The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual changed the tumor, node, metastasis (TNM) classification systems of genitourinary malignancies in 2017. However, some of the changes appear not well appreciated or recognized by practicing pathologists.
To review the major changes compared with the 7th edition in cancers of the prostate, penis, testis, bladder, urethra, renal pelvis/ureter, and kidney and discuss the challenges that pathologists may encounter.
Peer-reviewed publications and the 8th and 7th editions of the AJCC Cancer Staging Manual.
This article summarizes the updated staging of genitourinary malignancies, specifically highlighting changes from the 7th edition that are relevant to the pathologic staging system. Pathologists should be aware of the updates made in hopes of providing clarification and the remaining diagnostic challenges associated with these changes.
The American Joint Committee on Cancer (AJCC) published the 8th edition of the AJCC Cancer Staging Manual in late 2016, with an implementation date of January 1, 2018 for clinical practice and reporting to the cancer registry.1 This manual is fundamental not only for classifying malignancies, but also for prognostication, management, and data registry. A uniform staging system is also essential because treatment guidelines are often based on the tumor, node, metastasis (TNM) system. This review summarizes the major changes in the 8th edition from the 7th edition of the TNM staging for genitourinary cancers, including those of the prostate, penis, testis, bladder, urethra, renal pelvis/ureter, and kidney, with some examples.1,2
UPDATES IN PROSTATE CANCER STAGING
A notable change in the AJCC 8th edition is that pT2 is no longer a 3-tiered system of organ-confined disease, including T2a (involvement of one-half of one side), T2b (involvement of more than one-half of one side), and T2c (involvement of both sides) disease (Table 1). Numerous studies have demonstrated that the pathologic substaging lacked prognostic implications and there was justification to merge the subdivisions into a single category.3–6 In addition, there was no significant difference in cancer-specific survival among the substage groups.7 Therefore, localized prostate cancer (pT2) is highly dependent on nonanatomic factors such as Gleason score (GS) and correlating grade groups and serum prostate-specific antigen (PSA).
Reporting of grade group together with GS, which is based on the 2014 International Society of Urologic Pathology consensus criteria on Gleason grading, is now recommended (Table 1).8,9 The 2014 criteria attempted to clarify grading of variant morphologies such as glomeruloid and cribriform architectures as Gleason pattern 4, and mucinous carcinoma based on its underlying growth configuration.8,9 The grade groups were first described10 in 2013 and later validated by a large multi-institutional study11 that formulated the following prognostic groups based on GS: grade groups 1 (GS 6), 2 (GS 3 + 4 = 7), 3 (GS 4 + 3 = 7), 4 (GS 8), and 5 (GS 9–10). Based on radical prostatectomy grades, the 5-year biochemical risk-free survivals for the different grade groups were 96%, 88%, 63%, 48%, and 26%, respectively, and more accurately predicted disease progression than GS.11 The fundamental contributions of this new system is that grade group 1 tumors are the lowest grade possible, in contrast to a mid–GS 6 as part of a total score of 2 to 10; this is more reassuring when results are discussed with patients, as these tumors are the biologically least aggressive, and helpful in regard to counseling for active surveillance.8,9,12 Gleason score 7 disease is heterogenous, and separating these tumors into grade groups 2 (GS 3 + 4) and 3 (GS 4 + 3) accounts for the differences in prognosis and management of these tumors.8,9,11 Finally, GS 8 to 10, although often considered collectively as high-grade disease, can be prognostically stratified for different treatment modalities into grade groups 4 (GS 8) and 5 (GS 9–10).8–10,12–14 Therefore, if a radical prostatectomy revealed GS 6 disease with involvement of both lobes, confined to the gland (Figure 1), this would be staged based on the AJCC 7th edition as pT2cN0MX and based on the 8th edition as pT2N0MX, with mention of GS 6 (grade group 1).1,2
