Section 1 -

Classification and Grading of Urothelial Neoplasms David Grignon Wayne State University School of Medicine Detroit, USA

The last decade has seen a tremendous upheaval in this very important area that only recently seems to have settled down to a level of general though still not complete concurrence. For over 2 decades the WHO classification and grading of urothelial neoplasms [Mostofi, 1973] dominated although several variations and different schemes were published [Bergkvist, 1965; Malmstrom, 1987; Lipponen, 1992]. In the early 1990's several factors emerged that resulted in the need to re-evaluate this approach. First, the controversy of calling grade 1 papillary tumors "carcinoma" arose with several groups led by William Murphy beginning to call all tumors in the low-grade end papilloma [Jordan, 1987; Murphy, 1994]. Second, the use of intravesical therapy as a standard practice in the treatment of high-risk non-invasive papillary tumors demanded that high-risk tumors be identified. Third, the WHO (1973) was severely criticized for the imprecision of the histologic criteria (see table below), leading many pathologists to essentially use this 3 grade system to create 5 grade groups (1, 1-2, 2, 2-3, and 3); one result being that only a small percentage of cases were placed in the grade 3 group. The effect of the latter was confusion among clinicians as to how to treat grade 2 tumors that clearly included many high-risk patients that should receive intravesical therapy as well as many patients with very low-risk disease. 1973 WHO grading criteria [Mostofi, 1973] Grade 1 Tumors with the least degree of cellular anaplasia compatible with a diagnosis of malignancy Grade 2 Histologic features between grades 1 and 3 Grade 3 Tumors with the most severe degrees of cellular anaplasia Recognizing the many emerging issues, in 1997 Mostofi organized a meeting of a small group of urologic pathologists, urologists and oncologists to address these concerns. This was followed by a much larger consensus conference that was held under the auspices of the International Society of Urologic Pathology (ISUP) in March of 1998. The results of this consensus were subsequently adopted by the WHO and the results published in 1998 as the WHO/ISUP consensus classification [Epstein, 1998]. Most controversial was the adoption of the term Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP). PUNLMP represents a compromise term where the papilloma and carcinoma advocates could be comfortable and bring that controversy to conclusion. Most important was the adoption of the grading system that had been described by Malmstrom et al [1987]. The value of the latter was viewed as two-fold – first, the morphologic criteria were well defined and second, it appeared to place the majority of patients with high-risk disease into the high-grade category. The publication of the 1999 WHO blue book the following year introduced a new variation on this system with the splitting of the low and high grade categories of the 1998 WHO/ISUP into 3 groups (grades 1, 2 and 3) while retaining the PUNLMP category [Mostofi, 1999]. This re-ignited the controversy with some experts urging a return to the 1973 WHO [Cheng, 2000a]. Others criticized the 1998 WHO/ISUP system as simply representing a renaming of the 1973 WHO [Oyasu, 2000], a clearly incorrect interpretation [Lopez-Beltran, 2004a]. At a 2001 meeting in Ancona, Italy a modified version of the 1973 WHO was proposed. This issue became the primary focus of debate at the WHO meetings prior to the release of the 2004 WHO Classification. Following extensive debate and discussion it was agreed overwhelmingly to essentially reproduce the 1998 WHO/ISUP classification as the 2004 WHO recommended classification scheme [Eble, 2004]. Similarly the authors of the 4th Series AFIP fascicle covering bladder neoplasia have followed this system [Murphy, 2004]. With this consistent approach adopted by arguably the 2 most influential references for tumor classification and grading, work can continue on evaluating the biologic and clinical relevance and value of this system [Reuter, 2006]. The success of this in addressing the key issues outlined in the first paragraph has been stressed, in particular the reclassification of high-risk Grade 2 tumors (WHO 1973) in the high-grade papillary carcinoma category [Samaratunga, 2002; Lopez-Beltran, 