If the patient presents with metastatic disease, or at relapse after par- tial thyroidectom y, radical thyroidectomy and ablation is still required because optimal management is based on the ability of most differen- tiated cancers to concentrate radioiodine (I131) \200\224 albeit usually less avidly than the parent gland. A carefully conducted radioiodine pro- gr amme can prolong life substantially in many of these patients and achieve complete and dura ble response in a signi \201cant number \200\224 small bulk relapse and high iodine avidit y being better response predictors. Following radical thyroidectomy and radioiodine ablation of the stump, the patient has seri al clinical examinations with at least two whole body radioiodine whole body pro \201le sc ans in the next 11 \201\2042 years (each performed after 3 months off thyroxine, 8 days off liothyronine and the tracer dose being given when the TSH is known to be above 30 Uu/L or after 200 (cid:2)g of TRH iv \200\224hereafter referred to as \200\230optimal conditions f or radioiodine \200\231). Serum thyroglobulin is measured at each clinical consultation and this important serum marker is more sensi- tive for relapse under the optimal conditions j ust described, although OHO-21(375-388) 11/18/02 8:33 AM Page 377 THYROID CANCER 377 worthwhile when the patient is on thyroid replacement. If two iodine scans over the \201r st 1.5 years are negative, and the clinical examination and thyroglobulin are negative, the n iodine scanning is only used in suspected relapse (and even then many would go straight t o an iodine therapy dose with a whole body scan on the \200\230tail-end \200\231 of the do se, because of the possibility of a tracer dose scan missing low avidity, but therapeutical ly relevant, uptake). Papillary cancer tends to relapse \201rst in neck nodes (and then medi- astinal nodes) be fore the lungs and then bones. The treatment of neck nodal disease is surgical resection (p receded by an iodine pro \201le scan under optimal conditions) followed by radiodine thera py where appropriate. Pre-operative imaging to de \201ne the extent of the nodal disease s hould be with MRI and not CT, because of the iodine load with CT contrast agents. Metastatic disease further a \201eld is treated by serial doses of radio- iodine (150 mCi = 5500 MBq), using the whole body scans after each dose and the serial thyroglobulin estima tion to guide progress, as well as other imaging. Iodine therapy is continued at 4 \200\223 6 monthly inter- vals until maximal remission, so long as the FBC and creatinine are satisf actory; care is needed after a cumulative dose of 1 Ci. In patients who do not relapse, physical examination (with careful attention to the neck an d CXR) and blood checks to ensure TSH sup- pression and minimal serum thyroglobulin reading s (<2 (cid:2)g/L) con- stitute follow-up, the periodicity of which decreases with the passa ge of time; remember that this disease can relapse up to 15 years from diagnosis. Anaplastic carcinoma Again presenting as a lump in the neck, the treatment is altogether mo re palliative as these tumors are rarely a radical surgical proposi- tion and do not take u p iodine. Radiotherapy to the neck is the stan- dard treatment, with palliative chemotherap y a not very promising systemic alternative (as indeed it is not in differentiated cancers) . Lymphoma Lymphomas tend to occur in elderly women, frequently against a background of prolo nged autoimmune thyroid disease. They are high grade immunoblastic non-Hodgkin \200\231s tu mors and are treated with a combination of combination chemotherapy and wide \201eld radi o- therapy to the neck. Prognosis is guarded. Medullary carcinoma Medullary carcinoma of the thyroid arises from the parafollicular C cel ls (the cell of origin of calcitonin), and may be sporadic or famil- ial. If the latter, it may or may not be part of the MEN syndrome, and OHO-21(375-388) 11/18/02 8:33 AM Page 378 ENDOCRINE CANCERS 378 the diagnosing clinician should take a family history and screen for phaeochromocytoma. Sur gical clearance of apparently localized disease to the neck is the only curative hope and i s the \201rst therapeutic step. For recurrent disease (for which the serum calcitonin ser ves as a good marker), occasional avidity of uptake to meta-iodo-benzyl- guanadine (MIBG) m akes radioiodinated MIBG therapy a possibly useful therapeutic modality. Otherwise there is no useful therapy except for palliative radiotherapy where appropriate; we have had little to no success with palliative chemotherapy. OHO-21(375-388) 11/18/02 8:33 AM Page 379 THYROID CANCER 379 OHO-21(375-388) 11/18/02 8:33 AM Page 380 ENDOCRINE CANCERS 380 Adrenal cancer The adrenal gland is composed of a cortex and a medulla and the tumors that arise in these two regions are aetiologically and