), debulking, surgical in advanced epithelial ovarian cancer, 637–640 detecting recurrence, 86f for ovarian cancer, 180–181 pelvic and upper abdominal procedures, 640 decision node, 383, 383f decitabine, 693 deep venous thrombosis See DVT (deep venous thrombosis) definitive radiation therapy, 421 dehydroepiandrosterone (DHEA), 730, 733 delayed nausea and vomiting, 294, 312 delirium, 161, 868–869, 869t Delirium Rating Scale-Revised 98, 868 demographic patterns cervical cancer, 11–12 GTDs, 18 ovarian cancer, 6–7 uterine cancer, uterine corpus cancer, vaginal cancer, 18 vulvar cancer, 17 dendritic cells See DCs (dendritic cells) 1554 Denileukin diftitox, 350 denosumab, 842t density, pharmacologic principles, 284–285 Department of Health and Human Services (DHHS), 380 depo-medroxyprogesterone acetate (Depo Provera), 613 Depo Provera (depo-medroxyprogesterone acetate), 613 depression, 831, 832–833, 838t, 852, 869 dermatologic toxicities/side effects, 315, 325 DES (diethylstilbestrol), 18, 432, 445–446 desacetylvinblastine, 693 desipramine, 842t DESKTOP III trial, 686 desmoplasia, 405 desmoplastic noninvasive implant, 655 detemir, 134t developmental chemotherapy trials FDA approval, 297 postmarketing studies, 297 dexamethasone, 294, 307, 312, 315, 327, 758, 842t, 868 dexrazoxane (Zinecard), 294, 317 dextrose 5% in water (D5W), 756t, 758t DHEA (dehydroepiandrosterone), 730, 733 DHFR (dihydrofolate reductase) gene, 290, 324, 328 DHHS (Department of Health and Human Services), 380 diabetes, 4, 133–135 Diagnosis Related Group (DRG), 385 diagnostic biopsy, 471 diagnostic imaging techniques See also names of specific imaging techniques gestational trophoblastic disease (GTD), 200–201, 202–203f detection of, 200 post primary therapy, 200–201 primary treatment planning, 200 modalities CT (computed tomography), 189 MRI (magnetic resonance imaging), 189, 191 PET (positron emission tomography), 191–192 ultrasound, 189 1555 ovarian cancer, 203–205, 205–207f, 207t detection of, 203–204 post primary therapy, 205 primary treatment planning, 204–205 uterine cervical cancer, 192–194 detection of, 192 post primary therapy, 193–194, 195f primary treatment planning, 192–193, 192–193f uterine endometrial cancer, 194–198, 196–199f, 196t detection of, 194–195 post primary therapy, 198 primary treatment planning, 195–197 uterine sarcomas, 199–200, 199–201f detection of, 199–200 post primary therapy, 200 primary treatment planning, 200 vulvar cancer, 201, 203f detection of, 201 post primary therapy, 201 primary treatment planning, 201 diagnostic mammography, 768 diaminocyclohexane platinum (oxaliplatin), 277t, 288t, 294, 295, 305t, 677, 715 diarrhea, 308, 309, 317, 331, 819, 855 diaziquone, 584t, 590t DICER1 mutations, 47 dichlorodiphenyltrichloroethane (DDT), diclofenac (Voltaren), 837t dietary factors carcinogenic HPV infection, 16 ovarian cancer, 9–10 risk of, 615–616 uterine cancer, diethylstilbestrol (DES), 18, 432, 445–446 diffusion-weighted-magnetic resonance imaging (DWI-MRI), 479 diflunisal (Dolobid, Dolobis), 837t Digital Mammographic Imaging Screening Trial (DMIST), 769 digital mammography, film mammography versus, 769 1556 digoxin, 157, 161t dihydrofolate reductase (DHFR) gene, 290, 324, 328 dihydropyrimidine dehydrogenase (DPD), 288t, 289t, 291, 307–308, 321 diltiazem, 161t dinitrophenyl (DNP), 354 dipeptidal peptidase-IV inhibitor, 134t direct costs, 385 Disalacid (salsalate), 837t disease response categories, 284t disseminated