TUMORS OF THE KIDNEY AND URINARY TRACT

carcinoma in situ (CIS)

- CIS is defined by the presence of overtly malignant-appearing cells within a flat urothelium - Like high-grade papillary urothelial carcinoma, the tumor cells in CIS lack cohesiveness and are shed into the urine, where they can be detected by cytology. - CIS commonly is multifocal and sometimes involves most of the bladder surface or extends into the ureters and urethra. - Without treatment, 50% to 75% of CIS cases progress to invasive cancer.

Ten things medical students should learn about renal cell carcinoma:

(1) Renal cell carcinoma is uncommon, but not rare. (2) A typical renal cell carcinoma patient is a male smoker around 60 years old. (3) Renal cell carcinoma can present with hematuria, fatigue, malaise, anorexia, weight loss, flank pain or a variety of nonspecific symptoms (4) Renal cell carcinoma typically invades renal veins and hence metastasizes to the lungs. (5) The majority of renal cell carcinomas are clear cell type and almost all of these have inactivating mutation or loss of the Von Hippel-Lindau gene (both copies). (6) Von Hippel-Lindau syndrome (hemangioblastomas, renal cell carcinomas, renal cysts, pheochromocytomas) is due to hereditary loss of one copy of the gene. (7) The Von Hippel-Lindau gene product helps degrade hypoxia-inducible factor-1, a transcription factor that promotes angiogenesis and cell proliferation. (8) The second most common type of renal cell carcinoma is papillary and some of these have activating mutations in the MET oncogene. (9) Surgical excision is the mainstay of therapy for renal cell carcinoma. (10) Metastatic renal cell carcinoma often responds to targeted therapy with tyrosine kinase inhibition, vascular endothelial growth factor inhibition or various immunotherapies.

Two distinct precursor lesions of invasive urothelial carcinoma are recognized:

(1) The most common is a noninvasive papillary tumor (2) The other precursor is carcinoma in situ (CIS) In about one-half of patients with invasive bladder cancer, no precursor lesion is found; in such cases, it is presumed that the precursor lesion was overgrown by the high-grade invasive component.

Urothelial carcinoma of the renal pelvis

- 5 to 10% of primary renal tumors originate from the urothelium of the renal pelvis. - These tumors tend to present earlier than renal cell carcinoma, when they are small, because they bleed into the urine and cause hematuria. - Urothelial carcinomas used to be called transitional cell carcinomas because the tumor cells are near the middle of the spectrum (transition) from squamous to glandular morphology. - Half of patients with a urothelial carcinoma of the renal pelvis have a preexisting or concomitant bladder urothelial tumor. - Because urothelial carcinomas are so often multifocal, they do not have a great prognosis.

bladder cancer

- Bladder cancer accounts for approximately 5% of cancers and 3% of cancer deaths in the United States. - The vast majority of bladder cancers (95%-97% in the United States; 60%-90% in Africa) are urothelial carcinomas. - Squamous cell carcinomas represent about 3% to 7% of bladder cancers in the United States but are much more common in countries such as Egypt, where urinary schistosomiasis is endemic. - Adenocarcinomas of the bladder are rare. - Carcinoma of the bladder is more common in men than in women, in industrialized than in developing nations, in urban than in rural dwellers, and in whites than in African-Americans. - About 80% of patients are between 50 and 80 years of age

Clinical Features of Bladder tumors

- Bladder tumors most commonly present with painless hematuria. - Patients with urothelial tumors, whatever their grade, have a tendency to develop new tumors after excision, and recurrences may exhibit a higher grade. - The risk for recurrence is related to several factors, including tumor size, stage, grade, multifocality, mitotic index, and associated dysplasia and/or CIS in the surrounding mucosa. - Many recurrent tumors arise at sites different than that of the original lesion, yet share the same clonal abnormalities as those of the initial tumor; thus, these are true recurrences that stem from shedding and implantation of the original tumor cells at new sites. - Whereas high-grade papillary urothelial carcinomas frequently are associated with either concurrent or subsequent invasive urothelial carcinoma, lower-grade papillary urothelial neoplasms often recur but infrequently invade