func- tionally different, re \202ecting their cells of origin. Etiology The etiology of adrenocortical carcinomas is generally unknown. There are rare rep orts of familial incidence. About 10% of adrenal medullary tumors are familial, although in future more may be iden- ti \201ed as hereditary. These are usually associated with multi ple endocrine neoplasia (MEN) syndrome II and, occasionally, von Hippel \200\223Lindau dise ase. The RET proto-oncogene was the \201rst to be associated with MEN IIA and familial me dullary thyroid cancer and, subsequently, MEN IIB. The ability to identify this oncogene is of con- siderable importance in prophylaxis of the disease (discussed later). In over 80% of cases exons 10 and 11 are affected, which is useful for screening purposes. Epidemiology Both medullary and cortical tumors are rare. The incidence is about 1.0 per 10 6 population for cortical tumors and lower for phaeo- chromocytomas, at 0.6 per 106 populat ion. Pathology Both benign and malignant tumors are seen in the adrenal gland and, in the heredi tary variants, hyperplasia and pre-malignant changes may be evident. The differentiation be tween benign and malignant tumors is usually only made by their clinical behavior \200\224 the presence of local invasion or metastases indicates a malignant tumor. Only about 10% of adrenal medullary tumors are malignant. The hereditary tumors often occur in younger age groups, are more like- ly to be bilateral, and tend to be more benign in th eir behavior. Adreno-medullary tumors are usually phaeochromocytomas, so- called because of their golden or tan-colored appearance. About 10% of phaeochromocytomas are extra-adrenal and arise anywhere in the sympathetic chain. Rarely, neuroblastomas may present in late ado les- cence or adulthood. Immunocytochemistry is important in establishing the diagnosis. Adrenocortical carcinomas a re usually adenocarcinomas and malig- nancy is con \201rmed by the presence of metastatic spread. These OHO-21(375-388) 11/18/02 8:33 AM Page 381 ADRENAL CANCER 381 tumors extend locally to nodes and the liver but have a high fre- quency of distant spread when malignant. Presentation Adreno-medullary tumors (phaeochromocytomas) tend to present at a younger age when associated with the MEN syndrome, whereas sporadic tumors tend to occur in older patie nts. Classical symptoms include paroxysmal headaches, palpitations, tremors, and sweating a ttacks. A few may be diagnosed incidentally and a rare, but occasional case may be diagnose d after a maternal death in an unrecognized MEN family. Intermittent, severe hypertension i s a rare but classical presentation. Patients often have a long history and these tumors can be dif \201cult to diagnose. Many doctors will never see a patient with this condition, but a low threshold for investigation is appropriate. Adrenocortical tumors have a more varied presentation. About 40% are functioning; the rest are non-functional and only present with pressure symptoms such as pain in the abdomen or \202ank. They may also present with metastases. Others secrete steroids including oestroge ns, testosterone, aldosterone, or even combinations and, depending upon the predominant ste roid produced, the symptoms will vary. Diagnosis (cid:2) Clinical signs \200\224Cushing \200\231s syndrome \200\224virilization \200\224feminization \200\224neuromata, \200\230caf au lait \200 \231 spots (cid:2) Family history (cid:2) Hemoglobin, electrolytes, urea, liver function tests (cid:2) Urinary VMA, catecholamines Table 21.1 Endocrine syndromes associated with adrenocortical tumors Syndrome Steroid Cushing \200\231s syndrome (ACTH-independent) Cortisol Conn \200\231s syndrome/primary hyperaldosteronism Aldosterone Virilization syndrome Androgen secretion Feminization syndrome Estrogen secretion Precocious puberty syndrome/adrenogenital syndrome Sex hormones Non-functioning None OHO-21(375-388) 11/18/02 8:33 AM Page 382 ENDOCRINE CANCERS 382 (cid:2) Plasma catecholamines (cid:2) Chromogranin assays (cid:2) Blood, urinary cortisols (cid:2) Blood estrogen, testosterone (cid:2) Chest X-ray, ultrasound, CT, MRI abdomen (cid: 2) Ultrasound thyroid (MEN) 123I-MIBG, octreoscan \200\224adrenal tumor (cid:2) Selenocholesterol imaging \200\224corti cal tumor (cid:2) Treatment The mainstay of treatment in all these tumors is surgical resection. This is the only treatment likely to achieve cure. Before considering surgery it is necessary to carry out staging investigations, as already described, to exclude the presence of metastases. It may still be appro- priate to resect the primary tumor in the presence of metastases if it is slow-growing or where there are a small number of metastases, in order to achieve local control. The surgical resection of phaeochromo- cytomas requires a skilled multidisciplina ry team approach. As