Both PSA and grade groups have been included in the AJCC prognostic stage groups (Table 1), and a revision has been implemented to align practice guidelines with clinical experience in that stage group III may include organ-confined disease.15–17 This is to take into account tumor grade and PSA impact prognosis and treatment, so organ-confined prostate cancer with T1 or T2 disease and grade group 1 through 4 with PSA 20 ng/mL or higher may be staged as prognostic stage group IIIA, T3 or T4 with grade group 1 through 4 and any PSA level as IIIB, and any T disease and PSA level with grade group 5 as IIIC. This modified prognostic stage grouping has been validated in a large cohort of prostatectomy cases.18
UPDATES IN PENILE CANCER STAGING
Staging of penile nonurethral skin-derived cancers has now expanded to include noninvasive localized squamous cell carcinoma (Ta), which is different from the previous noninvasive verrucous carcinoma, which was misleading as it applied only to cases exhibiting a broad pushing border in which depth of invasion was difficult to determine (Table 2). This Ta category now encompasses noninvasive carcinomas such as those displaying warty, papillary, basaloid, verrucous and mixed features that do not demonstrate overt features of destructive invasion.19 Lesions displaying destructive invasion should be considered as T1 disease. In other words, Ta is equivalent to papillary noninvasive urothelial carcinoma and comparably Tis is equivalent to flat carcinoma in situ/penile intraepithelial neoplasia.
The definition of T1 invasive tumors is now divided according to the specific anatomic locations, glans, foreskin, and shaft, in comparison with the prior nonspecific generalized description of subepithelial tissue.1 T1 is also separated into 2 tiers depending on the risk for lymph node metastasis, which is 10.5% to 18.1% for T1a versus 33.3% to 50% for T1b tumors, which helps to determine when inguinal lymph node sampling is prudent.20,21 In addition to histologic grade and presence of lymphovascular invasion (LVI), perineural invasion (PNI) is now established as a predictor of lymph node metastasis, as 69% of cases with PNI also had nodal involvement.22,23 Therefore, an invasive moderately differentiated squamous cell carcinoma involving the subepithelial tissue of the glans penis with foci of PNI (Figure 2, A through D) would be staged based on the AJCC 7th edition as pT1aNXMX and based on the 8th edition as pT1bNXMX, involving the lamina propria of the glans (Table 2).1,2
Involvement of both the corpus spongiosum (CS) and corpora cavernosa (CC) was formerly considered as T2 disease. Large studies have shown that there is prognostic justification in separating invasion of these anatomic sites into T2 and T3 disease, as invasion of the CC was more commonly associated with inguinal lymph node metastasis (48.6%–52.5%) in comparison with those with involvement of the CS (33%–35.8%).20,24 A better disease-specific survival/cancer-specific mortality was also associated with invasion of CS versus CC.20,24 Recent studies suggest the presence of LVI with CS or CC involvement may also be associated with cancer-specific survival.25
Urethral involvement was previously staged as T3 disease, and penile cancers arising near the urethral meatus were often given a misleadingly high stage, as there was typically direct extension into the urethra while bypassing the corpora. Given no associations with poorer outcome in these tumors, urethral involvement no longer plays a role in staging and can be a part of either T2 or T3 disease. Therefore, an invasive moderately differentiated squamous cell carcinoma of the foreskin, involving the CS and CC without involvement of the urethra (Figure 3, A through C), would be staged based on the AJCC 7th edition as pT2NXMX and based on the 8th edition as pT3NXMX (Table 2).1,2
Studies20,26 have shown that there was no significant prognostic difference with involvement of a single versus multiple or bilateral lymph nodes as defined by the 7th edition. Rather, involvement of 3 or more unilateral or bilateral lymph nodes were associated with poorer outcomes when compared with metastasis involving 2 or fewer unilateral lymph nodes without extranodal extension (ENE), with a 3-year cancer-specific survival of 90.7% versus 60.5%.20,26 This change helps to separate patients with nodal metastasis into low- (N1) and high-risk (N2–N3) categories, which may allow N1 patients to avoid treatment with adjuvant chemotherapy.27 The N3 subcategory continues to be defined as involvement of pelvic lymph nodes or presence of ENE with a 3-year cancer-specific/relapse-free survival of 32% to 33% in which adjuvant chemotherapy is strongly considered.26–28 Additionally, recent studies suggest subclassification of pelvic lymph node involvement from metastasis with ENE may be prognostically important, as the 3-year cancer-specific survival is 28.6% versus 47.9%.29
