Urinary Bladder and Urinary Tract Tumors (Pathology Lecture)

Pathology and diagnostic P. Colombo - Pathology - lecture 04 Urinary bladder and urinary tract tumors 31/10/2024 - group 2 (Amadio, Grossi) Urothelial tumors can potentially develop anywhere. A differentiating urothelia...

Pathology and diagnostic P. Colombo - Pathology - lecture 04 Urinary bladder and urinary tract tumors 31/10/2024 - group 2 (Amadio, Grossi) Urothelial tumors can potentially develop anywhere. A differentiating urothelial lining is found in the: 1. Renal pelvis (1%) 2. Ureter (2%) 3. Urinary bladder (96%) 4. Urethra (1%) Pathogenesis of urothelial tumors Starting from a normal urothelium, irritative or carcinogenic triggers occur, which may trigger different processes: Hyperplasia can be described as an increase in the number of cell layers without atypia. Metaplasia can be described as an histological change in differentiation from urothelial epithelium to squamous epithelium (even if sometimes glandular metaplasia may occur), without atypia or DNA mutations. Dysplasia can be described as an increase in cell layers, atypia and architectural change. It can be considered as a neoplastic formation. Changes occurring in hyperplasia and metaplasia are reversible, changes occurring in dysplasia are instead irreversible. Moreover, from dysplasia, carcinoma can insurge, which cannot happen from hyperplasia or metaplasia. Carcinomas can be classified as following, from the least severe to the most severe: - Low grade non invasive carcinoma - High grade non invasive carcinoma - High grade invasive carcinoma There is a tight relation between the grading of the tumor and its potential of aggressiveness. Molecular background The most common genetic mutations in bladder cancers are the loss of retinoblastoma genes and mutations of p53. In particular, the molecular causes of superficial lesions can be distinguished from the ones of invasive lesions: A. Superficial lesions (mostly papillary lesions) - 9p (p16) and 9q deletions 1  B. Invasive lesions (mostly flat lesions) - 11p, 13q (Rb) and 14q, 17p (p53) deletions and mutations HYPERPLASIA - In the normal urothelium there are a maximum of 6-7 layers of cells without atypia, while in hyperplasia there is a thickened epithelium without cytological atypia. Therefore, compared to other epithelial tissues, in the urothelium hyperplasia isn’t easy to recognize histologically, as there is a very high intercellular variability. DYSPLASIA - difficult histological finding, again because of the higher intracellular variability compared, for example, with adenomatous lesions of the colon. In dysplasia, the mucosa has cytological and architectural abnormalities with preneoplastic significance (15-19% of progression to invasive cancer) but falls short of the diagnostic threshold for urothelial carcinoma in situ (CIS). Characteristics of dysplasia: 1. Low reproducibility 2. High interobserver variability between pathologists 3. Suggests follow up of the patient 4. Uncommon on first diagnosis Carcinoma In Situ : complete invasion of the wall layer of the urothelium by neoplastic cells without infiltration Bladder tumors Epidemiology 2 There is a 3.5:1 male to female ratio for urinary bladder tumors, whose rate of incidence is very similar to the one of kidney cancer, countries involved include West Nord Europe, Nord America and Australia. Its incidence didn’t change globally in the last 10 years, with the exception of the US (from 73,510 new cases in 2012 to 80,470 new cases in 2019). The death rate for bladder neoplasm is 2.91% Etiology 1. Tobacco (most common etiology for urinary tumors): - Increases six times the risk of developing cancer. - With high tobacco exposure, the same incidence of cancer is noticed both in males and females - Smoking, especially cigarette smoke, has long been recognized as a risk factor for urothelial carcinoma contributing to more than half of all cases. - The duration of smoking history is relevant, with reduction in risk following cessation. Aromatic amines in cigarette smoke cause the formation of DNA adducts, which in turn induce DNA mutations - E-cigarettes are currently under monitoring, but new papers now suggest that they may have high cancerogenic potential, too 2. Professional exposure (aromatic amines): higher incidence in amyuliun/benzidine exposed workers. 3. Costello syndrome: rare genetic condition caused by germiline HRAS mutations, which induce bladder cancer development during adolescence 4. Schistosoma haematobium infection: endemic in the Middle East and African continent, is associated with increased rates of squamous and urothelial carcinoma of bladder. Chronic inflammatory response to Schistosoma eggs residing within the bladder wall is thought to induce squamous metaplasia, hyperplasia, and ultimately carcinoma. Mechanistic studies suggest a skewed immune micro-environment and host epigenomic alterations to play a role 5. Dietary and herbal medicine exposure: Aristolochic acid (AA) is a carcinogenic and nephrotoxic nitrophenanthrene carboxylic acid produced by Aristolochia plants. Ingestion of Aristolochia-based herbal medicines or contaminated wheat grains, induces upper tract urothelial carcinoma in several populations in Taiwan and the Balkan regions 6. Radiation exposure for cancer treatment (external beam and brachytherapy): increases the risk of bladder cancer including tumors of non-urothelial histology. This evidence is supported by studies of patients treated for ankylosing spondylitis and findings among survivors of atomic bomb detonations in Japan 7. Chlornaphazine: used in several countries in the past as a chemotherapeutic agent for treatment of Hodgkin lymphoma and polycythemia vera, was found to increase the risk of invasive carcinoma and papillary carcinoma of the bladder. 