Chromophobe Renal Carcinomas

- Chromophobe renal carcinomas are the least common form, representing 5% of all renal cell carcinomas. - They arise from intercalated cells of collecting ducts. - Their name derives from the observation that the tumor cells stain more darkly (i.e., they are less clear) than cells in clear cell carcinomas. - These neoplasms are unique in having multiple losses of entire chromosomes leading to extreme hypoploidy. - Because of multiple losses, the "critical hit" has not been determined. In general, chromophobe renal cancers have a favorable prognosis. - Chromophobe- type renal cell carcinoma tends to be grossly tan-brown. - The cells usually have clear, flocculent cytoplasm with very prominent, distinct cell membranes. - The nuclei are surrounded by halos of clear cytoplasm. - Ultrastructurally, large numbers of characteristic macrovesicles are seen.

Clear Cell Carcinomas

- Clear cell carcinomas are the most common type, accounting for 65% of renal cell cancers. - Histologically, they are composed of cells with clear cytoplasm. - Although most are sporadic, they also occur in familial forms or in association with von Hippel-Lindau (VHL) disease. - Hundreds of bilateral renal cysts and bilateral, often multiple, clear cell carcinomas develop in 40% to 60% of affected individuals. - An uncommon familial form of clear cell carcinoma unrelated to VHL disease also is associated with cytogenetic abnormalities involving the short arm of chromosome 3 (3p). > LOF mut in genes that encode proteins that regulate histone methylation, suggesting that changes in the "epigenome" have a central role in the genesis of this subtype of renal carcinoma. - usually are solitary and large when symptomatic - They may arise anywhere in the cortex. - The cut surface of clear cell renal cell carcinomas is yellow to orange to gray-white, with prominent areas of cystic softening or of hemorrhage, either fresh or old - The margins of the tumor are well defined; However, at times small processes project into the surrounding parenchyma and small **satellite nodules** are found, providing clear evidence of the aggressiveness of these lesions. - the tumor invades the renal vein and grows as a solid column within this vessel, sometimes extending in serpentine fashion as far as the inferior vena cava and even into the right side of the heart. - Depending on the amounts of lipid and glycogen present, the neoplastic cells of clear cell renal cell carcinoma may appear almost vacuolated or may be solid. (1) The **classic vacuolated** (lipid-laden) cells or clear cells are demarcated only by their cell membranes; The nuclei are usually small and round (2) At the other extreme are granular cells, resembling the tubular epithelium, which have small, round, regular nuclei enclosed within granular pink cytoplasm. - The cells may form abortive tubules or may cluster in cords or disorganized masses.

Pathogenesis of bladder cancer

- Environmental factors are important in the pathogenesis of urothelial carcinoma and include cigarette smoking, various occupational carcinogens, and prior cyclophosphamide or radiation therapy. - A family history of bladder cancer is a known risk factor. - Squamous cell carcinoma is related to Schistosoma haematobium infections in areas where it is endemic. - Cancers occurring in the setting of schistosoma infections arise in a background of chronic inflammation, which you will recall provides the "soil" for the development of a number of different cancers - Acquired genetic aberrations have been identified in urothelial carcinoma. - Based on these observations, a model for bladder carcinogenesis has been proposed in which the tumor is initiated by deletions of tumor-suppressor genes on 9p and 9q, leading to the formation of superficial papillary tumors, which may then acquire TP53 mutations and progress to invasive disease. - A second pathway, possibly initiated by TP53 mutations, leads first to carcinoma in situ and then, with loss of genes from chromosome 9, progresses to invasion. - Additional genetic alterations in superficial tumors include mutations in telomerase, as well as mutations in fibroblast growth factor receptor 3 (FGFR3) and components of the RAS and PI3K/AKT pathways. - Muscle invasive tumors often have mutations involving both TP53 and RB

Invasive urothelial cancer

- Invasive urothelial cancer associated with papillary urothelial cancer (usually of high grade) or CIS may superficially invade the lamina propria or extend more deeply into underlying muscle. - The extent of invasion and spread (staging) at the time of initial diagnosis is the most important prognostic factor. - Almost all infiltrating urothelial carcinomas are high grade.