Lastly, the histologic grade has been modified to the 3-tiered World Health Organization/International Society of Urologic Pathology grading system, comprising grade 1, well differentiated; grade 2, moderately differentiated; and grade 3, poorly differentiated, including sarcomatoid/spindled and anaplastic morphologies.19 A higher histologic grade has been associated with more lymph node metastasis and worse outcome, particularly in staging T1a versus T1b tumors.20,22
UPDATES IN TESTICULAR CANCER STAGING
The revised manual now takes into consideration tumor size for pure seminomas, which studies have determined is associated with relapse and disease progression and may aid in deciding whether risk-adapted treatment with adjuvant radiation or carboplatin-based chemotherapy should be considered (Table 3).30–35 Because of variability in size cutoffs reported in the literature, a relatively conservative 3-cm size limit was determined.30–32,34 Mixed germ cell tumors, which may include a seminomatous component as well as pure nonseminomatous germ cell tumors, do not factor in tumor size and T1 is not subclassified. Therefore, a pure seminoma that is limited to the testis measuring 4.5 cm in greatest dimension without LVI (Figure 4, A and B) would be staged based on the AJCC 7th edition as pT1NXMX and based on the 8th edition as pT1bNXMX (Table 3).1,2
Both hilar soft tissue, which is defined as adipose and loose fibrous connective tissue beyond the rete testis at the same plane of the testis parenchyma, and epididymal invasion have been upstaged to T2 disease. The rete testis is still considered a part of the testis, because of conflicting data regarding whether involvement of the rete testis is associated with disease progression and risk for relapse.30–32,34,36–38 In part, this may be due to the lack of clarification between pagetoid involvement and stromal invasion of the rete testis, in which the latter may be associated with more advanced disease.38 Therefore, a pure seminoma involving the rete testis and epididymis without LVI (Figure 4, C through F) would be staged based on the AJCC 7th edition as pT1NXMX and based on the 8th edition as pT2NXMX (Table 3).1,2
The definition of spermatic cord involvement was also clarified in the revised staging manual. The beginning of the spermatic cord is delineated as beyond the angle of the epididymis, and its involvement, often identified by tumor surrounding or within the vas deferens, is considered T3 disease when there is direct (continuous) invasion of the spermatic cord (Table 3). However, discontinuous involvement of the spermatic cord soft tissue by LVI is regarded as a metastasis (M1). Presence of only LVI in the spermatic cord without soft tissue invasion is considered T2.1 However, these parameters remain unclear, as some have interpreted discontinuous LVI involvement of the spermatic cord without soft tissue invasion as M1 disease.39,40 In addition, a study found discontinuous LVI of the spermatic cord without soft tissue invasion to correlate with T3 disease.41 Recent studies also suggest spermatic cord LVI, whether continuous or discontinuous, with or without parenchymal involvement is associated with risk of recurrence and worse prognosis.39–42 Despite subcategorization of the M category into M1a and M1b, discontinuous involvement of the spermatic cord soft tissue was assigned only as M1 disease.1,39 Therefore, a mixed malignant germ cell tumor composed of embryonal carcinoma and seminoma with extensive LVI, including vessels of the spermatic cord with adjacent soft tissue involvement (Figure 5, A through D), would be staged based on the AJCC 7th edition as pT3NXMX and based on the 8th edition as pT2NXM1 (Table 3).1,2