a rule, surgery for adrenocortical tumors is less hazardous, but patie nts with electrolyte disturbances require careful preparation prior to surgery. Following s urgery, persistent biochemical disturbance indi- cates residual disease. This is best handl ed by a multidisciplinary expe- rienced team. The identi \201cation of the gene causing MEN has led to the screening of affected familie s and prophylactic surgery in children. When per- formed in specialist units this carries m inimal morbidity. Thyroid surgery for MCT is carried out at 5 \200\2237 years of age. For phaeochromocytomas with residual or unresectable disease, anti-hypertensive medication may be required to control the blood pressure. If the tumor takes up the radionuclide MIBG, a therapeutic dose of up to 10 000 MBq of 131I-MIBG may be administered and repeated at 3 \200\2236 monthly intervals. A number of tumors will not take up MIBG and consideration sho uld be given to chemotherapy. These tumors were traditionally considered to be chemo-resist ant, but a combination of DTIC, vincristine, and cyclophosphamide shows activity. Other reg imens which include cisplatin and etoposide have shown promise. For unresectable or metastatic adrenocortical tumors, Mitotane (opDDD) is the \201rst-lin e treatment. This drug may be associated with unpleasant symptoms and the dosage is usually built up slowly, to a maximum of 10 \200\22312 g daily. Control of the disease is transien t and after 6 \200\22312 months there is evidence of biochemical progression or symptoms re turn. Metyrapone, aminoglutethamide, and ketocona- zole are second-line medical therapies. OHO-21(375-388) 11/18/02 8:33 AM Page 383 ADRENAL CANCER 383 Chemotherapy is of limited bene \201t. There are no randomized clini- cal trials, but the most active drugs appear to be cisplatin and eto- poside. There are anecdotal reports of lo ng-term remission. The role of external radiotherapy is limited to the treatment of symptom atic metastases, usually in bone. OHO-21(375-388) 11/18/02 8:33 AM Page 384 ENDOCRINE CANCERS 384 Neuroblastoma Neuroblastoma is the commonest extracranial solid tumor in child- hood \200\224approximatel y 6% of all childhood cancers. Tumors arise in sympathetic nervous tissue (adrenal 30%, abd omen 30%, thorax 15%). The peak age incidence is 1 \200\2233 years of age. Localized intra-thoracic neuroblastoma may present with cough, pain, or Horner \200\231s sy ndrome or be detected on a chest X-ray (taken for an unrelated symptom). With abdominal dis ease there may be pain, abdominal distension, or general malaise. Bone or bone marrow metas tases usually result in the child developing non-speci \201c limb, joint, or back pain, wh ich may be misdiagnosed as arthritis or irritable hip. There may be persistent unexplained fever. Pancytopenia from bone marrow involvement causes anemia, petechiae, or infection. Pe riorbital ecchymoses indicate disseminated neuroblastoma. Staging investigations (cid:2) Abdominal ultrasound (cid:2) CT, MRI abdomen (cid:2) CT, MRI spine (cid:2) CT, MRI chest (cid:2) Urinary catecholamines (cid:2) Serum neuron-speci \201c enolase (NSE) elevat ed (cid:2) Serum LDH \200\224if very high, poor prognosis (cid:2) Techetium or I123MIBG sca n Pathology Morphology ranges from a very undifferentiated, small, round cell tumor that may be dif \201cult to distinguish from rhabdomyosarcoma, PNET, and NHL, to a highly different iated ganglioneuroblastoma. The Shimada classi \201cation combines age with an evaluation of tumor cell necrosis (karyorrhexis) and the extent of stromal component. Ampli \201catio n of n-myc oncogene, deletions on chromo- some 1, gains on chromosome 17, and diploid or te traploid tumors all indicate a poor prognosis. Treatment Stages 1 and 2 In the absence of n-myc ampli \201cation the cure rate for these tumors is extremely high, irrespective of completeness of excision. Surgery is OHO-21(375-388) 11/18/02 8:33 AM Page 385 NEUROBLASTOMA 385 usually performed at the thoracic site, although the indications for this are somewhat cont roversial, as the procedure may be associated with sequelae such as Horner \200\231s syndro me. A \200\230wait and watch \200\231 policy may be appropriate following non-invasive tum or biopsy to demon- strate favorable biology. Stage 3 In the past this stage was routinely treated with intensive chemo- therapy, but it is now clear that the non n-myc ampli \201ed tumors behave in a similar fashion to Stage 2 disease and a more conservative approach may be applied. If possible, surgical clearance s hould be attempted but if this is not feasible then non-intensive chemotherapy, such as OPE C/OJEC, followed by delayed surgery is appropriate. In the face of incomplete resection, lo cal radiotherapy is not indicated. Recently, a \200\230wait and watch \200\231 policy has been advocated