Squamous carcinoma of the Penis

- More than 95% of penile neoplasms arise on squamous epithelium. - In the United States, squamous cell carcinomas of the penis are relatively uncommon, accounting for about 0.4% of all cancers in males. - In developing countries, however, penile carcinoma occurs at much higher rates. - Most cases occur in uncircumcised patients older than 40 years of age. - Several factors have been implicated in the pathogenesis of penile squamous cell carcinoma, including poor hygiene (with resultant exposure to potential carcinogens in smegma), smoking, and infection with human papillomavirus (HPV), particularly types 16 and 18. - Squamous cell carcinoma in situ of the penis (Bowen disease) occurs in older uncircumcised males and appears grossly as a solitary plaque on the shaft of the penis. - Histologic examination reveals dysplastic cells throughout the epidermis with no invasion of the underlying stroma - It gives rise to invasive squamous cell carcinoma in approximately 10% of patients. - Invasive squamous cell carcinoma of the penis appears as a gray, crusted, papular lesion, most commonly on the glans penis or prepuce. - In many cases, infiltration of the underlying connective tissue produces an indurated, ulcerated lesion with irregular margins - Histologically, the tumor is most often a typical keratinizing squamous cell carcinoma. - The prognosis is related to the stage of the tumor. - With localized lesions, the 5-year survival rate is 66%, whereas metastasis to inguinal lymph nodes carries a grim 27% 5-year survival rate.

WAGR syndrome

- Of patients with WAGR syndrome approximately one in three will go on to develop this tumor. - Patients with the WAGR syndrome, as the name indicates, have Wilms tumor, aniridia, genital abnormalities and mental retardation. - Patients with WAGR syndrome demonstrate loss of genetic material (i.e., deletions) of WT1 - WT1 is critical to normal renal and gonadal development; it is not surprising, therefore, that constitutional inactivation of one copy of this gene results in genitourinary abnormalities in humans

sporadic (i.e., nonsyndromic) Wilms tumors

- account for 90% of cases overall in children - gain-of-function mutations of the gene encoding β-catenin have been demonstrated in approximately 10% of sporadic Wilms tumors. - Other recurrent mutations occur in genes encoding proteins involved in microRNA processing (DROSHA, DGCR8, and DICER1); these are seen in 15% to 20% of Wilms tumors with predominantly blastemal histology - It is postulated that aberrations in microRNA processing lead to reduced levels of many mature microRNAs, in particular in the miR-200 family, which is involved in "mesenchymal to epithelial transformation" during renal morphogenesis. - The lack of mesenchymal to epithelial transformation likely leads to persistent blastemal "rests" in the kidney which evolve into Wilms tumors. - Finally, tumors with TP53 mutations are associated with an especially poor prognosis and often have a distinctive anaplastic histologic appearance

Papillary Renal Cell Carcinomas

- Papillary renal cell carcinomas account for 10% to 15% of all renal cancers and are defined in part by their papillary growth pattern. - These neoplasms are frequently multifocal and bilateral and appear as early-stage tumors. - Like clear cell carcinomas, they occur in familial and sporadic forms, but unlike these neoplasms, papillary renal cancers are not associated with abnormalities of chromosome 3. - The culprit in most cases of hereditary papillary renal cell cancers is the MET proto-oncogene, located on chromosome 7q. - The MET gene encodes a tyrosine kinase receptor for hepatocyte growth factor. The increased dosage of the MET gene due to duplications of chromosome 7 seems to spur abnormal growth in the proximal tubular epithelial cell precursors of papillary carcinomas. - In familial cases, genetic analysis shows activating mutations of MET in the germ line, along with increased gene dosage in the cancers. - Activating mutations of the MET gene also are found in a subset of patients with sporadic forms of papillary renal cell carcinoma. - Papillary renal cell carcinomas exhibit various degrees of papilla formation with fibrovascular cores. - They tend to be bilateral and multiple. - They also may show gross evidence of necrosis, hemorrhage, and cystic degeneration, but they are less vibrantly orange-yellow because of their lower lipid content. - The cells may have a clear or, more commonly, pink cytoplasm.

