HISTORY
The first widely accepted prostate cancer staging system, introduced by Whitmore in 1956,⁷⁷  was based on anatomic factors that have remained important. With time, subclassifications have been introduced to refine the anatomic groups. Notably there was recognition of the very good prognosis for a patient with a small unilateral palpable nodule, designated as "Stage B1N" in a modified Whitmore-Jewett system.⁴⁴  As well, the poorer prognosis of patients who had local extra-prostatic extension of carcinoma into the seminal vesicles ("Stage C2") was recognized.^3,22,59  Different groups have introduced different modifications with their own nomenclature, making standardization difficult. A proposal to develop a staging system based on tumor volume, a known strong predictor of tumor progression and clinical outcome,^{4,20-22,45,46,51}  was published in 1993.⁴  However, the lack of adequate methods to determine tumor volume preoperatively, either by digital rectal examination, multiple needle biopsies or other modalities including transrectal ultrasound, CT scan, or transrectal MRI, hampers this approach. .^{29,40,43,50,54}  Tumor-nodes-metastases (TNM) systems have been in use for many years, and, in 1992, a major development was the proposal of a unified TNM system, formulated by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), with representation from the Euopean Organization for Research on Treatment of Cancer (EORTC), and the American Urological Association (AUA).⁵⁹  In 2002, the UICC published updated TNM rules of classification and staging of prostatic adenocarcinoma(^39-41 see Table).

RULES OF THE CURRENT TNM CLASSIFICATION AND STAGING SYSTEM
The TNM staging system is based on anatomic criteria (see Table). The original clinical criterion of dividing patients into those with non-palpable disease (T1) and those with palpable disease (T2) remains. In addition, imaging study results continue to be a criterion, a factor that was introduced in the 1997 4th edition UICC TNM manual. A T1 tumor is nonpalpable and non-visible. Detection of a tumor by an imaging study (eg. ultrasound) places the tumor in the T2 category. In the past, the detection of a non-palpable tumor almost always occurred with the histological examination of prostatic tissue fragments obtained by transurethral prostatic resection ("TUPR"). These incidental carcinomas are sub-classified as focal or diffuse based on whether less than 5% (T1a) or more than 5% (T1b) of the resected tissue is involved by carcinoma, as determined by a histologic estimate of the total percent of the surface area of the tissue involved by carcinoma.^36,41  With the advent of serum PSA testing and transrectal ultrasound directed needle biopsies, prostatic adenocarcinoma is now frequently detected by random needle biopsy in a patient who has non-palpable, non-visible disease associated with an elevated serum PSA, or who has a significant family history.⁵⁴  The sub-category T1c has been retained to identify this clinical stage.⁴¹  Of note, non-palpable, non-visible tumor that involves the right and left sides of the prostate gland on biopsy is clinically classified as T1c.⁴¹ 

The sub-classification of palpable/visible disease confined to the prostate has varied between two and three categories, depending on whether or not there is division of unilateral disease into that which involves less than one-half of a lobe versus that which involves more than one-half of a lobe. The current publication incorporates this concept, with the unilateral sub-categories designated as T2a and T2b respectively.⁴¹  Bilateral involvement is designated as T2c.⁴¹  A carcinoma involving the capsule or prostatic apex, without extending completely beyond these structures to involve extra-prostatic tissue remains classified as T2 disease.⁴¹  An unexpected prostatic adenocarcinoma in the prostate gland of a cystoprostatectomy specimen removed for transitional cell carcinoma is classified as a pT2 prostatic adenocarcinoma.⁴² 

In the past, there was sub-classification of T3 disease based on unilateral versus bilateral extra-prostatic extension of carcinoma.^54,85  Currently, this distinction is not made and a carcinoma that involves extra-prostatic tissue unilaterally or bilaterally is designated as T3a.⁴¹  Seminal vesicle involvement has consistently been given its own T sub-category. At present, a carcinoma that involves the seminal vesicle unilaterally or bilaterally is designated as T3b.⁴¹ 

