HISTOLOGY

The vast majority of prostate cancers are adenocarcinomas. Most exhibit acinar-type differentiation, but some also have features of ductal differentiation. Pure large duct prostatic adenocarcinomas are uncommon. Typical prostatic adenocarcinomas may contain foci of mucinous differentiation or neuroendocrine differentiation, but the prognostic significance of these features remains uncertain. Small cell undifferentiated carcinoma of the prostate is rare but when present is often associated with areas of adenocarcinoma. Whether presenting in pure form or intermixed with adenocarcinoma, small cell undifferentiated carcinoma in the prostate carries a grave prognosis. Other tumors occurring in the prostate include transitional cell carcinoma (most often by invasion from the urethra), sarcomas of stromal origin, and metastases from other organs.

The putative precursor of invasive adenocarcinoma is prostatic intraepithelial neoplasia (PIN), in which cytologically dysplastic cells are found lining normal ducts and acini. PIN is divided into low and high grades; however, only the latter is geographically associated with invasive adenocarcinoma. Although the natural history of PIN is unknown, many foci of high-grade PIN demonstrate partial loss of the basal cell layer, and a transition to small invasive glands is occasionally observed. A diagnosis of high-grade PIN on needle biopsy should prompt additional studies to rule out invasive tumor.

Small foci of adenocarcinoma are found incidentally at autopsy in more than 30% of men over the age of 50 who die of unrelated causes. Thus, there is a large pool of these so-called latent or “autopsy” prostate cancers present in the older male population. Whether clinical cancers arise from latent tumors or develop by an independent pathway is unknown.

Although a variety of grading schemes for prostate cancer have been developed, the most widely used in the United States is the Gleason grading system, which is based strictly upon architectural rather than cytologic features of the cancer. According to this scheme, the pattern of infiltrating tumor glands is assigned a grade from 1 (well differentiated) to 5 (poorly differentiated). Because many adenocarcinomas show more than one pattern, the grades for the two most common patterns present in a tumor are added together to give a Gleason sum or Gleason score. The prognostic utility of the Gleason grading system has been validated in numerous studies wherein patients diagnosed with low Gleason score cancers have an excellent prognosis, whereas those with high Gleason score cancers have a poor prognosis. The main shortcoming of the Gleason grading system is that the majority of cancers are intermediate in grade. Less than 30% of cancers in most studies are within the Gleason score 2–4 or 8–10 groups. As a result, the Gleason score provides little prognostic information in most cases.

Tissue staining for PSA has become an important adjunct to confirming the diagnosis of prostate cancer. This is particularly useful in poorly differentiated cancers or those cancers that manifest themselves initially at metastatic sites as poorly differentiated carcinoma.

DIAGNOSIS AND STAGING OF PROSTATE CANCER

The detection of prostate cancer has been greatly enhanced by the introduction of the PSA test. Optimal detection of prostate cancer is now achieved through the combination of the digital rectal examination (DRE) and PSA. Biopsies are facilitated by transrectal ultrasound, which allows the physician to locate the areas of abnormality. The morbidity from biopsy is now minimal with the use of spring-loaded biopsy guns. Optimal information is acquired when multiple specially coordinated biopsies are performed. With such biopsies, the grade of the cancer, the number of cores positive for cancer, and the percentage of cancer per core should be determined.

A bone scan should be performed after the diagnosis of prostate cancer is made, particularly in men with a PSA in excess of 20 ng/mL or high Gleason grade disease (Gleason scores of 8–10). Although the incidence of radiographically detected regional lymph nodes is quite low, scanning by computed tomography (CT) or magnetic resonance imaging (MRI) should be considered, particularly in patients with high-grade, high-stage cancers or in those with high PSA serum levels. Recent techniques with newer MRI contrast agents (lymphotrophic nanoparticle-enhanced MRI) may help identify regional lymph node involvement. Endorectal coil MRI should be performed at experienced centers in patients being considered for radical prostatectomy in whom it is necessary to assess the extent of local disease. With the widespread use of PSA, the proportion of localized prostate cancers has increased.

