Updated Protocol for the Examination of Specimens From Patients With Carcinoma of the Urinary Bladder, Ureter, and Renal Pelvis

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the “Surgical Pathology Cancer Case Summary” section of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons has mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with the document. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.This protocol applies to carcinomas of the urinary bladder, ureter, and renal pelvis. It applies primarily to invasive bladder carcinomas and/or associated epithelial lesions, including urothelial carcinoma in situ. It is based on the 6th edition of the American Joint Committee on Cancer/International Union Against Cancer TNM classification system for the staging of carcinomas of the urinary bladder, ureter, and renal pelvis.A relevant history is important for interpretation of all bladder specimens.3–6 A history of renal stones, recent urinary tract procedures, infections, or obstruction can influence the urinary cytologic interpretation or the interpretation of random biopsies obtained from patients with hematuria. Any neoplasms previously diagnosed should be specified, including the histologic type, primary site, and histologic grade. Primary tumors of the ureter may be associated with hereditary nonpolyposis colon cancer syndrome. Renal pelvic tumors are more often seen in analgesic abusers, who often have analgesic nephropathy, including papillary necrosis. If prior therapy has been given, it should be described (systemic or intravesical chemotherapy, immunotherapy, radiation, etc). The method of collection and date also should be specified in urine cytology specimens. Cytologic specimens from the ureter or renal pelvis may be overinterpreted if their site of sampling is not stated.The vast majority (>95%) of carcinomas of the urinary bladder, renal pelvis, and ureter are urothelial or transitional cell in origin. A working histologic classification encompassing the wide histologic diversity and histologic range within the different types of carcinomas of the urothelial tract is tabulated in this note. Benign tumors are included in this classification because, within the same patient, a spectrum of differentiation from benign to malignant tumors may be seen in the bladder, either at the same time or over the clinical course of the disease. Also, clinicians stage most tumors irrespective of histologic grade.7–12 The distinction between a urothelial carcinoma with aberrant squamous or glandular differentiation and a primary squamous cell carcinoma or adenocarcinoma is rather arbitrary. Most authorities require a pure histology of squamous cell carcinoma or adenocarcinoma to designate a tumor as such, all others with recognizable papillary, invasive, or flat carcinoma in situ (CIS) urothelial components being considered as urothelial carcinoma with aberrant differentiation.* Modified from Amin et al.7† Papillary tumors may be invasive or noninvasive, and when invasive may be microinvasive (invasive to a depth of ≤2 mm) or frankly invasive (like nonpapillary tumors).‡ Refers to tumors that are undifferentiated by light microscopy.Flat intraepithelial lesions and papillary and invasive lesions are graded separately.11–16 Until recently, there was significant controversy in the classification of these lesions. Flat lesions were graded as mild, moderate, and severe dysplasia and CIS; or atypical hyperplasia and CIS; or dysplasia and CIS.79 Papillary lesions were classified as papillomas (grade 0) and transitional cell carcinomas (grades I, II, and III); or as papillomas, low-grade transitional cell carcinomas, and high-grade transitional cell carcinomas.12–14 Due to variable classification systems and the need for a universally acceptable system, the WHO/ISUP consensus classification was proposed.12 Other systems (that were being used previously) may still be used according to institutional preference. Until the WHO/ISUP system is clinically and prognostically validated, tumor grade according to both the WHO/ISUP system12 and the older WHO14 system, for example, papillary urothelial neoplasm of low malignant potential (WHO/ISUP, 1998)/transitional cell carcinoma, grade I (WHO, 1973), may be used concurrently.The WHO (1999) classification of bladder tumors11 differs only slightly from the WHO/ISUP (1998) system12 in that carcinomas are graded on a scale of I to III in the former and as low-grade and high-grade in the latter. Most cases designated as grade II and III by the WHO (1999) system correspond to high-grade carcinomas in the WHO/ISUP (1998) Consensus Classification.* May include cases formerly diagnosed as “mild dysplasia.”† Includes cases with “severe dysplasia.”‡ Option exists to add comment as to the presence of marked anaplasia.Squamous carcinomas and adenocarcinomas may be graded as well-differentiated, moderately differentiated, and poorly differentiated.A critical role of the surgical pathologist is to diagnose the depth and extent of invasion into the subepithelial connective tissue/lamina propria/submucosa (pT1), muscularis propria (pT2), or beyond (pT3 or pT4).17–19 In papillary tumors, invasion occurs most often at the base of the tumor and very infrequently in the stalk. In the urinary bladder, a tumor infiltrating the lamina propria (pT1) is sometimes overdiagnosed as vascular invasion; hence, caution should be exercised when diagnosing this feature, which in some cases may be supported by performing immunohistochemical studies for endothelial markers.20–22 Although attempts at substaging bladder pT1 tumors have been made, the WHO/ISUP committee recommended that it is currently not necessary for the practice to be universally adopted.12 Pathologists are, however, encouraged to provide some assessment as to the extent of lamina propria invasion (ie, focal vs extensive, or depth in millimeters, or by level—above, at, or below muscularis mucosae). Designation of a tumor as merely muscle invasive is inappropriate, but the type of muscle invasion, that is, muscularis mucosae (pT1 tumors) versus muscularis propria (pT2 tumors) invasion, needs to be clearly stated.23 Descriptive terminology, such as “urothelial carcinoma with muscle invasion, indeterminate for type of muscle invasion,” may be used when it is not possible to be certain whether the type of muscle invaded by the tumor is hypertrophic muscularis mucosae or muscularis propria. A comment on thermocoagulation effect may be made, especially if its presence impedes diagnostic evaluation.24 In transurethral