T4, a category meant to represent advanced local disease, denotes a carcinoma that has invaded adjacent anatomic structures, other than the seminal vesicles, such as the external sphincter, rectum, levator ani muscles or pelvic side-wall. This also includes tumors that involve the bladder neck. In the UICC TNM supplement, it has been proposed that the T4 category be subdivided into T4a, to classify tumors that invade the bladder neck, external sphincter, or rectum, and T4b, to classify tumors that invade the levator muscle or the pelvic side-wall,⁴²  and these criteria have been previously published.^{3,54, 85} 

The N1 and M1 categories are for regional lymph node metastases and distant (bone marrow or non-regional lymph nodes ) metastases, respectively. For the prostate gland, the regional lymph nodes are defined as the lymph nodes of the true pelvis, located below the bifurcation of the common iliac arteries. The N classification is not affected by the laterality of the involved lymph nodes. Currently, the UICC TNM classification does not have specific subgroups to stratify N1patients,⁴¹  although past publications have sub-classified the lymph node metastases into N1, N2 and N3 to represent metastases </=2 cm, >2 cm and </=5 cm, and > 5 cm respectively.^3,54  A lymph node micrometastasis (less than .2cm) may be designated as pN1mi.⁴¹  M1a designates non-regional lymph node metastases and M1b is assigned to those patients with bone marrow metastases. All other sites of distant metastases are designated as M1c. Sub-notations to identify specific structures or organs may be used.⁴¹ 

CLINICAL STAGE VS PATHOLOGICAL STAGE
It is important to distinguish between the clinical stage and pathological stage. The former is based on evidence obtained before treatment whereas the latter is based on evidence derived from the post-surgical histopathological findings.⁴¹  Clinical classification systems depend on physical examination and all pre-treatment investigative findings, including imaging studies, biochemical tests, endoscopy, surgical exploration and tissue biopsy. The pathological classification system requires microscopic examination of the post-treatment, post-surgical tissue specimen, sufficient to determine the most advanced stage. In addition to standard determinations of anatomic structures involved and tumor size, a number of parameters may be used to define "stage groups". Anatomic stage and morphologic grade are most often combined to stratify patients into treatment and prognostic groups. Non-anatomic determinations, such as aetiology, biochemical tests, DNA content, molecular and genetic investigations, may serve to further stratify patients. Currently, for prostatic adenocarcinoma, anatomic extent of disease and histologic grade are the only two variables used to determine TNM stage groupings.⁴¹  The Partin tables utilize clinical anatomic extent of disease, Gleason Score, and serum prostatic specific antigen (PSA) levels to predict the final pathological stage in patients with clinically localized prostate cancer.⁶¹ 

The categories determined by clinical parameters in the pre-treatment patients are identified by the prefix "c", (eg. cT2) or no prefix at all. In the post-surgical patient who has had histopathological examination of the surgical specimen, the pathological stage is identified by the prefix "p" (eg. pT2). There is no pT1 category corresponding to the cT1 category. There is no histopathological equivalent of a "non-palpable" tumor.

EXAMINATION OF RADICAL PROSTATECTOMY: DETERMINATION OF STAGE
Thorough histopathological examination and strict application of criteria must be performed on a properly dissected surgical specimen to allow determination of the maximum pT classification possible .^{3,29,41,42,65}  Extent of unilateral involvement and bilateral involvement is usually readily assessed but determination of extra-prostatic spread may, a times, be more difficult.

Adipose tissue virtually always represents extra-prostatic tissue ^3,29,39 and its involvement by carcinoma is a good indication of T3 disesae. Unfortunately, most radical prostatectomy specimens are not uniformly covered with fatty tissue.³⁹  The posterior surface is the most common surface to lack attached fat.³⁹  There is one report documenting intraprostatic fat in two middle-aged men of Polynesian descent, with an illustration showing a focus of intraprostatic adipose tissue surrounding prostatic glands.¹¹ 