Approximately 80% of cancers arising in the prostate gland arise in the peripheral zones, whereas 20% arise in the periurethral, or transition, zone. Cancers arising in the transition zone traditionally had been diagnosed by transurethral resection of the prostate. However, with increasing use of PSA and of medical therapies for benign prostatic hyperplasia, the frequency of cancers diagnosed in this manner has diminished.

Two systems are commonly used for staging of prostate cancer: the Whitmore-Jewett system (stages A through D) and the American Joint Committee on Cancer (AJCC) tumor/node/metastases (TNM) system last modified in 2002 (see Fig. 8.11 ). The AJCC TNM system is used more commonly now.

Clinical staging of prostate cancer, using the 2002 AJCC TNM classification and the Whitmore-Jewett system.

The majority of cancers that are currently diagnosed are detected as a result of an abnormal PSA or DRE, or both. Organ-confined, palpable cancers are classified as T2 (see Fig. 8.11 ). Cancers diagnosed strictly on the basis of an abnormal PSA with no associated palpable abnormality are currently classified as T1c. Cancers that on physical examination extend into the seminal vesicles or palpably extend beyond the prostate are categorized as T3 cancers. Stage IV cancers are those that have metastasized either to regional lymph nodes (N1) or distant lymph nodes, bone, or viscera (M1) (see Fig. 8.11 ).

Careful examination of the prostate following its removal at the time of radical prostatectomy provides critical prognostic information. There is good correlation between the grade of cancer found at the time of biopsy and that found at the time of radical prostatectomy; when discrepancy occurs the biopsy results most frequently undergrade the cancer. With careful examination of the prostate, the volume of cancer can be ascertained, as can the degree of local extension. Cancers that are confined within the capsule are less likely to recur than those that invade through the capsule or into the seminal vesicle or demonstrate positive margins. Clinically localized tumors are frequently upstaged into T3 cancers pathologically. The frequency of lymph node involvement at the time of radical prostatectomy has apparently decreased in recent years, perhaps in part because of the more careful selection of surgical patients afforded by the use of the PSA.

CLINICAL MANIFESTATIONS

Most patients diagnosed with prostate cancer are asymptomatic, and the diagnosis is made as a result of an abnormal PSA or DRE. Because the prevalence of benign prostatic hyperplasia in the population of men susceptible to prostate cancer is high, many men will manifest mild degrees of prostatism. With locally advanced prostate cancer, urinary obstruction may occur, as may hematospermia. Carcinoma should be considered when obstructive urinary symptomatology develops over a short period of time. Some patients initially present with symptoms of metastatic disease either from painful bony metastasis or from lymphadenopathy. In such patients, immunostaining for PSA may be of particular value in distinguishing a carcinoma of prostatic origin.

HISTOLOGY

Ninety percent of bladder cancers are transitional cell carcinomas, also known as urothelial carcinomas. These are designated grade 1 (well differentiated) to grade 3 (poorly differentiated), although in recent staging, tumors are designated simply as low grade or high grade. They often show a papillary architecture when presenting as superficial lesions. High-grade tumors may be localized within the bladder but are sometimes associated with widespread transitional cell carcinoma in situ. Alternatively, patients may present with carcinoma in situ in the absence of grossly recognizable tumor. Both high-grade papillary lesions and carcinoma in situ are associated with a substantial risk for developing muscularis invasion. Some transitional cell carcinomas show areas of squamous or adenocarcinomatous differentiation, the significance of which is uncertain. Pure squamous cell carcinomas and adenocarcinomas of the bladder are much less common than transitional cell carcinomas but are less responsive to therapy.

STAGING OF BLADDER CANCER

Because bladder cancer can metastasize rapidly, sometimes even before symptoms become apparent, staging studies in a patient with this diagnosis are imperative. Chest films, radionuclide bone scanning, tests of liver and renal function, and CT scans are all valuable.