2004a; Yin, 2004]. For example, in the study by Yin et al [2004], 13 of 46 WHO (1973) grade 2 tumors (28%) were placed in the WHO (2004) high-grade category resulting in 23% of the cases being considered high-grade in WHO 2004 compared to only 4% being called grade 3 in the 1973 WHO. Undoubtedly further changes will follow in the years ahead, however at the present time this is the system of choice. The College of American Pathologists (CAP) utilizes WHO 2004 in its recommendations for the reporting of urothelial tumors [Amin, 2005]; other authors have recommended reporting both grades until there is complete resolution of the issue [Lopez-Beltran, 2004b]. Relationship between 1973 and 2004 WHO (from Lopez-Beltran, 2004a) 2004 WHO CLASSIFICATION OF UROTHELIAL NEOPLASMS NORMAL HYPERPLASIAS FLAT LESIONS WITH ATYPIA Reactive (inflammatory) atypia Atypia of unknown significance Dysplasia (low grade intra-urothelial neoplasia) Carcinoma in situ (high grade intra-urothelial neoplasia) PAPILLARY NEOPLASMS Papilloma Inverted papilloma Papillary urothelial neoplasm of low malignant potential Papillary carcinoma, low grade Papillary carcinoma, high grade INVASIVE NEOPLASMS FLAT LESIONS "FLAT" HYPERPLASIA Historically the term "hyperplasia" has been equated with counting cell layers and specifically considering the epithelium to be hyperplastic if there were more than 7 cell layers. It is well recognized that the apparent number of cell layers in the normal urothelium is variable and dependent on the state of contraction of the bladder wall. The current classification recognizes hyperplasia as when there is a "markedly thickened mucosa without atypia." Counting cell layers is not recommended. The relationship between hyperplasia and neoplasia is unknown. REACTIVE ATYPIA In the presence of acute and/or chronic inflammation, the urothelium shows a wide range of reactive changes. There is usually a history of instrumentation, infection or treatment with intravesical agents. Some patterns of atypia are associated with specific etiologies. In reactive atypia the epithelium may or may not be thickened. Although a thickened epithelium is typically associated with a reactive process, carcinoma in situ can also produce a thicker than normal epithelium. Nuclei are uniformly enlarged, vesicular, and may have prominent usually centrally located nucleoli. Mitoses may be frequent and are in the lower epithelial layers. Inflammation is almost always present. ATYPIA OF UNKNOWN SIGNIFICANCE One of the major grey zones in any consideration of intraepithelial lesions lies between reactive atypias and true neoplastic (dysplastic) alterations. Reproducibility studies have clearly demonstrated the lack of consistency in this particular area. This category was created to include those instances where a lesion cannot be confidently placed in the reactive vs dysplastic categories. Histologically there is usually an inflammatory background. The degree of cytologic atypia is judged to be outside of the accepted range for reactive processes although this possibility cannot be excluded. Reevaluation after inflammation subsides may resolve the problem, particularly in the follow up of patients with known urothelial neoplasia who have been treated with intravesical therapy. DYSPLASIA (LOW GRADE INTRAUROTHELIAL NEOPLASIA) This category also suffers from a significant problem in diagnostic reproducibility. The natural history of lesions with dysplastic features of a lesser degree than the moderate to severe categories is unknown. There is however some evidence, largely genetic that it shares some abnormalities with CIS and therefore likely represents a precursor lesion. It is most often diagnosed in the context of known urothelial neoplasia. One study that applied the 1998 WHO/ISUP criteria indicated a 15% risk of developing cancer with a mean follow up of 4.9 years [Cheng, 1999]. Histologically there is some architectural distortion. The nuclei are irregularly enlarged with some hyperchromasia and pleomorphism present. Overall the features are those of a neoplastic atypia but fall short of the criteria for carcinoma in situ outlined below. CARCINOMA IN SITU (HIGH GRADE INTRAUROTHELIAL NEOPLASIA) The classification recognizes the need to expand the category of CIS to include lesions that had been graded in the moderate to severe dysplasia categories in previous systems. This change