The presence of carcinoma within a ganglia is usually indicative of extra-prostatic spread, and this is readily identified when the ganglia is part of the extra-prostatic neurovascular bundles.³  Occasionally, a ganglia is found just within the contour of the prostate gland, adjacent to glandular tissue, typically in the region of the prostatic base.^73,82  Perineural spread of carcinoma is a frequent intraprostatic finding, and it appears to have no independent predictive value 18,73). At times, the extra-prostatic carcinoma incites a fibrotic reaction, obliterating the fatty tissue. Such a focus can be recognized by observing the capsular disruption, and lack of continuity with the general rounded contour of the prostatic capsule, and by observing the focus of carcinoma at the level of near-by extra-prostatic fat. Similar observations may identify extra-prostatic carcinoma within the skeletal muscle of the genitourinary diaphragm beyond the prostatic apex, or within extra-prostatic anterior muscle tissue where there is admixed smooth muscle and skeletal muscle. At these sites, such interpretation can be particularly problematic as the capsule is not well-defined ^1,36 and extra-prostatic spread can only be confidently identified when there is unequivocal evidence of cancer extending beyond the contoured edge of the prostate gland.^3,29  It is important to be aware that, due to the normal blending of skeletal muscle with the apical and inferior anterolateral peripheral prostatic glandular tissue, carcinoma within skeletal muscle is not, in itself, evidence of extra-prostatic spread.

Identification of extra-prostatic involvement of the seminal vesicles requires the presence of invasive carcinoma within the smooth muscle wall of the seminal vesicle ^{19, 58} and there is evidence that the most significant finding is involvement of the free portion of the seminal vesicle by carcinoma. ^16,19  Seminal vesicle-type epithelium surrounded by benign prostatic glandular tissue is considered intra-prostatic and it may represent ejaculatory duct tissue.

A pT4 tumor is obviously not normally treated with a radical prostatectomy. However, carcinoma found within the proximal prostate, adjacent to the bladder neck resection margin may lead to a T4 designation, if this is accepted as bona fide bladder neck involvement as envisioned by TNM system ^83,84 .

RESECTION MARGIN STATUS
It is important to be aware that a tumor positive resection margin, defined as carcinoma cells at and covered by ink of the resection margin, can occur at an extra-prostatic site, an intra-capsular site, or an intra-prostatic site, depending on the surgeon's plane of dissection.^3,45  In itself, a tumor positive margin does not equate to extra-prostatic spread, although it indicates the likelihood of residual in-vivo tumor that obviously cannot be histologically assessed. Surgical resection margins are not included in the TNM categories, but it has recently been suggested that a tumor positive margin that cannot be identified as being extra-prostatic, be designated as T2+.³  Positive surgical margins are a predictor of clinical recurrence and biochemical failure,^{25, 48}  with a reported recurrence rate ranging from 25% to 50% (26,27,60,76)

Discussion OF THE CURRENT TNM SYSTEM
A basic issue is the validity of dividing patients into those with and without palpable tumor. Cinical staging has been estimated to understage up to 59% of patients and overstage up to 5% of patients based on subsequent examination of the radical prostatectomy specimen.³  Neither the digital rectal examination (DRE) nor transrectal ultrasound or endorectal MRI are very accurate in detecting prostatic carcinoma or determining its volume.^3,54,67  For detection of prostate cancer, the sensitivity, specificity, and positive predictive values for DRE have been reported as 57.9%, 96.3% and 28% respectively.⁵³  For transrectal ultrasound, the sensitivity, specificity, and positive predictive values have been reported as 77.2%, 89.4% and 15.2% respectively.⁵³ 

T1: Non-palpable/ Non-visible Carcinoma Localized to the Prostate Gland
A transurethral prostatectomy, performed for clinically benign prostatic hyperplasia, does not sample the peripheral zone or apical regions, thus limiting its ability to assess the extent of disease. Up to 60% of patients with a clinical T1a carcinoma will have residual cancer on repeat TUPR.³  Up to 92% of patients with a clinical T1a+b carcinoma will have residual carcinoma upon complete histological examination of a subsequent radical prostatectomy, frequently in the apical or peripheral prostatic tissue.^3,9,23  T1a+b tumors may largely represent transition zone carcinomas, but there is no corresponding pathological TNM category that can be used to confirm the clinical stage when examining a radical prostatectomy specimen.^36,41 