Standard staging systems have been based on intravenous urography, bimanual examination, and transurethral resection. At present, two systems are used: the Jewett-Strong-Marshall (JSM) system and the AJCC system (see Fig. 8.30 ). Both classify bladder cancers as superficial, invasive, or metastatic. Superficial disease is limited to the mucosa or submucosa (JSM stages O and A or AJCC Ta and T1); this is the most common form of bladder cancer. Lesions that extend through the submucosa and into the muscularis are classified as invasive bladder cancer. These include lesions that involve superficial or deep muscles (JSM stages B1 and B2 or AJCC T2a and T2b). Although it was formerly believed that the depth of muscle invasion (superficial vs deep) was most important, it now seems that the presence of any muscle involvement is prognostically significant. Almost 50% of patients with muscle invasion eventually die of disease, usually associated with distant metastases. Stages III (T3, T4) and IV (N+) denote lesions invading the perivesicular fat and extending beyond it, respectively.

The Jewett-Strong-Marshall (JSM) and AJCC staging systems for bladder cancer.

CLINICAL MANIFESTATIONS

The most common symptom of bladder cancer is painless hematuria. Carcinoma in situ can cause symptoms of urinary tract irritation. Endoscopically the bladder mucosa may appear normal; a definitive diagnosis can be established only after a urinary cytologic specimen or a mucosal biopsy specimen is obtained and examined. Urinary obstruction caused by urethral blockage and pain secondary to metastatic disease occur occasionally but are relatively uncommon initial manifestations. Sites of metastases include the liver, lung, lymphatic system, and bones.

HISTOLOGY

RCCs constitute a group of heterogeneous tumors (adenocarcinomas) arising from the epithelium of the renal tubules. These tumors have unique pathologic, cytogenetic, and molecular characteristics. They also have distinct biologic behavior, clinical manifestations, and therapeutic response. The current classification, published by the World Health Organization in 2004 ( Table 8.1 ), is based on histomorphology, presumptive histogenic origin, and cytogenetic and molecular characteristics of the renal tumors.

Clear cell carcinoma is by far the most common type of RCC and arises from the proximal tubules. It typically has a deletion in the short arm of chromosome 3, often in the area of the von Hippel-Lindau (VHL) gene. The product of this gene, the VHL protein, plays a crucial role in the “hypoxia-inducible pathway.” It forms with several proteins a complex that has ubiquitin ligase activity and targets cellular proteins for ubiquitin-mediated degradation by proteasomes. One of the substrates is hypoxia-inducible factor (HIF), a heterodimeric transcription factor critical for the expression of hypoxia-inducible genes. Under normal conditions, the two isoforms of HIF, HIF1α and HIF2α, are hydroxylated on one of the proline residues. VHL proteins can then bind to and target the hydroxylated HIF for polyubiquitination and eventual degradation. Under hypoxic conditions, or when VHL is mutated or absent, HIF cannot bind to VHL and therefore is not directed for degradation. As the result, HIF accumulates within the cell and activates many hypoxia-inducible genes, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, and others ( ), leading to tumor growth and invasion. Microscopically, tumor cells have “clear” cytoplasm due to the loss of cytoplasmic lipid and glycogen during the processing of the tissue and preparation of slides, although high-grade clear cell RCC often has more eosinophilic and granular cytoplasm. Indicative of a worse prognosis, sarcomatoid differentiation is found in about 5% of the cases.

Papillary RCC (PRCC) is the second most common subtype of RCC. Two types of PRCC are recognized based on the histomorphology. Accounting for about two thirds of PRCCs, type I contains papillae that are lined with a single layer of tumor cells with scant pale cytoplasm and low-grade nuclei. In contrast, type II tumor cells have abundant eosinophilic cytoplasm and large pseudostratified nuclei with prominent nucleoli. Type I PRCC has a better prognosis than type II PRCC. Chromosomal gain, including tri- or tetrasomy 7 and 17, and loss of Y chromosome are the most common cytogenetic changes observed in PRCC ( ). On the other hand, papillary adenomas are benign epithelial neoplasms of papillary or tubular architecture, with increased incidence with age, and in patients on long-term dialysis or acquired renal cystic disease.

Chromophobe RCC accounts for approximately 5% of RCCs. It is a malignant tumor characterized by large pale cells with prominent cell membranes and irregular nuclei. The prognosis is significantly better than in clear cell RCC with mortality less than 10%. This subtype shows extensive chromosomal loss, most commonly involving chromosomes 1, 2, 6, 10, 13, 17, and 21 ( ).