Clinical Course of Wilms Tumor

- Patients typically present with a palpable abdominal mass, which may extend across the midline and down into the pelvis. - Less often, the presenting features are fever and abdominal pain, hematuria or, occasionally, intestinal obstruction as a result of pressure from the tumor. - The prognosis for Wilms tumor generally is very good, and excellent results are obtained with a combination of nephrectomy and chemotherapy. - Anaplasia is a harbinger of adverse prognosis, but only if it is diffuse. - If the anaplasia is focal and confined within the resected nephrectomy specimen, the outcome is no different from that for tumors without evidence of anaplasia.

Renal Cell Carcinoma

- Renal cell carcinomas are derived from the renal tubular epithelium, and hence they are located predominantly in the cortex. - These neoplasms represent 80% to 85% of all primary malignant neoplasms of the kidney and 2% to 3% of all cancers in adults. - Carcinomas of the kidney are most common from the sixth to seventh decades, and men are affected about twice as commonly as women. - The risk for developing these neoplasms is higher in smokers, hypertensive or obese patients, and those who have had occupational exposure to cadmium. - The risk for developing renal cell cancer is increased 30-fold in individuals with acquired polycystic disease as a complication of chronic dialysis.

Clinical Features of Renal cell carcinomas

- Renal cell carcinomas have several peculiar clinical characteristics that create especially difficult and challenging diagnostic problems. - The signs and symptoms vary, but the most frequent presenting manifestation is hematuria, occurring in more than 50% of cases. - Macroscopic hematuria tends to be intermittent and fleeting, superimposed on a steady microscopic hematuria. - Less commonly, the tumor may declare itself simply by virtue of its size, when it has grown large enough to produce flank pain and a palpable mass - Because of the widespread use of imaging studies for unrelated conditions, even smaller tumors are detected. - Extrarenal effects are fever and polycythemia, which, because they are nonspecific, may be misinterpreted for some time before their association with the renal tumor is appreciated. - Polycythemia affects 5% to 10% of affected individuals and results from production of erythropoietin by the cancer cells. - Uncommonly, these tumors produce other hormone-like substances, resulting in hypercalcemia, hypertension, Cushing syndrome, or feminization or masculinization. - These are paraneoplastic syndromes. In some patients, the primary tumor remains silent and is discovered only after metastases produce symptoms. - The common locations for metastases are the lungs and the bones. - It must be apparent that renal cell carcinoma manifests in many ways, some quite devious, but the triad of painless hematuria, a palpable abdominal mass, and dull flank pain is characteristic.

Superficial Fibromatosis:

- Superficial fibromatosis is an infiltrative proliferation that can cause local deformity but has an innocuous clinical course - They are characterized by nodular or poorly defined broad fascicles of fibroblasts in long, sweeping fascicles, surrounded by abundant dense collagen. - Several clinical subtypes have been identified: > Palmar (Dupuytren contracture): Irregular or nodular thickening of the palmar fascia either unilaterally or bilaterally > Plantar: Common in young patients, unilateral and without contractures > Penile (Peyronie disease): Palpable induration or mass on the dorsolateral aspect of the penis

papillary urothelial neoplasms

- The most important prognostic factor in noninvasive papillary urothelial neoplasms is their grade, which is based on both architectural and cytologic features. - the grading system subclassifies tumors as follows: (1) papilloma (2) papillary urothelial neoplasm of low malignant potential (PUNLMP) (3) low-grade papillary urothelial carcinoma (4) high-grade papillary urothelial carcinoma **These exophytic papillary neoplasms are to be distinguished from inverted urothelial papilloma, which is entirely benign and not associated with an increased risk for subsequent carcinoma.**

von Hippel-Lindau (VHL) disease.