Lastly, intratubular germ cell neoplasia was renamed as germ cell neoplasia in situ.19,43 This new term helps to distinguish intratubular spread of germ cell tumors such as seminoma and embryonal carcinoma from intratubular germ cell neoplasia, which is a precursor lesion. Currently, only postpubertal tumors related to germ cell neoplasia in situ and malignant sex cord–stromal tumors are staged. Spermatocytic seminoma was changed to spermatocytic tumor because of its indolent behavior and is no longer staged.19
UPDATES IN BLADDER AND URETHRAL CANCER STAGING
Updates in Bladder Cancer Staging
Urothelial carcinoma that concurrently involves the prostate and bladder can be staged in 2 different ways. First, if there is a bladder primary with direct involvement of the prostatic stroma through the bladder wall, it is staged as T4 (Table 4). Second, if there is bladder urothelial carcinoma as well as concurrent involvement of the prostatic urethra, typically by extension (periurethral spread) of additional independent primary urethral lesions with prostatic stromal invasion, this would be staged as both a bladder and prostatic urethral primary. Therefore, a cystoprostatectomy performed for muscle invasive high-grade urothelial carcinoma, found to also contain involvement of the prostatic urethra and prostatic ducts with stromal invasion (Figure 6, A through C), would be staged based on the AJCC 7th edition as pT4aNXMX and based on the 8th edition as bladder: pT2NXMX and prostatic urethra: pT2 NX MX (please see Updates in Urethral Cancer Staging).1,2 Hence, both thorough microscopic and gross examinations are necessary to appropriately evaluate the pathologic stage.
The revised staging manual recommends subcategorization of T1 disease, albeit there is no completely endorsed method.1 Separating T1 tumors into focally invasive or microinvasive disease from those with more extensive invasion correlates with outcome and risk of recurrence and/or progression.44–54 Several substaging systems have been proposed, including diagnostic criteria of microinvasion, defined as an invasive front or invasive tumor diameter of less than 0.5 mm, less than 1.0 mm, less than 3 mm, or less than 5 mm in a high-power field, with most using the cutoff of less than 0.5 mm or less than 1.0 mm.44,46–53 Separating lamina propria involvement of papillary urothelial carcinoma into invasion of just the stalk or fibrovascular core, focal invasion of the tumor base, and extensive invasion of the tumor base has also correlated with risk of progression and death.45 More recently, a study proposed the aggregate linear length of invasive carcinoma 2.3 mm or more was significantly associated with disease progression.55 Therefore, a bladder biopsy of a high-grade papillary urothelial carcinoma with invasion of the lamina propria comprising just a few small nests measuring less than 0.5 mm (Figure 7, A and B) would be staged based on the AJCC 7th edition as pT1NXMX and based on the 8th edition as pT1(microinvasive) NXMX.1,2
Most bladder diverticula are acquired and lack muscularis propria (Figure 7, C and D). The new staging manual acknowledges this finding and has removed the T2 category when staging cancers involving diverticulae.1,56 Most studies evaluating involvement of diverticular disease by invasive carcinoma do not report muscle invasion (T2), resulting in upstaging. Tumors involving peridiverticular soft tissue are often associated with increased risk of local recurrence and progression, including metastasis.57–61
Perivesical lymph nodes were added as a primary drainage site for bladder urothelial carcinoma as involvement correlates with a worse prognosis (Table 4).62,63 Therefore, pathologic evaluation of the perivesical soft tissue for lymph nodes are prudent.
The revised staging manual has now created 2 tiers in the substaging of metastatic disease, as involvement of visceral organs is associated with a poor overall survival (Table 4).64–66 In addition, cases with nonregional lymph node involvement have better outcomes than those with visceral organ metastasis.64 Therefore, cases with nonregional lymph node involvement beyond the common iliac lymph nodes are now considered M1a in comparison with distant metastasis within visceral organs or non–lymph node sites such as the liver, lung, and bone as M1b.1 The prognostic stage groups III and IV are subcategorized into A and B according to the amount of regional LN metastases and M1 disease, respectively.