reflects current practice in major institutions treating bladder cancer. It also recognizes the general trend for under diagnosis of higher grade lesions. There is also recognition that this is the most reproducible diagnostic category. CIS is accepted as a precursor of invasive carcinoma. MORPHOLOGIC PATTERNS OF CIS Small cell CIS Large cell CIS Denuding CIS "denuding cystitis" Underming (lepedic) growth Pagetoid CIS Histologically CIS is characterized by architectural disorder and nuclear pleomorphism. The cytologically atypical cells need not involve the full thickness of the epithelium and at the minimum single malignant cells growing in a pagetoid fashion are sufficient for the diagnosis of CIS. Individual cells tend to show marked cytologic atypia but increased N:C ratio is not a prerequisite (not present in the large cell type of CIS). In some cases only a few isolated cells are present clinging to the basement membrane (denuding CIS). HISTOLOGIC FEATURES OF VALUE IN EVALUATING FLAT LESIONS Thickness of urothelium Polarity Nuclear size Nuclear crowding Nuclear borders including notches Nuclear chromatin distribution Nucleoli Mitoses Accompanying inflammation Neovascularity at base PAPILLARY LESIONS In the majority of cases the diagnosis of a lesion as being "papillary" in the urinary bladder is straight forward and the questions are more related to proper classification (grading) and evaluation of stage related issues. Occasionally there can be problems in differential diagnosis with lesions that can mimic a papillary process (polypoid or papillary cystitis, fragmented or tangentially cut flat lesions) or papillary lesions that are not strictly speaking urothelial (nephrogenic adenoma, condyloma accuminatum). More problematic is the entire concept of papillary hyperplasia and particularly in the setting of know papillary neoplasia when to call a small lesion a true papillary neoplasm. I personally rarely use the term papillary hyperplasia as a diagnosis – if a true papillary stalk is evident then the lesion is graded and classified into the categories of papilloma, PUNLMP, etc. A papillary stalk is defined by the presence of a central fibrovascular core in an exophytic lesion. In the presence of known neoplasia I am quite aggressive in diagnosing a lesion as a papillary tumor. For cases with an undulating or tenting of the urothelium where no fibrovascular core is evident, the term papillary hyperplasia has been suggested [Taylor, 1966]. These are more "pseudopapillary" than truly papillary and diagnosis is dependent on evaluating the surface urothelium as a "flat" lesion. In this setting if unequivocal dysplasia or CIS is present the diagnosis is dysplasia or CIS. The term "atypical papillary hyperplasia" has been applied by one group but this is not widely utilized [Swierczynski, 2002]. If the latter term is used, the report must explicitly indicate the nature of the surface change. In the report by Swierczynski [2002], the surface epithelium showed frank CIS in 8 of 15 cases and in 13 of 15 cases there was a concurrent urothelial neoplasm (high grade papillary carcinoma with or without invasion [6], carcinoma in situ [8], invasive urothelial carcinoma [1] and papilloma [1]. In one of the 2 lesions without concurrent pathology, a high-grade papillary carcinoma subsequently developed and in the other no follow up was available. This whole issue revolves around the concept of what appears first – changes in the flat epithelium followed by development of the papillary architecture or development of a papillary architecture followed by transformation of the epithelium or a combination of both. "PAPILLARY" HYPERPLASIA In the 1998 WHO/ISUP classification, papillary hyperplasia was included as a category with the group of papillary lesions. In the 2004 WHO classification, this is no longer included as a specific designation but it is recognized that hyperplasias may be flat or pseudopapillary [Eble, 2004]. In the current classification, hyperplasia with a pseudopapillary architecture refers to a slight tenting or undulation of the urothelium lacking a well defined central fibrovascular core, although small vessels may be present at the base of the papillae. There is no significant cytologic or architectural atypia. These have most often been described in the setting of known papillary neoplasia. When identified de novo the significance