Prostate carcinomas classified as T1c are a heterogenous group that represent a clinical method of detection more than a single biological entity. Placement in this category does not depend on the amount of carcinoma present in the biopsy cores, although there is some correlation between the amount of carcinoma in the needle cores and the size of the carcinoma in the radical prostatectomy specimen, particularly if there is extensive carcinoma in the needle cores.⁸¹  However, a small amount of carcinoma (ie. a single microscopic focus of carcinoma in one needle core) does not correlate well with a small amount of tumor in the radical prostatectomy specimen (14,56,67). In one study, 64 of 917 (7%) patients treated with a radical prostatectomy had a diagnosis based on a single microscopic focus of carcinoma on needle biopsy, and of these 64 patients, 92% had a tumor size involving at least half of a single lobe.¹⁴  Another study found that, of 222 men with clinical stage T1c, only 10% of men had a tumor volume < .5 cc in the radical prostatectomy specimen.⁵⁶  Yet another study, involving 142 men undergoing radical prostatectomy for clinical stage T1c, found that 65% had a tumor volume > 1cc.⁶⁶  As there is no pathologically equivalent stage for clinical T1c, all T1 carcinomas are necessarily upstaged on radical prostatectomy, usually to pT2 or pT3. The Johns Hopkins study of 157 patients with T1c carcinomas undergoing radical prostatectomy, 51% of patients had organ confined disease, 6% had seminal vesicle involvement and 4% had lymph node metastases.²⁴  Possibly clinical stage T1c carcinomas can be stratified using serum PSA and Gleason Score.^56,81,85  PSA- detected cancers that are visible on ultrasound have no significant differences when compared to PSA- detected cancers that are not visible on ultrasound.³ 

T2: Palpable/Visible Carcinoma Confined to the Prostate Gland
Clinical T2 tumors often do not match the pathological stage as DRE and imaging studies cannot accurately detect the microscopic extent of disease.³  DRE underestimates the local extent of tumor in up to 40% to 60% of patients.⁵⁴  The accuracy of detecting extra-prostatic extension by ultrasound or MRI ranges from 63% to 83% respectively.³ 

The validity of dividing unilateral disease into T2a and T2b categories remains to be established. The clinical concept of "lobes" does not reflect the true zonal anatomy of the prostate gland. There appears to be no difference in lymphatic drainage between the transition zones and peripheral zones.⁵ 

"Bilateral disease" may not be a uniform criterion. A small posterior midline tumor in the peripheral zone that extends to the right and left sides probably does not have the prognosis that one typically associates with a T2c tumor.^68,85  As well, the significance of right versus left designations in the prostatic apical tissue, where the distance between the right and left sides markedly shortens, remains to be determined. Of note, the lymphatic drainage of the prostate is not strictly unilateral in its distribution.⁸⁶  One study found no significant difference in 10 year survival rates between unilateral or bilateral T2 disease, both groups having a 10-year freedom- from-relapse rate of 74% and 72% respectively.⁸⁵  It seems probable that the tumor volume, rather than bilaterality per se, is the significant prognostic factor.^{4,20-22,45,46,51}  Whether multifocal bilateral disease is equivalent to a single large tumor that contiguously involves the right and left sides of the prostate gland needs to be studied further.^36,74  There is some evidence that predictive indices need only measure the largest carcinoma in a prostate gland that has multifocal prosatic adenocarcnioma.⁷⁸ 

T3: Local Extra-Prostatic Spread of Carcinoma
There appears to be no prognostic basis to stratify this group based on unilateral or bilateral extra-prostatic extension ^12,85 and this is reflected in the current TNM classification system. The amount of extra-prostatic carcinoma and whether or not this is associated with a tumor positive resection margin is probably of greater importance.^25,27  In one series of 196 patients, those with focal capsular penetration had an 82% progression-free survival at 8 years, whereas those with extensive capsular penetration had a 65% progression-free survival at 8 years.²⁸  This study high-lights the need to determine the clinical significance of a pathologically determined stage where the critical finding can only be detected on microscopy. Of interest, is the use of molecular techniques to detect the anatomic extent of disease. An enhanced reverse transcriptase-polymerase chain reaction for prostate specific antigen mRNA has been used to detect circulating PSA synthesizing cells in the peripheral circulation prior to radical prostatectomy. A positive assay correlated with extraprostatic disease at the time of surgery with a sensitivity of 72% and a specificity of 88%.⁴⁷ 