as for stage 2 disease. There remains controversy about the importance of attempting to achieve complete clearance at the primary site, as this is often dif \201cult and necessitates several hours of compl ex surgery. The main problem is in \201ltration of the tumor around IVC and aorta, or in \201ltration of the adjacent liver. MIBG positivity, post-operatively, indicates likely residual primary tumor, and local radio therapy is indicated. An alternative is the use of I131 MIBG-targeted radiotherapy. High-do se melphalan with peripheral blood stem rescue is standard in some protocols but this appro ach remains to be clearly proven. One randomized study indi- cates a signi \201cant prolon gation of progression-free survival. Alternative high-dose intensity strategies, such as ad ministering treat- ment every 10 days or escalating the dose of cyclophosphamide, are curre ntly under evaluation. Stage 4 This unusual stage occurs in infants less than one year of age and requires a caref ul balance between a very conservative \200\230wait and watch \200\231 policy and appropri ate intervention with chemotherapy or radio- therapy. In the majority, disease will resolve spontaneously, but where there is signi \201cant respiratory decompensation, low-dose irr adiation to the liver or low-dose chemotherapy using vincristine or combina- tions of cyclo phosphamide, doxorubicin, or carboplatin/etoposide are indicated. Screening of neuroblastoma Attempts have been made to detect neuroblastoma within the \201rst year of life by screening for raised urinary catecholamines. Almost invari- ably th e tumors detected by screening are localized and of favorable biology and there is a signi \201cant incidence of spontaneously resolving OHO-21(375-388) 11/18/02 8:33 AM Page 386 ENDOCRINE CANCERS 386 Table 21.2 International staging system for neuroblastoma Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral and contralateral lymph nodes negative for tumor microscopicall y (nodes attached to and removed with the primary tumor may be positive). Stage 1 Localized tumor with incomplete gross excision; representative ipsilateral and non-adherent lymph nodes negative for tumor microscopically. Stage 2a Localized tumor with complete or incomplete gross excision; with ipsilateral non-adherent l ymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microsco pically. Stage 2b Unresectable unilateral tumor in \201ltrating across the midline with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph nod e involvement; or midline tumor with bilateral extension by in \201ltration (unresectable) or by lymph node involvement. Stage 3 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver skin, and/or other organs (except as de \201ned in Stage 4S). Stage 4 Localized primary tumor (as de \201ned for Stage 1, 2a, or 2b) with dissemination limited to skin, liver, and/or bone marrow (limited to infants less than one year old). Stage 4S neuroblastoma at this age. Screened patients have double the expected incidence of the dise ase. There is no evidence that the detection of tumors by this method, for this age group, reduces the incidence of unfavorable biology or metastatic tumors during the following 2 \200\2233 years. Screening at a later age is under consideration. OHO-21(375-388) 11/18/02 8:33 AM Page 387 NEUROBLASTOMA 387 Further reading Mazzaferri, E.L. and Samaan, N.A. (1993) Endocrine tumors. Blackwell, Oxford. Sheaves, R., Jenkins, P. and Wass, J. (1997) Clinical endocrine oncology. Blackwell, Oxford. OHO-21(375-388) 11/18/02 8:33 AM Page 388 This page intentionally left blank OHO-22(389-416) 11/18/02 8:33 AM Page 389 Chapter 22 Genitourinary cancers Renal cancer 390 Wilms \200\231 tumor 394 Cancer of the bladder and ureter 398 Prostate can cer 402 Screening for prostate cancer 406 Testicular cancer 410 Further reading 416 OHO-22(389-416) 11/18/02 8:33 AM Page 390 GENITOURINARY CANCERS 390 Renal cancer Epidemiology and etiology Renal cancers are more common in men (1.9% of male cancers) than in women (1.2%) and increase in frequency with increasing age, being most common in the six th, and eighth decades. There has been a slow increase in the incidence over the past 10 ye ars. Approximately 65% of patients die of their disease. The most important aetiological factor is smoking. A higher inci- dence of renal carcinoma has also been reported in urban dwellers, workers in the petroleum industry, and in the obe se. Chronic renal dialysis is a risk factor, as is analgesic abuse. Over 98% of adult renal cancers are sporadic, but an inherited pre- disposition occurs in t he von Hippel-Lindau familial cancer syn- drome (1/36 000 births) and in the rarer heredita ry papillary renal carcinoma syndrome. Pathology Adenocarcinomas make up the vast majority (85%) of renal cancers. They were previ ously known as \200\230Hypernephroma \200\231 or \200\230Grawitz tumors \200\231 and demo nstrate several histological types: (cid:2) Clear cell (cid:2) Papillary (cid:2) Spindle ce ll or sarcomatoid Transitional cell carcinomas can arise within the urothelium of the renal pelvis and represent the majority of the remaining tumors. Presentation and natural history \200\223 The presenting symptoms are: (cid:2) Haematuria (50%) (cid:2) Loin pain (50%) (cid:2) Palpable mass (40%) (cid:2) Anemia (40%) (cid:2) Weight loss (35%) (cid:2) Pyrexia (20%) (cid:2) Hypertension (37%) (cid:2) H ypercalcaemia (6%) (cid:2) Polycythaemia (<5%) OHO-22(389-416) 11/18/02 8:33 AM Page 391 RENAL CANCER 391 Renal tumors may invade locally causing pain and occasionally lymphoedema, or may metastasi ze to the lungs, lymph nodes, bone, and brain. Investigations (cid:2) CT scan, chest and abdomen (cid:2) Chest x-ray (cid:2) Brain CT and bone scan if in dicated by symptoms (cid:2) Routine blood and coagulation studies (cid:2) Tumor markers are unhelpful Staging The Robson staging system is commonly used. Surgery Resection of all the tumor is the only potentially curative modality and should be offered to patients without metastases who are \201t for surgery. In patients with limite d metastatic disease who are \201t, nephrectomy may be indicated to control local symptom s. There are documented cases of regression of metastases following nephrectomy. However, t his is extremely rare and nephrectomy cannot be justi \201ed on this basis in patients who are frail or have extensive metastatic disease. Partial nephrectomy is occasionally perfor med for localized tumors or in patients without a second kidney. Surgery for metastases is occasionally indicated for isolated metas- tases that occur after a long disease-free interval or, rarely, at presenta- tion in young, \201t patients. Alt hough supported by anecdotal evidence, randomized data are lacking. Although surgery is the cornerstone of management of localized disease, some patients are u n \201t for nephrectomy. Tumor emboliza- tion (infarction) may provide some symptom contro l but can itself Table 22.1 The Robson staging system Stage Description % of cases 5-year survival I Con \201ned to the kidney 20 \200\22340% 50 \200\22360% II Extends into peri-renal fat but con \201ned to Gerota \200\231s fascia 4 \200\22320% 27 \200\22360% III Involvement of renal vein or IVC or lymph node involvement 10 \200\22342% 20 \200\22350% IV Involvement of adjacent organs or metastatic disease 11-49% 0 \200\22318% OHO-22(389-416) 11/18/02 8:33 AM Page 392 GENITOURINARY CANCERS 392 cause considerable morbidity. Adjuvant therapy has not been proven to offer a survival bene \201t. Cytotoxic chemotherapies, endocrine therapy, radiotherapy, and interferon have bee n tested. There is cur- rent interest in testing more complex biological therapies in this set- ting, but no positive studies have yet been reported. Spontaneous remissions One of the most pervasive of \200\230oncological folklore \200\231 is the expectation of spontaneous remissions in renal cancer. Although these certainly occu r, the true rate is less than 1%, and they tend to occur following resection of the primary tumor or after an episode associated with immune activation, such as following severe seps is. Such regressions are not usually durable. Management of advanced disease The management of patients with advanced and/or metastatic d isease is palliative. There is now good evidence that a very small subset of patients who h ave complete responses to biological therapy may enjoy long-term, disease-free survival. Treatment Radiotherapy Irradiation is indicated for painful or obstructing lesions, but responses are seen in only 50% of patients. Higher palliative doses may be appro- priate to give durable control of isolated non-resectable metastases after nephrectomy. Endocrine therapy Progestins are widely used on the basis of the identi \201cation of prog es- terone receptors in some renal tumors and evidence of activity in animal models. The ob jective response rate for systemic progestagen therapy is less than 10% and probably only 1 \200\2232% by modern response criteria. However, the anabolic effects of progesterone are often valuable in patients with advanced disease, who may feel better on treatment. Chemotherapy Cytotoxic drugs are of little value in renal carcinoma. The chemo- resistance may, in part, be due to the very high expression of a multi- drug resistance phenotype in b oth normal and malignant renal tissue. Response rates for single agents are generally under 15% and for com- bination regimens no more than 25%. Vinca alkaloids have been the most co mmonly prescribed drugs but there are no gains in survival after chemotherapy. OHO-22(389-416) 11/18/02 8:33 AM Page 393 RENAL CANCER 393 Biological therapy