Other rare type of RCC include collecting duct and medullary carcinoma (both with very aggressive behavior), oncocytomas (benign tumors), and others ( Table 8.1 ).

Although the majority of RCCs are sporadic in nature, less than 5% of the cases present as part of the inherited cancer syndromes, including VHL syndrome (clear cell RCC), hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis, renal cell cancer (papillary RCC), and Birt-Hogg-Dube syndrome (chromophobe RCC). In general, hereditary cases present at a younger age and are much more likely to be multifocal and bilateral. A comparison of genetic defects between sporadic and hereditary RCC based on histologic appearance is provided in Table 8.2 .

STAGING OF KIDNEY CANCER

The most widely used system to assess the extent of invasion and dissemination of RCC is the AJCC staging method that is based upon the TNM classification ( Table 8.3 ). These criteria clearly define the anatomic extent of disease and stage and have been shown to correlate with survival.

The 2002 version of the AJCC staging system separates T1 lesions into T1a (tumors limited to the kidney and <4 cm) and T1b (intrarenal tumors >4 cm and <7 cm) ( ). This division of T1 reflects the higher rate of survival in patients with T1 tumors smaller than 4 cm and the increasing tendency to use nephron-sparing surgery (such as partial nephrectomy, radiofrequency ablation, cryoablation, and others) in these patients.

CLINICAL MANIFESTATIONS

The classic triad of symptoms—hematuria, flank pain, and abdominal mass—is observed in only about 10% of patients. However, individual symptoms occur in almost half of patients with kidney cancer. A variety of paraneoplastic phenomena can be associated with renal adenocarcinoma, including hypertension and hepatosplenomegaly not caused by metastases.

NOVEL TARGETED AGENTS IN THE TREATMENT OF ADVANCED RENAL CELL CARCINOMA

Although surgery is the mainstay of therapy for RCC in its localized form, advanced disease has been classically treated with immunotherapy such as interferon-α and interleukin-2. Responses were modest at best, and long-term disease control was rare. However, over the last few years RCC has become a model disease for targeted therapeutics based on the growing understanding of the underlying molecular pathways in this disease. Clear cell RCC is characterized by the inactivation of the VHL tumor suppressor gene, which results in the dysregulation of hypoxia response genes and subsequent promotion of tumor angiogenesis, growth, and metastasis. In advanced RCC substantial clinical activity has been reported with VEGF blockade using a variety of approaches including antibodies (bevacizumab) and small-molecule VEGF receptor inhibitors (sunitinib and sorafenib). These novel agents are replacing immunotherapy as a new standard of care. Several clinical trials are still in progress with the goal of defining the optimal efficacy of these agents as monotherapy or in combination ( ).

HISTOLOGY

Germ cell cancers of the testis can be divided into seminomas and nonseminomas. This distinction is based on the extreme radioresponsiveness of seminomas and their tendency toward localized tissue invasion, as opposed to the tendency of nonseminomas to be more radioresistant and to metastasize via hematogenous routes to the lung or liver. Histologic variants of nonseminoma include embryonal carcinoma, teratoma, choriocarcinoma, and yolk sac tumor (also known as endodermal sinus tumor). Germ cell tumors can also arise from extragonadal sites, including the retroperitoneum and the mediastinum. Mediastinal nonseminomas have a particularly poor prognosis, whereas mediastinal seminomas have a similar prognosis to testicular seminomas.

Fewer than 5% of testicular malignancies originate from the gonadal stroma; these are mainly Leydig cell tumors, which can occur at any age and secrete both testosterone and estradiol, causing sexual precocity in prepubertal boys and gynecomastia in adults. About 10% of Leydig cell tumors metastasize; these demonstrate histologic features of aggressive behavior, such as blood vessel invasion and poor cell differentiation. Sertoli cell tumors are rare (only about 100 cases have been reported) and are also found in all age groups. They may secrete estrogens and thus cause gynecomastia. Metastases occur in 10% to 20% of cases.

Lymphomas, usually of the diffuse large cell type, represent 5% or less of testicular malignancies. They tend to be bilateral and often disseminate, particularly to the central nervous system. Involvement of the testes may occur in systemic lymphomas (about 10% of cases) and in some patients may herald an underlying malignant lymphoma.