regarding subsequent development of neoplasia is unknown. UROTHELIAL PAPILLOMA There has been a long standing controversy regarding the nature of papillary lesions with minimal cytologic atypia. The application of this term by some experts to up to 1/3 of all papillary lesions, was a major stimulant to the reevaluation of these lesions that began in 1997. The current classification retains the very restrictive traditional WHO criteria. Histologically, papilloma is characterized by a few fine papillary fronds without fusion or complexity. Individual fronds are covered by an essentially normal urothelium without architectural or cytologic atypia. The number of cell layers is not a criteria for diagnosis. Papillomas meeting these restricted criteria occur at a younger age than other urothelial bladder tumors and often present with only one or a few papillary processes. They have a low recurrence rate with a low risk for the subsequent development of higher grade tumors [Cheng, 1999; Eble, 1987;McKenney, 2003] INVERTED PAPILLOMA Inverted papilloma is a distinct clinical pathologic entity typically arising in the trigone region in a younger patient population than papillary neoplasia. It is associated with a low risk of recurrence (< 5%), distinctly different from papillary urothelial neoplasms [Cameron, 1976; Cheng, 2005]. Recent genetic data supports the idea that these are not related to papillary urothelial neoplasms [Sung, 2006]. Cases of synchronous inverted papilloma and papillary carcinoma are well described although distinction from papillary carcinoma with an inverted growth pattern can be problematic. Grossly these lesions typically have an exophytic polypoid growth pattern. Histologically inverted papilloma consists of anastomosing trabeculae of urothelium covered by a normal or attenuated urothelium. There is no significant nuclear pleomorphism and few mitoses. Squamous or glandular differentiation may be present. In TUR material the fragmentation of the lesion may result in apparent true papillary structures making diagnosis difficult. PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL The creation of this category represented a compromise between the "papilloma" camp and those insisting on the use of "carcinoma" for all papillary lesions. The 1998 consensus statement acknowledged that the lower grade papillary neoplasms were not intrinsically malignant but were associated with a significant risk for the development of new papillary tumors (recurrence). These lesions at the lower end of the spectrum were acknowledged to be clinically significant with close clinical follow up necessary but further intravesical therapy not indicated. Morphologically this category largely though not completely corresponds to grade 1 papillary carcinoma in the old WHO system. The tumor consists of delicate papillae with little or no fusion. The covering urothelium shows minimal if any architectural irregularity. Nuclei are roughly normal in size, lack significant nuclear hyperchromasia or pleomorphism. The chromatin is fine and nucleoli are inconspicuous. Mitoses are infrequent and basally located. These tumors have a significantly lower rate of recurrence than either low- or high-grade papillary carcinomas and a very low rate of stage progression [Malmstrom, 1987; Cheng, 1999; Holmang, 2001; Alvarez Kindalan, 2001; Oosterhuis, 2002; Campbell. 2005; Yin, 2004]. In a review of published studies, Lopez-Beltran [2004a] found the mean tumor recurrence rate to be 36% and stage progression rate to be 3.7%. PAPILLARY UROTHELIAL CARCINOMA, LOW GRADE This category contains the intermediate group of lesions. In the 1973 WHO system this would include the lower ½ of grade 2 papillary carcinoma. These tumors have a low but definite risk of invasion. Additionally they are associated with a high risk of "recurrence" and may progress to higher grade lesions and require close clinical follow up but may not need additional intravesical therapy. The latter needs to be studied in clinical trials. Histologically the papillae are largely delicate and separate but some fusion may be seen. At low magnification there is a generally ordered appearance to the cells within the epithelium. The nuclei tend to be uniformly enlarged and retain the elognated to oval shape of normal urothelial cells. The chromatin remains fine with small and generally inconspicuous