- VHL disease is inherited as an autosomal dominant trait and is characterized by predisposition to a variety of neoplasms, but particularly to hemangioblastomas of the cerebellum and retina. - Those with VHL disease inherit a germline mutation of the VHL gene on chromosomal band 3p25 and lose the second allele by somatic mutation. - The VHL gene also is involved in the majority of sporadic clear cell carcinomas. > Cytogenetic abnormalities giving rise to loss of a segment on chromosome 3p that harbors the VHL gene are often seen in sporadic renal cell cancers. > The second, nondeleted allele is inactivated by a somatic mutation or hypermethylation in 60% of sporadic cases. - **loss or inactivation of both copies of the VHL gene seems to be the common underlying molecular abnormality in both sporadic and familial forms of clear cell carcinomas.** - The VHL protein causes the degradation of **hypoxia-induced factors (HIFs),** and in the absence of VHL, HIFs are stabilized. > HIFs are transcription factors that contribute to carcinogenesis by stimulating the expression of **vascular endothelial growth factor (VEGF),** an important angiogenic factor, as well as a number of other genes that drive tumor cell growth

Verrucous carcinoma

- a non-HPV-related variant of squamous cell carcinoma characterized by papillary architecture, virtually no cytologic atypia, and rounded, pushing deep margins. - Verrucous carcinomas are locally invasive but do not metastasize.

Renal oncocytoma

- benign neoplasm that arises from the intercalated cells of collecting ducts, represents about 10% of renal neoplasms. - These neoplasms are associated with genetic changes—loss of chromosomes 1 and Y—that distinguish them from other renal neoplasms. - Oncocytomas are characterized by a plethora of mitochondria, providing the basis for their tan color and their finely granular eosinophilic cytoplasm, seen histologically. - A central stellate scar, which is another feature of oncocytomas, provides a characteristic appearance on imaging studies.

Treatment of bladder cancer

- depends on tumor grade and stage and on whether the lesion is flat or papillary. - For small, localized papillary tumors that are not high-grade, transurethral resection is both diagnostic and therapeutically sufficient. - Patients with tumors that are at high risk for recurrence or progression typically receive topical immunotherapy consisting of intravesical instillation of an attenuated strain of the tuberculosis bacillus called Bacillus Calmette-Guérin (BCG), sometimes followed by intravesical chemotherapy. > BCG elicits a granulomatous reaction that also triggers an effective local anti-tumor immune response. - Patients are closely monitored for tumor recurrence with periodic cystoscopy and urine cytologic studies. - Radical cystectomy is reserved for (1) tumor invading the muscularis propria (2) CIS or high-grade papillary cancer refractory to BCG (3) CIS extending into the prostatic urethra and down the prostatic ducts, where BCG cannot come in contact the neoplastic cells. - Advanced bladder cancer is treated using chemotherapy, which can palliate but is seldom curative.

Peyronie disease

- he development of fibrous scar tissue inside the penis that causes curved, painful erections. - Penises vary in shape and size, and having a curved erection isn't necessarily a cause for -concern. - But Peyronie's disease causes a significant bend or pain in some men. - This can prevent you from having sex or might make it difficult to get or maintain an erection (erectile dysfunction). - For many men, Peyronie's disease also causes stress and anxiety. - Peyronie's disease sometimes goes away on its own. But in most cases, it will remain stable or worsen. - Treatment might be needed if the curvature is severe enough that it prevents successful sexual intercourse.

Nephrogenic rests

- putative precursor lesions of Wilms tumors and are sometimes present in the renal parenchyma adjacent to the tumor. - Nephrogenic rests have a spectrum of histologic appearances, from expansile masses that resemble - Wilms tumors (hyperplastic rests) to sclerotic rests consisting predominantly of fibrous tissue with occasional admixed immature tubules or glomeruli. - It is important to document the presence of nephrogenic rests in the resected specimen, because these patients are at an increased risk for the development of Wilms tumors in the contralateral kidney.