8. Cyclophosphamide: antineoplastic agent used in the treatment of lymphomas, soft tissue and osteogenic sarcomas. Case-control studies of survivors have demonstrated an association between cyclophosphamide therapy and bladder cancer development 3  9. Phenacetin: over-the-counter analgesic used during the 19th and 20th century. Since then, it has been banned in many countries due to its association with increased risk of renal pelvis and ureter cancer 10. Opium consumption: The smoking or ingestion of raw or minimally processed forms of opium have recently been identified as carcinogenic to the bladder, based on studies conducted throughout the Islamic Republic of Iran. Opium is consumed in minimally processed form by nearly 4 million people worldwide, primarily in countries of southeastern Asia and the Middle East 11. Exposure to benzidine-based dyes (or dyes that metabolize to benzidine): aromatic amines and arsenic increase the risk of developing bladder cancer. Exposure can be through inhalation or ingestion. Arsenic exposure may occur through consumption of contaminated drinking water, as seen in certain geographic regions. Occupational exposures in the production of aluminium, auramine, magenta, and rubber, as well as occupational exposure as a painter, are all associated with risk of developing bladder cancer. From a pathologist point of view, one of the greatest challenges faced everyday is to reach such a high quality biopsy, that a very early diagnosis can be achieved. This would be useful, because tumors are harder to treat if diagnosed in later stages. Therefore, early changes in urothelium should be analyzed and preneoplastic lesions must be differentiated from cancer. However, the histological exam for this type of tumor is very difficult because of the high intercellular variability. Some lesions appear pre-neoplastic in the histological analysis, but then subsequently turn out to be cancer. Mutations associated with bladder urothelial carcinoma Telomerase Reverse Transcriptase (TERT) promoter and Fibroblast Growth Factor Receptor 3 (FGFR3) mutations have been widely accepted as the driver mutations of bladder urothelial carcinoma. This may support the idea that papillary urothelial hyperplasia has a precursor nature: it may be an early stage or a precursor to the development of more serious conditions or tumors in the urinary bladder. In other words, alterations in these specific genes may be 4 associated with the initial stages of abnormal cell growth in the bladder lining, which could then progress to more severe conditions. TERT promoter mutations involve alterations in the regulatory sequence of the TERT gene, leading to increased telomerase activity. FGFR3 mutations involve changes in the FGFR3 gene itself, leading to abnormal activation of the receptor. Clinical symptoms Urinary bladder tumors symptoms are mainly aspecific and include: Not painful hematuria (most common) Dysuria Suprapubic pain Pelvic mass Pyelonephritis, when the ureter is involved.. multiple lesions These tumors are single lesions in 60% of cases, but can also be multiple lesions in 40% of cases. Since this is an organ disease, all the mucosa has a predisposition to develop the tumor. Definition of bladder tumor A bladder tumor can be defined as a neoplasm, mostly malignant, originating from the epithelium of the bladder mucosa, the urothelium. These tumors can be divided in two main categories, which are in turn sub-categorized depending on their level of wall invasion: Superficial bladder cancer - tumor which hasn’t invaded the muscularis propria ○ pTIS or CIS = in situ carcinoma ○ pTa = non-invasive papillary urothelial carcinoma ○ pT1 = invading the lamina propria, but still considered superficial Invasive bladder cancer ○ pT2 = invading the muscle wall ○ pT3 = found in perivisceral fat ○ pT4 = invasion of other organs 5 Gross pathology The gross pathology of a bladder tumor generally displays a solid, papillary, polyploid and nodular appearance. Sometimes, it can also have ulceration in the superficial region of the lesion and transmural infiltration of the bladder wall (very common). In most cases, the adjacent mucosa is normal or reddened (associated with CIS). In the image, an MRI with contrast reveals the lumen of the bladder with a solid papillary polypoid mass, indicated by the arrow. Wall infiltration is present, too. The