nucleoli. Mitoses may be present but are few and remain basally located. These tumors have a significantly higher recurrence rate than for PUNLMP and similar to high-grade papillary carcinomas. They also have a significantly higher rate of stage progression than PUNLMP but significantly lower than for high-grade papillary carcinoma [Malmstrom, 1987; Alvarez Kindalan, 2001; Oosterhuis, 2002; Yin, 2004]. A review of the literature revealed a mean recurrence rate of 50% and mean stage progression rate of 10% [Lopez-Beltran, 2004a] PAPILLARY UROTHELIAL CARCINOMA, HIGH GRADE Tumors that in many cases would have been included in the 1973 WHO grade 2 category (upper ½) have a significant frequency of invasion and biologically have more in common with the grade 3 tumors. These tumors not only have a risk of invasion but have a significant risk of recurrence and progression. For this reason the consensus was that these were better included in a high-grade category with the traditional WHO grade 3 neoplasms. The overall progression rate (to invasive carcinoma) ranges from 15% to 40%. These tumors, when noninvasive (pTa) likely all require additional intravesical therapy. Heterogeneity of grade is recognized in papillary lesions [Cheng, 2000] and the consensus was that tumors should be graded on their worst part although this needs further study. In high grade tumors the papillae are frequently fused forming apparent solid masses. The overall impression is one of disordered growth. The epithelium is of variable thickness and may resemble "denuding CIS" in some instances. Individual cells are haphazardly arranged within the epithelium and have a generally discohesive nature. Nuclei are hyperchromatic and pleomorphic. The chromatin is dense, irregularly distributed and often clumped. Nucleoli may be single or multiple and are often prominent. Mitoses are generally frequent and may be seen at any level of the epithelium. PAPILLARY UROTHELIAL NEOPLASMS ARCHITECTURAL FEATURES LMP LOW GRADE HIGH GRADE PAPILLAE Delicate Delicate Delicate Rarely fused Occasionally fused Fused and branching ORGANIZATION Polarity normal Predominantly ordered with minimal crowding and loss of polarity Predominantly disordered with crowding, overlapping cells and loss of polarity Any thickness Any thickness Any thickness - may be single cells (denuding) Cohesive cells Cohesive cells Often discohesive PAPILLARY UROTHELIAL NEOPLASMS NUCLEAR FEATURES LMP LOW GRADE HIGH GRADE SIZE Enlarged Uniform Enlarged Some variation Enlarged Marked variability SHAPE Elongated Uniform Elongated - oval -round Slight variation Pleomorphic CHROMATIN Fine Fine with some variation Frequently coarse with marked variation NUCLEOLI Absent to inconspicuous Usually inconspicuous Prominent Single to multiple MITOSES Rare Basal if present Infrequent Basal if present Frequent Any level Several studies have looked at a variety of biologic markers in papillary tumors at their relationship to the 3 groups; for the most part these have demonstrated significant differences of the respective marker in the different categories [Cina, 2001; Pich, 2001; Yin, 2004]. DIAGNOSIS OF INVASION Having made a diagnosis of either a papillary neoplasm or carcinoma in situ, the next decision that must be reached is whether there is or is not invasion of the underlying tissue. In most cases this is straightforward however it is not uncommon to face cases where this can be quite problematic. Several reports have documented significant differences in the diagnosis of the presence or absence of invasion and in the presence or absence of muscularis propria invasion when cases are reviewed [Abel, 1998; True, 1996; Tosoni, 2000; van der Meijden, 2000]. In two large series, 35% and 53% of cases reported to be pT1 were considered to be noninvasive on review [Tosoni, 2000; van der Meijden, 2000; Witjes, 2006]. Any case of high-grade papillary carcinoma or CIS should be studied with the mindset that invasion is common and must be excluded. For papillary lesions invasion can occur at the tumor base or within the fibrovascular cores so both areas must be evaluated. The literature contains many series that include Grade 1 tumors reported to be invasive (pT1); the occurrence of such cases has been challenged [Jordan, 1987; Mikulowski, 2005]. In my experience all tumors reported as grade 1, pT1 tumors have not demonstrated convincing invasion and I