Biological therapy has been extensively tested in renal cancer, partly b ecause of its chemo-resistance, but mainly because of the presump- tion that immunological mechanisms underly the occasional sponta- neous regression of metastases. In addition, the very late relapses seen in some patients and the increased incidence of renal cancers in im munosuppressed patients suggest that some intrinsic immuno- logical surveillance can operat e in patients with renal cancer. Interleukin-2 (IL-2) is the most widely tested biological agents and induces responses in 1 0 \200\22325% of patients with advanced disease. Those patients with a complete radiologica l response have a signi \201cant survival bene \201t, with durable remissions in a few. The original studies of IL-2 employed high-dose intravenous IL-2, either alone or in combin ation with lymphokine-activated killer cells (LAK). These regimens are associated with cons iderable morbidity, in particular capillary leak syndrome, and some mortality. Less toxic subcutaneous (SC) IL-2 regimens are probably equally effective and can be combin ed with interferon-(cid:2) (IFN) and/or cyto- toxics, although comparative studies are lack ing to con \201rm a bene \201t for combination regimens. As a single agent, SC IFN also p rovides a response rate of approximately 15% and use of this agent has a proven survival ad vantage over endocrine therapy in an important MRC trial. Prognostic factors that predict b etter response and survival time after biological therapy include: (cid:2) Long time for diagnosis to relapse (cid:2) Nephre ctomy (cid:2) Good performance status (cid:2) Pulmonary metastases as the sole site of dise ase Transitional cell carcinoma These tumors arise in the renal collecting system and may be as soci- ated with TCC in the ureter and bladder. Their biology, management, and prognosis is similar to that of TCC of the bladder. OHO-22(389-416) 11/18/02 8:33 AM Page 394 GENITOURINARY CANCERS 394 Wilms \200\231 tumor Introduction Wilms \200\231 tumor (WT) is an embryonal neoplasm arising in the kidney. Clas sical \200\230triphasic \200\231 WT has stromal, blastemal, and epithelial ele- ments. the bone-metastasizing renal tumor (clear cell sarcoma) and malignant rhabdoid tumor are patho logically and genetically distinct entities, with their own clinical courses. WT represents about 8% of all childhood neoplasia. The peak age for diagnosis is 3 \200\223 4 years of age. It is very rare after the age of 10 years, but is occasionally diagnosed in adults. There are a number of conditions known to predispose to the development of WT: (cid:2) Genitourinary abnormalities (cid:2) Hemihypertrophy (cid:2) Anir idia (cid:2) Beckwith \200\223Wiedeman syndrome (cid:2) Denys \200\223Drash syndrome (cid:2 ) Perlmann syndrome (cid:2) Simpson \200\223Golabi \200\223Behmel syndrome This group of pa tients represents only a small proportion of the total number seen however. Clinical features (cid:2) Abdominal mass \200\224smooth, rounded, or lobulated mass arising in the loin (cid:2) Pain (cid:2) Haematuria (cid:2) Hypertension Investigations (cid:2) Abdominal ultrasound to con \201rm organ of origin, determine extent of any spread within the abdomen, con \201rm patency of the inferior vena cava (cid:2) Chest X-ray to detect pulmonary metastases (cid:2) Full blood count to detect anemi a resulting from hemorrhage into the tumor (cid:2) Prothrombin and partial thromboplastin times \200\224some patients may acquire von Willebrand disease OHO-22(389-416) 11/18/02 8:33 AM Page 395 WILMS \200\231 tumor 395 (cid:2) Urea, creatinine, and urinalysis to detect any gross abnormalities of renal function (cid:2) Urinary catcholamines to exclude neuroblastoma (cid:2) CT scan of chest and abdomen It is important to know that the contralateral kidney is functioning adequately before sur gery and IVU, DMSA scan, or excretion of con- trast at the end of a CT scan of the chest/ab domen is useful in this role. Pathology Two broad groups of tumors may be recognized by their histological appearances: Favorable histology \200\224by far the larger group (cid:2) Classical triphasic histology \200\224epithelial, blastemal, and stromal elements are all present. (cid:2) Rhabdomyoblastic differentiation, such that the cells resemble fetal rhabdomyoblasts. (cid:2) Monomorphic epithelial variant. Unfavorable histology (cid:2) Anaplasia is an unfavorable, often patchy occasionally observ ed in triphasic tumors. The major unfavorable histological types are probably distinct tumo rs, rather than true variants of Wilms \200\231 tumor. (cid:2) Bone-metastasizing renal tumor of childhood. (cid:2) Malignant rhabdoid tumor. Treatment There is overwhelming evidence that Wilms \200\231 tumor ought to be treated only in pediatric oncology centers and there is no place for the casual