resection of bladder tumor specimens invasive into muscularis propria, no attempt should be made to substage the depth of muscularis propria invasion. Since fat may be present in the lamina propria and muscularis propria, the presence of tumor in adipose tissue is not necessarily diagnostic of extravesical spread; this determination is reserved for cystectomy specimens.25Involvement of the prostate gland may occur in several different patterns. The prostatic urethra may be involved (flat CIS, papillary or invasive carcinoma), or the prostate gland may be involved. Involvement of the prostate gland may be evident as involvement of prostatic ducts and acini without stromal invasion (CIS involving prostate glands), or as urothelial carcinoma involving prostatic stroma (either from prostatic urethral carcinoma, carcinoma extending directly through the bladder wall, or carcinoma involving prostatic ducts and acini additionally with stromal invasion).26The TNM Staging System for carcinomas of the urinary bladder of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) is recommended and is shown in this note.1718By AJCC/UICC convention, the designation “T” refers to a primary tumor that has not been previously treated. The symbol “p” refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment, during initial evaluation of the patient or when pathologic classification is not possible.Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, regardless of whether the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer.* The suffix “m” should be added to the appropriate T category to indicate multiple tumors. The suffix “is” may be added to any T to indicate the presence of associated CIS.Regional lymph nodes are those within the true pelvis; all others are distant nodes.TNM DescriptorsFor identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.The “m” suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.The “y” prefix indicates those cases in which classification is performed during or following initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to multimodality therapy (ie, before initiation of neoadjuvant therapy).The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval and is identified by the “r” prefix: rTNM.The “a” prefix designates the stage determined at autopsy: aTNM.Additional DescriptorsTumor remaining in a patient after therapy with curative intent (eg, surgical resection for cure) is categorized by a system known as the R classification.For the surgeon, the R classification may be useful to indicate the known or assumed status of the completeness of a surgical excision. For the pathologist, the R classification is relevant to the status of the margins of a surgical resection specimen, that is, tumor involving the resection margin on pathologic examination may be assumed to correspond to residual tumor in the patient and may be classified as macroscopic or microscopic according to the findings at the specimen margin(s).Urothelial carcinoma may invade blood vessels or lymphatic channels. In suspicious cases, blood vessels can be highlighted by immunohistochemical staining for factor VIII–related antigen, CD31, or CD34.19–22 Staining will not resolve the problem of differentiating lymphatic versus artifactual space entrapment by tumor cells, and as mentioned, this is frequently seen in urothelial tumors invading the lamina propria. Retraction artifact is also prominent in the “micropapillary variant” of urothelial carcinoma.7Sections of bladder needed for microscopic evaluation are as follows: in transurethral resection of bladder tumor specimens, submit 1 section per centimeter of tumor diameter (up to 10 cassettes). If the tumor is noninvasive by the initial sampling, additional submission of tissue (including possibly submitting all tissue) is necessary to diagnose or rule out the presence of invasion. If tumor is invasive into the lamina propria in the initial sampling, additional sections (including possibly submitting the entire specimen) may be necessary to diagnose or rule out the possibility of muscularis propria invasion. In cystectomy specimens, several representative sections of the tumor, including the macroscopically deepest penetration, should be sampled. Submit several sections of the mucosa remote from the carcinoma, especially if abnormal, including the lateral wall(s), dome, and trigone. Submit one section of ureteral margin, unless submitted separately as frozen section specimens, and one section of urethral margin. If a long segment of the ureter(s) is present, then additional sections from the mid-portion may be necessary, as urothelial cancer often is multifocal.Prostatic urethral involvement should be carefully investigated in cystectomy specimens. Sections should include the prostatic urethra, including at the margin and with the surrounding prostatic parenchyma. Representative sections of the peripheral zone, central zone, and seminal vesicles should be included. Parenthetically, it must be noted that there is a higher incidence of prostatic adenocarcinoma in cystoprostatectomy specimens of bladder carcinoma. Close gross examination may help target sampling of selective, abnormal-appearing areas.Submit one section from each grossly positive lymph node. All other lymph nodes should be entirely submitted, as presence of nodal disease may be used as an indication for adjuvant therapy. Lymph nodes may be grossly or microscopically detected in the perivesical fat.Submit one or more sections of uterus (as indicated) and one or more sections of vagina, seminal vesicles, and other organs (as indicated). If the tumor grossly appears to invade the prostate, uterus, or vagina, sections should be targeted such that the relationship of the infiltrating tumor in the bladder wall and the adjacent viscus is clearly demonstrable.Resection margins, including those mentioned in note G, should be carefully specified. Statements about deep soft tissue margins should specify whether peritoneal surfaces are involved by tumor. In cases of urachal adenocarcinoma in which partial cystectomy with excision of the urachal tract and umbilicus is performed, the margins of the urachal tract, ie, the soft tissue surrounding the urachus and the skin around the umbilical margin, should be specified. In renal pelvis, ureter, and nephroureterectomy specimens, the margins may include radial hilar soft tissue margin; bladder cuff; and ureteral, renal parenchymal, and Gerota fascia margins, depending on the type of surgical specimen.

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