Invasion of the seminal vesicle tissue, has generally been found to significantly worsen the prognosis more than extra-capsular extension alone,^19,22,27,29  with a 5 year progression-free rate as low as 5% in men who have seminal vesicle invasion without lymph node metastases at the time of surgery.^13,19  There are two studies that did not find a signficant difference in the progression-free rate between irradiated, lymph node negative patients with seminal vesicle invasion versus those with extra-capsular spread without seminal vesicle invasion.^12,85  Patients with T3 disease may be further stratified by non-anatomic factors such as serum PSA levels.¹²  There is recent evidence to suggest the prognosis of patients with seminal vesicle positive, lymph node negative disease is not uniformly poor, and such patients can be stratified according to Gleason Score, resection margin status, vascular invasion, and pattern and extent of spread to the seminal vesicle.^16,19,58  In one study, the 5-year PSA progression-free rate of the patients with limited seminal vesicle involvement by carcinoma was 45.4% whereas those patients with extensive involvement of the seminal vesicles had a 4.2% survival rate at 4 years.¹⁶ 

T4: Extensive Local Extra-Prostatic Spread
Clinical T4 prostatic adenocarcinoma is a high-stage category intended to identify a tumor that has extensively infiltrated locally to involve adjacent extra-prostatic organs and structures, excluding the seminal vesicles. Patients with clinical T4 disesase are typically inoperable with a poor prognosis that is worse than the prognosis for patients with irradiation-treated T3 disease ⁸⁵ Following radiotherapy, up to 80% of patients with carcinoma that invades the levator muscles or the pelvic wall have a PSA relapse at two years, in contrast to patients with T3 disease who have a PSA relapse rate of up to 40% at two years.⁸⁵ 

The pathologist is faced with the issue of evaluating the bladder neck area of a radical prostatectomy specimen, where the surgeon has separated the prostate from the urinary bladder. The frequency of involvement of this region is low. One study found that 60 of 1123 (5%) patients treated with radical prostatectomy as monotherapy had involvment of this region by carcinoma ¹⁵ and another found 72 of 2,571 cases (2.8%) had such a finding.⁸³  Involvement of this bladder neck tissue does not appear to be an independent predictor of PSA recurrence and it has been suggested that this finding be reclassified as pT3 disease ¹⁵ . This concept has been reinforced in other studies that have found microscopic bladder neck involvement provides no independent information for predicting disease progression.^83,84  Bladder neck involvement, identified in the radical prosatectomy specimen, may carry a lower risk of progression than seminal vesicle involvement ⁸⁴ One study did find a higher risk of progression in those patients with tumor positive bladder neck resection margin, implying residual disease within the urinary bladder proper.⁵⁷  However, patients with microscopic bladder neck involvement, found in a radical prostatectomy specimen, do not appear to have an outcome as poor as the outcome for patients who have prostatic carcinoma involving the rectum. In the latter group, survival is usually less than one year.³¹ 

pT0: No Residual Carcinoma in the Radical Prostatectomy Specimen

Up to 3 to 4% of radical prostatecomy specimens will have minimal or no residual prostatic adenocarcinoma.¹⁷  This has been referred to as the vanishing cancer syndrome.^3,33  This occurs in the absence of previous TUPR or pre-operative hormone therapy ^17,33 and it is likely a result of our increased ability to detect prostatic carcinoma at an increasingly early, low-volume stage. If no carcinoma is found, the case is classified as pT0. In one series of 3,038 consecutive radical prostatecomies, 4 cases (.13%) had no residual carcinoma identified.¹⁷  In another seires of 6,843 radical prostatectomies, 38 cases (.56%) had no residual carcinoma.³  Given that the specimen has been totally submitted for histological examination, that the pre-operative diagnosis is confirmed and there is no misidentity of specimens, it is reasonable to assume that the cancer is very small, without resorting to exhaustive sectioning of the wax block material.³ 