Updates in Urethral Cancer Staging
The prostatic urethra and male (penile) and female urethra are separately staged (Table 5). In urothelial carcinoma of the prostate, carcinoma in situ involving the prostatic urethra was previously delineated Tis pu and prostatic ducts Tis pd, but these have now been merged into a solitary Tis category for simplification. As mentioned previously, bladder cancer with intraurethral (noncontiguous) prostatic stromal invasion is staged separately from transmural (contiguous) prostatic stromal invasion because of the association with poorer outcomes with the latter (please see the first example in Updates in Bladder Cancer Staging above).67–71
Lastly, the definition of the N category has been changed from a 2.0-cm metastasis size cutoff to single versus multiple lymph node(s) involvement (Table 5). In addition, as for the bladder, perivesical lymph nodes have also been added as part of the regional lymph nodes.1 Studies have shown that nodal stage correlates with survival.72
UPDATES IN STAGING OF CANCERS OF RENAL PELVIS, URETER, AND KIDNEY
Update in Renal Pelvis and Ureteral Cancer Staging
Only a minor change has been made in the N category, consisting of dissolving N3, which is defined as metastasis in a single lymph node more than 5 cm in greatest dimension, into the N2 category, as there was no evidence to corroborate this category (Table 6).1
Updates in Kidney Cancer Staging
Modifications in the staging for kidney cancer were nominal and included adding pelvicalyceal involvement, removing requirement of gross identification from the description of renal vein involvement, and replacing muscle containing with the general term segmental branches of the renal vein for the T3a tumor category (Table 7). Studies have identified that the amount of muscle within the vessel walls varied and gross suspicion for vascular invasion was often identified without a histologic correlate.73–75 Fingerlike projections or multinodularity of tumor architecture should also raise suspicion for renal vein or sinus invasion.75 Renal sinus invasion has also been identified as the most common pathway for extrarenal extension and may be associated with a more aggressive disease than tumors with perinephric fat involvement alone.76
The World Health Organization/International Society of Urologic Pathology nucleolar grade is now used in place of the Fuhrman nuclear grade.1,19,77,78 This grading system is based on nucleolar prominence for grades 1 through 3, whereas grade 4 consists of more aggressive rhabdoid, sarcomatoid, and anaplastic morphologies.1,19,77,78 The World Health Organization/International Society of Urologic Pathology nucleolar grade correlates with prognosis in both clear cell and papillary renal cell carcinoma, but not with chromophobe renal cell carcinoma, and the latter should not be graded. Other subtypes of renal cell carcinoma may be graded, albeit with the understanding that this does not correlate with outcome.78
Coagulative tumor necrosis, defined as necrotic/degenerative cells or eosinophilic/granular coagulation material admixed with cellular debris, that characteristically retains some recognizable form of tumor-related cells or debris78,79 has also been reported to correlate with prognosis.1 Other changes such as hemorrhage, hyalinization, and fibrosis should not be considered as part of coagulative necrosis. A variety of reporting systems have been proposed that correlate with metastasis, prognosis, and survival regarding coagulative necrosis, albeit none have been completely endorsed.78–83 Microscopic LVI, which is defined as a focus of tumor within small vascular spaces that cannot be identified macroscopically on the slide, has also been shown to correlate with survival and is considered a prognostic factor.1,75,77
The revised AJCC Cancer Staging Manual has incorporated changes that have clarified some of the problems pathologists face when evaluating genitourinary malignancies, and have taken into consideration alterations related to management. The AJCC Cancer Staging Manual provides standardized cancer reporting protocols. It thus provides not only a standardized template for reporting important pathologic findings, but also a means to accurately classify tumors and report data needed for prognostication, management, and cancer registry.
The authors have no relevant financial interest in the products or companies described in this article.
Presented in part at the 5th Princeton Integrated Pathology Symposium; April 15, 2018; Plainsboro, New Jersey.