patient could be eligible for cystectomy. slide 19 Sampling After receding parts of the bladder’s wall, this is opened for the identification of the lesion and to better observe the infiltration in the wall, since this impacts on the TNM staging, which in turn reflects on survival rates. In the image, a bladder was coloured with black ink to perform margin evaluation. An ulcerated lesion is present, which corresponds to the location of the cancer. An ulceration may occur if the patient underwent a previous transurethral resection or if the tumor grows very fast, which is typical of epithelial tumors. Trabeculations may also be noticed in the mucosa. In this bladder a multifocal lesion spreading all around the wall can be noticed. It is a polypoid mass with multiple modular regions. 6 This picture represents a cut surface of the bladder after fixation with a flat lesion invading the walls. All the yellow areas present are composed of the tumor infiltrating behind the bladder. The original mucosa is completely destroyed by the tumor and necrotic lesions with residual peri-visceral fat can be found on the upper right border. Here, fungi are invading the outside fat of a bladder affected by squamous carcinoma This tumor developed in the diverticulum of the bladder and is dangerous, as there isn't any muscle wall there, so invasion is easier. Urothelial cancer classification Bladder tumors can be divided in 2 subtypes: 1. Non-invasive ○ Flat (urothelial in situ carcinoma) ○ Papillary 2. Invasive ○ Flat ○ Papillary A flat tumor, like colon cancer, doesn’t grow in the lumen and is more prone to invading the wall, while a papillary tumor grows in the lumen and is less prone to invading the wall. According to the WHO classification of 2022, urothelial tumors can be divided as following: Invasive urothelial cancer (flat or papillary) ○ Variants BUT ALL HIGH GRADES Non-invasive urothelial tumor (flat or papillary) ○ In situ carcinoma ○ Urothelial papilloma, inverted papilloma ○ Urothelial neoplasm of low malignancy potential ○ Papillary urothelial carcinoma, low grade ○ Papillary urothelial carcinoma, high grade Others: squamous cell carcinoma, neuroendocrine carcinoma, sarcoma (rare tumors) 7 In situ urothelial carcinoma - Flat non invasive proliferation of malignant cells in full thickness - 5-6° decade - Incidence: - De-novo 1-3% as primitive neoplasm, usually with good prognosis - 45-65% association with invasive carcinoma (secondary CIS), common but worse prognosis - 7-15% association with papillary cancer (secondary CIS), common but worse prognosis - Site: - Bladder (most common) - 30% urethral tract - Prostatic urethra - Renal pelvis Macroscopic and microscopic evaluation Gross pathological evaluation of CIS can show: Oedema and reddened mucosa Erosions Unifocal, multifocal or diffuse growth pattern Microscopical and histological evaluation of CIS can show: Nuclear anaplasia equal to that of high-grade carcinoma High mitotic index with atypical mitosis Sometimes only focal involvement of the urothelial layer - “pagetoid spread” Umbrella cells, cells of the outermost center of the urothelium, may be detectable Loss of cell cohesion (loss of desmosomes) with denuded mucosa or cystitis or with only a few malignant cells layering - “Clinging CIS” Normal epithelium above, below a neoplastic urothelium of a CIS. In the second image detachment of superficial cells can be noticed. CIS with very high nuclear-cytoplasmic ratio, loss of polarity and increase in cell layers. These are very atypical cells which allow for an easy diagnosis from a urine sample. Slide 33 8 In this case, cells can be barely seen in the histological sample, but are detected in urine, which is very sensitive to CIS. Prognosis a) Primitive tumor - low rate of progression to invasion b) Secondary tumor - rate of progression and invasion associated to the type: i) Papillary non-invasive urothelial carcinoma 1) DOD* in 7-15% of cases ii) Papillary/flat invasive urothelial carcinoma 1) DOD* in 45-65% of cases Therefore, the association between CIS and invasive urothelial carcinoma all around the mucosa impacts harshly on survival. *DOD = death of disease Histology of urothelial flat (non-papillary) invasive carcinoma Malignant cells infiltrate the lamina propria or the muscular wall High mitotic index Desmoplastic stromal reaction when the tumor starts to infiltrate the lamina propria or the muscular wall Perilesional inflammatory cells in the stroma CIS in the adjacent mucosa Normal bladder wall The bladder wall is composed of 1. Mucosa - made of epithelium and lamina propria, the region between the epithelium and the vessels 2. Submucosa - here vessels and muscularis mucosae, small thin fascicles of smooth muscle cells, are found 3. Muscularis mucosae (or muscular wall) - made of large fascicles of smooth muscle cells. Its distribution varies in the bladder: - Prominent and continuous - 3% - Discontinuous and interrupted - 20% - Sparse cells - 71% - Absent - 6% N.B. It is not easy to locate a tumor in the mucosa! 