therapist. Surgeons, ra diotherapists, pediatricians, or nephrologists not working in a center with pediatric oncol ogical expertise who \201nd themselves unexpectedly dealing with a child with Wilms \200 \231 tumor should make an urgent referral to an appropriate unit. Surgery Surgical extirpation is, and almost certainly will remain the funda- mental treatme nt for Wilms \200\231 tumor. There is debate about the timing of surgical intervention, the place of percutaneous needle biopsy, and the use of pre-operative chemotherapy. US practic e remains stead- fastly in favor of immediate surgery followed by adjuvant therapy dictated by the surgical stage. In contrast, the SIOP group in Europe has conducted a series of tri als based on the use of pre-operative therapy, and while it remains to be proven that the l atter approach is OHO-22(389-416) 11/18/02 8:33 AM Page 396 GENITOURINARY CANCERS 396 superior, there is increasing recognition that pre-operative treatment may be of bene \201 t in some circumstances. In an attempt to resolve the issues posed by the \201ndings from these two groups, the UK CCSG is currently conducting a prospective randomized trial comparing immediate surgery wit h six weeks of chemotherapy and delayed surgery. Adjuvant therapy The use of chemotherapy and radiotherapy as adjuvants to surgery is now an essential part of WT treatment. Major advances in treatment have come as a result of multi centre co-operative trials run by the US National Wilms \200\231 Tumor Study (NWTS) Group, the International Society of Pediatric Oncology (SIOP), and the UK Children \200\231s Cance r Table 22.2 Main \201ndings in NWTS 1, 2, and 3 NWTS 1 Group I Patients under two years of age do not all need radiotherapy. Group II/III AMD plus VCR is better than either alone. Group IV Pre-operative vincristine is of no bene \201t. Other \201ndings Unfavorable histology and lymph-node involvement are adverse features. NWTS 2 Stage I No patients bene \201t from radiotherapy regardless of age. 6 months of VCR and AMD is as good as 15 months. Stages II, III, and IV Addition of doxo to VCR and AMD improves survival. Other \201ndings Stages II and III have the same survival. Local spillage and invasion of the renal vein do not affect outcome. NWTS 3 Stage I 10 weeks therapy with VCR/AMD is as effective as 6 months. Stage II Intensive VCR/AMD is as effective as three drugs. Addition of radiotherapy does not affect survival. Stage III Intensive VCR/AMD is as effective as three drugs. 10 Gy \202ank irradiation is as effecti ve as 20 Gy. Other \201ndings Addition of cyclophosphamide to VCR/AMD/doxo does not improve survival. Key: VCR = vincristine; AMD = actinomycin D; doxo = doxorubicin OHO-22(389-416) 11/18/02 8:33 AM Page 397 WILM \200\231S tumor 397 Table 22.3 Outcome for patients in NWTS III Stage 2-year relapse-free survival (%) 2-year overall survival (%) Treatment I 92 97 10 weeks vincristine + actinomycin D II/III 87 91 15 months vincristine + actinomycin D + doxorubicin III 78 86 10 Gy + vincristine + actinomycin D +/- doxorubicin IV + UH 72 81 UH = Unfavorable histology Table 22.4 Outcome for patients in UKW1 Stage 3-yr event- free survival (%) 3-yr overall survival (%) 6-yr event- free survival (%) 6-yr overall survival (%) I 90 96 89 96 II 85 94 85 93 III 82 83 82 83 IV 58 65 50 65 Study Group (UKCCSG). An essential part of all therapy protocols is the \200\230stage \200 \231 of the tumor. The NWTS staging system is: (cid:2) Stage I (cid:2) Stage II Tumor within renal capsule and fully resected. Tumor outside renal capsule but fully resect ed; biopsy; ruptured; con \201ned to the \202ank. Tumor outside capsule and incompletely resected; lymph-node involvement at the hilum or paraortic chain. (cid:2) Stage III (cid:2) Stage IV Haematogenous metastases e.g. to lungs, liver, bone, or brain. Bilateral renal tumors. (cid:2) Stage V OHO-22(389-416) 11/18/02 8:33 AM Page 398 GENITOURINARY CANCERS 398 Cancer of the bladder and ureter Etiology The occupational risk of developing bladder cancer for workers in the dye industry was established more than 90 years ago. The association was supported when 2-napthylamine was shown to cause bladder cancer in animals and related carcinogens were associated with i ncreased risk for those working in the aniline dye and the rubber industries. Now, the rang e of known human bladder carcinogens identi \201es risks associated not only within these industries mentioned but also for those working in: (cid:2) Gas works (cid:2) Rodent care ( cid:2) Laboratory work (cid:2) Sewage work (cid:2) Textile printing (cid:2) Manufacture of \201relighters. Squamous cancers of the bladder are associated with chronic bladder infec tion by Schistosoma haematobium. Cigarette smoking is known to increase, 2 \200\2236-fold, the risk of devel- oping bladder cancer. Epidemiology