STAGING OF TESTICULAR CANCER

The staging evaluation of testicular cancers usually includes an abdominopelvic CT scan and chest radiography; sometimes suspicious abnormalities on a chest film prompt CT scanning of the chest as well. In certain high-risk patients, a bone scan and brain MRI are performed. Stage I nonseminomas are often surgically staged by retroperitoneal lymph node dissection. Circulating biologic markers, such as human chorionic gonadotrophin (β-hCG), lactate dehydrogenase, and α-fetoprotein (AFP), are prognostically important and are useful in following the clinical course.

Cancer confined to the testis, with no clinical, laboratory, or radiologic evidence of distant metastases, constitutes stage I disease (see Fig. 8.69 ). If there is no disease above the diaphragm but evidence of retroperitoneal adenopathy is demonstrated on CT scan or lymphangiogram, the cancer is classified as stage II disease. Stage III disease is marked by persistence of positive biologic markers after orchidectomy or by subdiaphragmatic visceral involvement (e.g., of the liver, spleen, or inferior vena cava) or supradiaphragmatic metastases to the lung parenchyma or central nervous system. Prognosis can be determined by criteria established by the International Germ Cell Consensus Criteria ( Table 8.4 ).

CLINICAL STAGING OF TESTICULAR CANCER. The AJCC TNM staging system is less commonly used, because it is based upon histologic evaluation of the orchidectomy specimen and retroperitoneal peri-aortic lymph node dissection. Because the latter may not be performed in every patient, the clinical staging system is generally more practical.

CLINICAL MANIFESTATIONS

The manifestations of testicular cancer are protean, ranging from detection of an asymptomatic nodule or swelling on self-examination of the testes to the development of symptoms secondary to metastatic disease. Patients who present with a painful lesion in the scrotum are often initially diagnosed and treated for epididymitis before the true diagnosis of cancer is established. Epididymitis often occurs concomitantly in patients with testicular cancer and may explain the associated pain. The sudden, acute appearance of a rapidly enlarging testis, particularly characteristic of choriocarcinoma, is usually associated with hemorrhage into neoplastic tissue. Back or abdominal pain secondary to retroperitoneal adenopathy, dyspnea caused by pulmonary metastases, weight loss, gynecomastia, supraclavicular lymphadenopathy, and urinary obstruction may also be evident at the time of presentation.

HISTOLOGY

The vast majority of penile cancers are squamous cell carcinomas. Rare cases of adenocarcinoma, melanocarcinoma, and sarcoma have been reported, the latter being in some instances associated with Kaposi’s sarcoma. Metastatic disease of the penis originating from primary tumors of the rectum, prostate, or bladder also occurs but is quite uncommon.

Approximately 50% of penile cancers metastasize via lymphatic vessels to the deep and superficial inguinal nodes. Most of these malignancies are relatively unresponsive to radiation therapy, and a consistently effective chemotherapeutic protocol has yet to be developed. Treatment of penile cancer is therefore heavily reliant on surgery. Depending on the extent of disease, this may involve partial, complete, or radical penectomy, with inguinal lymphadenectomy when necessary to remove affected nodes. In cases of penile cancer detected at an early stage, cure is sometimes achieved by a partial penectomy that preserves a penile stump adequate for sexual activity and urination. The overall 5-year survival for cancer of the penis is 80% for men without nodal involvement, but less than 50% in men with nodal metastases.

CLINICAL MANIFESTATIONS

At the time of presentation, the penile lesion, invariably located in the preputial area, may appear either as a flat ulcer with raised edges, usually extending into the underlying tissues, or as a clustered papillomatous growth resembling the much more common, sexually transmitted condyloma acuminatum. All such penile lesions are suspect and should be biopsied to confirm the histologic diagnosis. Because of overlying psychological factors associated with any abnormality of the penis, patients may delay seeking medical attention until the malignancy is well established. However, most of these lesions are slow to grow and metastasize, and therefore the prognosis even for fairly well advanced cases remains relatively good unless extensive involvement of the inguinal lymph nodes is already present.