9 The muscularis mucosae and the muscular wall must be differentiated. For this, a brown pigment is used to stain an intermediate sarcomere filament called desmin, a muscle-specific protein. Tumor in the epithelial region (upper part) : pTIs (CIS) or pTa (non-invasive papillary) Tumor invading the lamina propria (a bit lower) : pT1 Tumor lower near the first desmins : pT1 starting to infiltrate the muscolari mucosae Tumor towards the middle in the white area : pT1, as it is still in the submucosa Tumor in the muscular wall (lower right) : pT2, with survival rate half of pTa With pT1, lamina propria infiltration occurs and cancer cells are found in the mucosa but not in the submucosa. This condition has generally a good prognosis, but local treatment is needed, which consists of the instillation of Calmette Guerin bacillus and mitomycin. The former is a bacterium able to produce granulomatous inflammation in the bladder, thanks to which it can destroy the tumor, the latter is an antibiotic used as a chemotherapy drug. However, not all pT1 tumors respond to this type of therapy. High grade carcinoma infiltrating the lamina propria slide 43 Patients have to be stratified: last year a different approach has been used to differentiate patients, because some pT1 patients, with infiltration in the lamina propria, progressed quickly. Mostly in the US there are trials in which patients will undergo cystectomy for a pT1, not the gold standard, to be more aggressive toward them to avoid the progression of the 10 disease. So in this moment they stratify patients in different types of pT1 because they are able to predict if a pT1 patient will progress or not. They produced a technique in which they analyzed with a precise method the size of the infiltration to stratify patients based on this criteria. More or less 1 mm is used as a reference in this paper. In this case they found that there is a difference between patients with an infiltration of more than 1 mm compared to those with an infiltration of less than 1mm. There is a high intercellular reconducibility. With this approach there is the possibility to predict if patients will progress or not. Blue line indicates patients that will not progress, the red line indicates patients that will progress. In pT2 the tumor infiltrates the muscle wall (muscularis propria). Desmin is a protein present in muscle cells that could be identified underlying the presence of destruction of the muscle. 11  In pT3 the tumor infiltrates perivesical tissue outside of the bladder. In men infiltrations in the prostate or in the seminal vesicles correspond to a pT4 tumor infiltration. Example of a very dangerous tumor inside a diverticulum in which pT2 cannot be used because there is a region of absence of muscle wall so there is the need to go from pT1 to pT3. The most fascinating variant is the papillary one and they are common. Grading in papillary urothelial carcinoma is characterized by an atypia of grade 1-2-3. The rate of progression of tumors is related to the grade of the tumor. Grading: differentiation of neoplastic cells (G1: well differentiated cells, G3 or G4 are purely differentiated cells). In G1 tumors, malignant neoplastic tumors, is uncommon to see an invasion. Grading is based on increase in cellularity, loss of cell polarity, no differentiation in superficial layers, increase in nuclear pleomorphism with irregularity of nuclear membrane, different size of cells, frequent mitosis in outer layers, atypical mitosis, giant cells and necrosis. This is the old classification but now after many evolutions they use the Low and high grade classification. Papillary urothelial tumors of the bladder Urothelial papilloma (benign) Papillary neoplasm of low malignant potential Papillary urothelial carcinoma low grade Papillary urothelial carcinoma high grade Urothelial papilloma Urothelial papilloma - Benign - Fibrovascular structures layered by urothelium similar to the normal mucosa - Low incidence (1-4% bladder tumors) - Young, sometimes childs - Location: uretheral ostium and urethra - Single - Recurrence is rare Histology: there is a normal urothelium that covers a fibrous vascular core with no evidence of mitosis and atypicalities. 12 Papillary neoplasm of low malignant potential (PUNLMP) - 1-2 cm (cystoscopy) so large in size - Multilayered papillae (increased number of layers over normal urothelium) with minimal atypia - Increased cell density with preserved polarity slight nuclear enlargement (histologically) - Umbrella cells may be seen - Rare and only basal mitosis - Low recurrence - Excellent prognosis (not benign but not so malignant) Histology: mild increase in cell density and atypicality, no evidence of mitosis. Papillary urothelial carcinoma low grade - Most common (5/100.000 – year) - Location: posterior/lateral wall or close to uretheral ostium (70% cases) - Ordered papillae but with abnormal and well recognizable atypical histology (architectural and cytological) - Polarity variations; uniformly enlarged nuclei - Visible but small nucleoli - Few mitosis but throughout full thickness epithelium - Common recurrence (48-71% pts) - Prognosis: fatal progression in