METASTATIC DISEASE

N1: Regional Lymph Nodes Metastases
Lymph node metastases found at the time of radical prostatectomy are uncommon. The reported frequency ranges from 3% to 12.5%.^{6,10,27,55,75}  The frequency of finding pN1 disease rises with increasing extent of local disease.²  For many years, it has been generally accepted that the spread of prostatic carcinoma to the regional lymph nodes significantly worsens the prognosis.^6,7,32  However, more recent studies have found that patients with prostatic adenocarcinoma metastatic to the regional iliac and obturator lymph nodes form a heterogeneous group ^6,7 with a prognosis that is not uniformly poor. Different approaches to treatment, cohort size, and length of follow-up, among other variables, may contribute to wide-ranging survival statistics. Overall five year progression-free survival of up to 90% of N1 patients has been reported.⁷  In one study of 790 patients with lymph node metastases who were treated with radical prostatectomy and adjuvant hormonal therapy, a 10 year overall survival rate of 69% was achieved.⁷⁰  A recent study found that 37 of 832 radical prostatectomy patients (4.4%) had peri-prostatic and/or peri-seminal vesicle lymph nodes and 4 of 5 patients with metastases to these lymph nodes had disease progression, suggesting that metastases to these lymph nodes should be included as N1 disease.⁴⁹ 

The number of positive lymph nodes and the volume of metastatic carcinoma appears to have prognostic significance.^6,7,32,69,72  Cheng et al, in a study of 3463 consecutive patients who underwent radical prostatecomy and bilateral pelvic lymphadenectomy, found the risk of death from prostate carcinoma was lowest for patients with a single lymph node metastasis, intermediate for those with two positive lymph nodes and highest for those with three or more positive lymph nodes.⁶  Patients with a single lymph node metasases had a 5-year and 10-year cancer specific survival rate of 99% +/- 1% and 94% +/- 3%, respectively.⁶  Using an arbitraty size of </ = 5mm in greatest dimension to define micrometastases, Schmidt found that patients with micrometastases had a survival advantage compared to those with more extensive lymph node involvement, whereas Sgrignoli found no difference between the two groups in the risk of developing distant metastases.^69,71  Cheng et al found that lymph node cancer volume was the most significant nodal determinant of progression to distant metastisis in a study involving 269 men who were treated with radical retropubic prostatectomy, the majority of whom (94%) received post-operative androgen deprivation therapy.⁷  The five-year progression-free survival was 87% in patients with nodal cancer volume between .05cc to .19 cc and 78% for those with a nodal cancer volume > or = to 0.2cc.⁷ 

It appears that screening for occult lymph node metastases by immunohistochemical methods, or reverse transcription polymerase chain reaction methods, may yield small numbers of additional patients, ranging from <1% to 3%, with metastatic deposits.^34,55,63  The significance of isolated carcinoma cells discovered with molecular techniques within lymph nodes has yet to have a clearly defined role in the management of prostate cancer patients,³⁸  and such a finding does not constitute a micrometastases in the TNM classification.^41,42  There is some evidence that extra-nodal extension by metastatic prostatic carcinoma to the lymph nodes worsens the prognosis. Griebling et al found that of 42 of 60 patients (70%) with N1 disease had extranodel extension of the carcinoma into perinodal tissue.³⁵  The 5 year survival rate for these patients was 54.6%, compared to 71.4% of patients with histologically confined nodal metastases ³⁵ .