The incidence increases with age with rates of 90 per 105 population in Americ an men aged 60 \200\22369 years and 26 per 105 for women of the same age. These incidences almost double in the age range 70 \200\22379 years. Pathology The majority of urothelial tumors presenting in the UK are transi- tional cell ca rcinomas. Pure squamous carcinomas and adenocarcino- mas represent 5% of tumors, though met aplasia can occur in a primary transitional tumor. There is a link between adenocarcinoma o f the bladder and presentation of the tumor in the bladder dome, often associated with pers isting urachal remnant. This type of tumor also occurs in the context of a congenital malfo rmation exstrophy. Primary squamous cancers are the commonest subtype with bladder schistos omiasis. Transitional carcinomas have a number of characteristic chromo- somal abnormalities includi ng, in particular, loss of chromosome 9. Other common abnormalities include a mutation of t he p53 gene that appears more often in advanced cancers and has been associated with an inc reased risk of treatment failure. OHO-22(389-416) 11/18/02 8:33 AM Page 399 CANCER OF THE BLADDER AND URETER 399 Transitional cancers are characterized by de \201nition of both grade and local T stage. T here is a strong association between well- differentiated tumors and early stage. Most rece nt reports are based on the UICC TNM staging classi \201cation (1987): (cid:2) T1 tumors a re con \201ned to the urothelium. (cid:2) T2 tumors invade super \201cial muscle. (cid:2) T3 tumors extend to deep muscle and through the bladder wall. (cid:2) T4 tumors extend int o adjacent organs. Even when the tumor is localized the T stage is highly relevant to progn osis, with \201ve-year survival rates of 75% for T1 tumors, 40 \200\22350% for T2 tumors, 20 \200\22330% for T3 tumors, and 10% or less for T4 tumors. Recently, this classi \201ca tion has been revised in UICC TNM staging (1997). Typical metastatic sites include: (cid:2) Pelvic and para-aortic lymph nodes (cid:2) Lung \201elds (cid:2) Liver (cid:2) Bo ne Bone metastasis is recognized increasingly as more patients have systemic control of dis ease with combination chemotherapy. Presentation The commonest presentation is with macroscopic haematuria, though some patient s also have frequency of micturition, dysuria, or symptoms of metastases. Haematuria should be con \201rmed by urine analysis and investigated by analysis of the cy tology of voided urine and by cystoscopy. An IVU can demonstrate the possibility of disease involving the ureter and the diagnosis is established by resection of the primary tumor at cysto- scopy. During the same procedure, bimanual examination is per- formed and this, tog ether with the biopsy \201ndings with associated evidence of depth of tumor invasion, ena ble the T stage of the tumor to be established. Nodal and metastatic staging is achieved wi th a CT scan of the thorax and abdomen. MRI is an excellent alternative for investigating t he local extension of disease and the pos- sibility of pelvic lymphadenopathy. The staging demonstrated following radical cystectomy may in many cases be different from t hat established from pure clinical investigation; this is important for comparison of diffe rent treatment series. Treatment options (cid:2) Super \201cial tumors (Ta, T1) \200\224resection \200\224super \201cial recurrence is common (60%) \200\224poorly diff erentiated, worse prognosis OHO-22(389-416) 11/18/02 8:33 AM Page 400 GENITOURINARY CANCERS 400 (cid:2) Frequent recurrences/high-risk tumors \200\224intravesical chemotherapy: mitomycin C; doxorubicin \200\224intravesical immunoth erapy: BCG monitored by cystoscopy reduces recurrences; no long-term effect on survival (cid:2) Muscle-invasive, local tumor \200\224radical radiotherapy \200\224radical cystectomy \200\224occasionally radiotherap y followed by salvage cystectomy (cid:2) Metastatic disease \200\224palliative chemotherapy \200\224usually relapse again after 2 years Surgical principles The usual procedure is cystoprostatectomy in male patients or anteri- o r bladder exenteration in female patients, with dissection of local lymph nodes. Bladder re section is associated with urinary diversion \200\224 most commonly, a non-re \202uxing il eal conduit and urinary bag. Complications include loss of sexual potency in the male and l oss of the vagina in the female. It is important for patients to have advice from a special ized stoma therapist before surgery. In specialist centers, excellent results can be achieved in selected patients treated by ra dical cystectomy with continent diversion based on urinary tract reconstruction by ileocyst ostoplasty. This can pro- duce urinary continence and, in experienced centers, the surgical complication rates are less than 10% and operative mortality less than 2%.