have downstaged them to pTa (or upgraded them). A variety of histologic features are associated with the development of invasion into the underlying submucosa including disruption of the smooth outline of the basement membrane, the presence of single cells or clusters of cells apparently disconnected from the surface urothelium, irregularly shaped nests or finger-like projections from the surface [Amin, 1997; Grignon, 1997; Epstein, 2004]. With even early invasion the individual cells often have different morphological features than the in situ tumor including more abundant eosinophilic cytoplasm or higher nuclear grade. There is often an associated stromal response including desmoplasia, edema (myxoid), fibrosis and inflammation. Retraction artifact around small clusters of cells suggests that they are invasive. In some cases however there is no apparent stromal reaction. The type of stromal reaction has not been found to have prognostic significance in pT1 tumors [Samaratunga, 2005]. If there is a marked inflammatory infiltrate care must be taken to look for obscured tumor cells or nests of cells and occasionally a cytokeratin stain is needed to clarify the nature of suspicious cells. Certain variants of urothelial carcinoma can mimic lymphoid lesions including so-called lymphoma-like patterns [Zukerberg, 1991], the plasmacytoid variant [Sahin, 1991] and lymphoepithelioma-like carcinoma [Amin, 1994]. Criteria for Diagnosis of Invasion into Lamina Propria by Urothelial Carcinoma Histologic grade: Invasion seen much more frequently, although not exclusively, in high grade (1998 WHO/ISUP classification) lesions. Invading epithelium: Irregularly shaped nests Single cell infiltration Irregular or absent basement membrane Tentacular finger-like projections Invasive component with higher nuclear grade and/or more cytoplasm (or morphologically different) than overlying non-invasive component Stromal response: Desmoplasia or sclerosis Retraction artifact Inflammation Myxoid stroma Pseudosarcomatous stroma Absent stromal response DEPTH OF INVASION Having determined that invasion is present, the next most critical feature is assessing the specimen for muscularis propria invasion. This is often viewed as the most critical parameter in treatment algorithms with pT1 tumors managed primarily by TURBT and intravesical therapy (most often BCG) and pT2 tumors by cystectomy or cystoprostatectomy. Muscularis propria must be distinguished from muscularis mucosae (MM) [Ro, 1987]. The former is characterized by thick, compact bundles of smooth muscle cells forming a "solid" tissue. In contrast, MM is characterized by wispy collections of smooth muscle cells that only rarely form a "solid" layer. The MM layer is typically associated with a layer of large vascular channels. The trigone region is problematic in that the muscularis propria has a pattern of interweaving smooth muscle bundles with a thin submucosa. In this region the muscularis mucosae is for practical purposes impossible to define. Over diagnosis of MP invasion has been documented to occur in a significant number of cases [Abel 1988; True 1996; van der Meijden, 2004].Thermal artifact related to cautery can also result in the submucosa having a dense eosinophilic appearance mimicking the MP – on occasion I have resorted to doing a trichrome or desmin stain to try to elucidate the nature of cauterized tissue. If no muscle invasion is present, the concept of substaging pT1 tumors has been advocated by many. Two approaches have been taken. In 1982 Farrow introduced the idea of microinvasion based on measuring the depth of invasion with invasion less than 5 mm considered microinvasive. More recently, Cheng [2000] applied this approach in a study of TURBT specimens and found 4 mm to be the best cut off for predicting the likelihood of extravesical extension in the subsequent cystectomy specimen. In a similar study van der Aa [2005] found 5 mm to be a significant cutpoint. McKenney [2001] suggested using 2 mm to define microinvasion but presented no data in support of this measurement. The possibility of using the muscularis mucosae as a layer to substage pT1 tumors was first proposed by Younes [1990] who demonstrated that tumors invading to the level of the MM or deeper behaved more like pT2 tumors than those with invasion superficial to this layer. 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