The method of lymph node sampling by the surgeon may influence staging results. There are conflicting results whether, extended lymph node dissections in patients with clinically localized prostate cancer identifies significantly greater numbers of patients with lymph node metastases ^2,10 Positive lymph nodes are most often found along the internal iliac artery and, in one study this was the only site of regional lymph node metastases in 17 of 88 patients (19%) with lymph node metastases.²  There may be a role for sentinel lymph node analysis in prostate carcinoma.⁷⁵ 

M1: Bone Marrow or Non-regional Lymph Node Metastatic Disease
Clinical evidence for distant metastases is typically derived from bone scans, coupled with serum PSA levels. Unfortunately up to 30% of patients with clinically localized prostate cancer and a negative bone scan eventually experience relapse with recurrent disease.⁷⁹  Patients with established bone metastases do poorly. In one study, 50 of 76 (66%) patients with metastases of prostate carcinoma to the bone died with a median survival time of 24.5 months.⁸⁰  There may be a role for molecular techniques to detect distant spread of disease before it is clinically manifest.^47,79  The use of reverse-transcriptase polymerase chain reaction assay for PSA , combined with immunohistochemistry for PSA, in the bone marrow of patients with apparently localized extra-prostatic spread of prostate cancer, has found 65% of patients with evidence of micrometastases.⁷⁹  The clinical significance of micrometastases detected in this manner requires further study.

The pattern of the bony metastatic deposits may be prognostically significant. In a study of fifty-one patients with bone metastases, there were two distinct patterns of metastatic lesions; those with a sequential appearance of osteoblastic metastases followed by osteolytic bone lesions, and those with simultaneous appearance of osteoblastic and osteolytic bone lesions. The former was found to be more hormone sensitive with longer remisssions whereas the latter was usually accompanied by the appearance of metastases in other organs.⁶² 

Patients with metastases to the supradiaphragmatic lymph nodes have a very poor prognosis. In one study, 18 of 26 patients with this disease died, with an average survival of 19.8 months. .⁸  Distant non-regional lymph node metastases are commonly accompanied by bone metastases. In a study of 205 patients with distant metastases, 17 (8.3%) had non-regional lymph node metastases and 10 of the 17 (59%) patients had concomitant bone metastases.³⁰ 

ADDITIONAL PROGNOSTIC FACTORS
Anatomic factors alone are not entirely predictive of clinical outcome. This is emphasized by one study of 117 patients where 8 of 64 (12.5%) patients with pT2 tumors developed lymph node metastases .⁷⁵  A full discussion of non-anatomic factors is beyond the scope of this discussion. To be useful, new prognostic factors must be significant (ie. rarely occur by chance alone), independent (ie. retains value when new prognostic factors are added), and clinically important (ie. influences patient management, treatment, and prognosis). There are a wide range of potentially useful non-anatomic prognostic factors, including oncogenes, tumor suppressor gene, karyotype, growth factors, hormonal factors, enzyme activities, proliferation and apoptotic markers, enzyme and secretory proteins, cytoskeletal proteins, stromal proteins, growth factors, receptors, and numerous genetic factors.^29,40  However, to date, it appears there is no prognostic marker superior to anatomic extent of disease, histologic grade, and serum PSA levels.⁴⁰ 

TNM CLASSIFICATION AND STAGING - PROSTATIC ADENOCARCINOMA

(Summary from UICC 6th edition TNM Manual, 2002) TX - Primary tumor cannot be assessed T0 - No evidence of primary carcinoma T1 - Carcinoma not palpable or visible T1a - </= 5% of resected tissue involved, incidental finding T1b - >/= 5% of resected tissue involved, incidental finding T1c - needle biopsy positive for carcinoma (usual biopsy indication - elevated serum PSA) T2 - Carcinoma Palpable/Visible, Confined to the prostate T2a - </= half of one lobe T2b - > half of one lobe involved, but not both lobes T2c - Both lobes involved by carcinoma T3 - Carcinoma extends through the prostatic capsule to involve extra-prostatic tissue T3 - aextra-prostatic spread, unilateral or bilateral T3 - bcarcinoma invades seminal vesicles, unilateral or bilateral T4 - Carcinoma invades adjacent structures: urinary bladder neck, external sphincter, rectum, levator muscles, pelvic wall N1 - Regional lymph nodes (pelvic) involved by metastatic carcinoma, unilateral or bilateral M1 - Distant metastases M1a - non-regional lymph nodes involved by metastases M1b - metastases to bone M1c - metastases to other sites

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