abdominal tuberculosis, definition of, 627t distribution, 285 diverticulitis, definition of, 626t DLT (dose-limiting toxicity), 275, 294, 311, 315, 366 DMIST (Digital Mammographic Imaging Screening Trial), 769 DMOT4039A, 693 DNA copy number, 24t, 39, 42–43, 47 DNA methylation, 24, 372t, 693 profile, 89, 94 DNA mismatch repair genes, 5, 34–35, 291 Lynch syndrome, 37–38, 59–60, 512, 620–621 risk of ovarian cancer, 108t DNA repair, 291 molecular pathogenesis double strand break repair, 36–37 mismatch repair (MMR), 34–35 nucleotide excision repair/base excision repair, 35–36 pathway, 266–267, 266f DNIB0600A, 693 DNP (dinitrophenyl), 354 dNTP (2’-deoxyribonucleoside triphosphate), 496 dobutamine, 132, 148, 157, 159 docetaxel (Taxotere), 276t, 285, 288, 288t, 289, 289–290t, 293, 294, 295, 297, 305t, 308, 314–315, 497, 585t, 590t, 594t, 595t, 678t, 679, 685, 783, 783t, 784–785, 796 Dolobid, Dolobis (diflunisal), 837t Domeboro, 252 dopamine, 148, 866 dopamine antagonists, 842 1557 dose-dense therapy, 285 dose intensity, pharmacologic principles, 284–285 dose-limiting toxicity (DLT), 275, 294, 311, 315, 366 dose profiles, 221, 224, 225 dose-volume histograms (DVHs), 240, 253, 257 double-stranded breaks (DSB), 36–37, 36f, 43, 54, 216, 310 doubling times, human tumors, 280t Doxil (liposomal encapsulated doxorubicin, Caelyx), 244, 324 doxorubicin (Adriamycin), 276t, 288t, 449, 485, 584t, 585t, 586, 588, 592t, 593t, 594t, 595t, 596t, 687, 783t, 784, 786t endometrial cancer, 544 intravenous dosing guidelines, 317t liposomal encapsulated, 324 overview, 315–318 PEG-liposomal, 316 skin reactions, 252 uterine cancer, 587, 589t, 590t doxycycline, 161t DPD (dihydropyrimidine dehydrogenase), 288t, 289t, 291, 307–308, 321 DRG (Diagnosis Related Group), 385 dronabinol, 857 drotrecogin alfa (activated-Xgris), 159 drug clearance, 303–304 drug interactions, 288–290, 297–298 bleomycin, 307 carboplatin, 310 cisplatin, 312 cyclophosphamide, 313 doxorubicin, 318 ifosfamide, 323 methotrexate, 325–326 paclitaxel, 328 vinorelbine, 330 drug resistance, 290–292 drug scheduling, 297–298 drug sequence, 297–298 DSB (double-stranded breaks), 36–37, 36f, 43, 54, 216, 310 1558 DSMB (Data Safety Monitoring Board), 693 dualistic model of ovarian cancer pathogenesis, 646–647 ductal carcinoma in situ See DCIS (ductal carcinoma in situ) ductal hyperplasia atypical, 772f usual, 771f duloxetine, 685, 842t, 867 Dutch TLH trial, 826 DVHs (dose-volume histograms), 240, 253, 257 DVT (deep venous thrombosis), 823 prophylaxis, 150 risk associated with tamoxifen, 787 DWI-MRI (diffusion-weighted-magnetic resonance imaging), 479 dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI), 479 dynamic transmission models, 389 dysgerminoma, 90, 706, 706f, 710, 716–717 dyspareunia, 448, 456 dysplasia cervical cancer HIV/AIDS, 488 during pregnancy, 486 severe, 479–480 dyspnea, 330, 868 1559 ... coexistence of HPV and the incidence of both VIN and stage I vulvar cancer HPV infection was present in 61.5% of cases of VIN and vulvar cancer in women aged 45 years or less, and in 17.5% of women... associated SCC (22 ) In a retrospective study of 18 dVIN cases, 14 were found to have associated SCC, and of these, 12 had associated vulvar LS (24 ) Trimble et al (25 ) postulated that SCC of the vulva... IA T1a, N0, M0 IB T1b, N0, M0 II T2, N0, M0 IIIA T1 or T2, N1a or N1b, M0 IIIB T1 or T2, N2a or N2b, M0 IIIC T1 or T2, N2c, M0 IVA Either T1 or T2, N3, M0 or T2, any N, M0 IVB any T, any N, M1