Squamous cell carcinomas

- represent about 3% to 7% of bladder cancers in the United States but are much more common in countries such as Egypt, where urinary schistosomiasis is endemic. - Squamous cell carcinoma is related to Schistosoma haematobium infections in areas where it is endemic. - Cancers occurring in the setting of schistosoma infections arise in a background of chronic inflammation, which you will recall provides the "soil" for the development of a number of different cancer

Wilms tumor (nephroblastoma)

- the most common primary tumor of the kidney in children, with most cases occurring in children between 2 and 5 years of age. - Three groups of congenital malformations are associated with an increased risk for Wilms tumor. (1) WAGR syndrome (i.e., Wilms tumor, aniridia, genital abnormalities, and mental retardation) (2) Denys-Drash syndrome (DDS) (3) Beckwith-Wiedemann syndrome (BWS) - Wilms tumor typically is a large, solitary, well-circumscribed mass, although 10% are either bilateral or multicentric at the time of diagnosis. - On cut section, the tumor is soft, homogeneous, and tan to gray, with occasional foci of hemorrhage, cystic degeneration, and necrosis - The classic triphasic combination of blastemal, stromal, and epithelial cell types is observed in most lesions, although the percentage of each component is variable - Sheets of small blue cells, with few distinctive features, characterize the blastemal component . - Epithelial "differentiation" usually takes the form of abortive tubules or glomeruli . - Stromal cells are usually fibrocytic or myxoid in nature, although skeletal muscle "differentiation" is not uncommon. - Approximately 5% of tumors contain foci of anaplasia (cells with large, hyperchromatic, pleomorphic nuclei and abnormal mitoses) - The presence of anaplasia correlates with the presence of acquired TP53 mutations and the emergence of resistance to chemotherapy. - The pattern of distribution of anaplastic cells within the primary tumor (focal versus diffuse) has important implications for prognosis

Beckwith-Wiedemann syndrome (BWS)

- those with Beckwith-Wiedemann syndrome (BWS), also are at increased risk for the development of Wilms tumor. - These patients exhibit enlargement of individual body organs (e.g., tongue, kidneys, or liver) or entire body segments (hemihypertrophy); enlargement of adrenal cortical cells (adrenal cytomegaly) is a characteristic microscopic feature. - The genetic locus that is involved in these patients is in band p15.5 of chromosome 11 distal to the WT1 locus. > Although this locus is called "WT2" for the second Wilms tumor locus, the gene involved has not been identified. - Of all candidate "WT2" genes, imprinting abnormalities of insulinlike growth factor-2 (IGF2) have the strongest relationship to tumor predisposition in persons with BWS. > IGF2 normally is expressed solely from the paternal allele, whereas the maternal allele is imprinted. > In some Wilms tumors, loss of imprinting (i.e., reexpression of IGF2 by the maternal allele) can be demonstrated, leading to overexpression of the > IGF2 protein, which is postulated to result in both organ enlargement and tumorigenesis. - In addition to Wilms tumors, patients with BWS also are at increased risk for the development of hepatoblastoma, adrenocortical tumors, rhabdomyosarcomas, and pancreatic tumors.

Denys-Drash syndrome (DDS)

- those with so-called "Denys-Drash syndrome" (DDS), have an even higher risk (approximately 90%) of Wilms tumor - DD syndrome is characterized by gonadal dysgenesis and early onset nephropathy leading to renal failure. - persons with DDS harbor a dominant negative inactivating mutation in WT1 that interferes with the function of normal WT1 protein made from the other WT1 allele. - WT1 is critical to normal renal and gonadal development; it is not surprising, therefore, that constitutional inactivation of one copy of this gene results in genitourinary abnormalities in humans

Renal papillary adenoma

benign neoplasms such as small cortical papillary adenomas (<0.5 cm in diameter), which are found in up to 40% of adults in autopsies, have limited clinical significance