Updated Protocol for the Examination of Specimens From Patients With Carcinomas of the Prostate Gland

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol based on the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.This protocol applies only to carcinomas of the prostate gland. The Histologic Classification of Prostate Carcinoma is recommended as shown below.1 However, this protocol does not preclude the use of other systems of classification or histologic types. Mixtures of different histologic types should be indicated.Histologic Classification of Carcinoma of the ProstateAdenocarcinoma (conventional, not otherwise specified)Special variants of adenocarcinoma and other carcinomasProstatic duct adenocarcinomaMucinous (colloid) adenocarcinomaSignet ring cell carcinomaAdenosquamous carcinomaSquamous cell carcinomaBasaloid and adenoid cystic carcinomaTransitional cell carcinomaSmall cell carcinomaSarcomatoid carcinomaLymphoepithelioma-like carcinomaUndifferentiated carcinoma, not otherwise specifiedThe Gleason grading system is recommended for use in all prostatic cancer specimens.2–6 The Gleason score is the sum of the primary (most predominant) Gleason grade and the secondary (second most predominant) Gleason grade. Where no secondary Gleason grade exists, the primary Gleason grade is doubled to arrive at a Gleason score. The primary and secondary grades should be reported in parentheses after the Gleason score, that is, Gleason score 7(3,4) or 7(3+4). In needle biopsy specimens in which more than 2 patterns are present and the worst grade is neither the predominant nor the secondary grade, the predominant and the highest grade should be chosen to arrive at a score (eg, 60% grade 3, 30% grade 2, 10% grade 4 is scored as 3 + 4 = 7). When multiple needle biopsy specimens are submitted and they have differing Gleason scores, an overall (composite) Gleason score for the case should be clearly reported in a note.In radical prostatectomy specimens in which more than 1 separate tumor is identified, the Gleason scores of the individual tumors may be reported separately, or at the very least the Gleason score of the most significant lesion should be recorded. For instance, if there is a large Gleason score 5 transition zone cancer and a separate smaller Gleason score 7 peripheral zone cancer, both scores or at least the latter score should be reported rather than the scores being averaged.Another grading system may be used according to institutional preference (eg, World Health Organization, M. D. Anderson), but the Gleason score must be included to facilitate comparison of data.Gleason Grades (Patterns)Grade 1 Single, separate, closely packed aciniGrade 2 Single acini, more loosely arranged, less uniformGrade 3 Single acini of variable size, and separation, cribriform and papillary patternsGrade 4 Irregular masses of acini and fused epithelium, can show clear cellsGrade 5 Anaplastic carcinomaGleason scores may be grouped into differentiation (prognostic) categories:2–4 Well differentiated5–6 Moderately well differentiated7 Moderately poorly differentiated8–10 Poorly differentiatedor2–6 Well differentiated7 Moderately differentiated8–10 Poorly differentiatedThere are many methods of estimating the amount of tumor in prostatic specimens.7–16 In core biopsies, the absolute number or percentage of cores involved, the linear extent of involvement in millimeters, and the proportion (percent) of surface area of prostatic tissue involved may be used. In transurethral resectates, the proportion (percent) of tissue involved by carcinoma and the number of positive chips (foci) may be used. In subtotal and radical prostatectomy specimens, the percentage of tissue involved by tumor can also be “eyeballed.” Additionally, in these latter specimens it may be possible to measure a dominant tumor nodule in at least 2 dimensions and to indicate the number of blocks involved by tumor over the total number of prostatic blocks submitted.For the purpose of this protocol, it is recommended that at the very least, the proportion (percent) of prostatic tissue involved by tumor be included for all specimens.Occasionally in needle biopsies, periprostatic fat is present and involved by tumor.7–9 This observation should be noted since it indicates that the tumor is at least stage pT3a. Furthermore, if seminal vesicle tissue is present (either unintentionally or intentionally as in a directed biopsy) and is involved by tumor, this should be reported since it indicates that the tumor is at least stage pT3b. Seminal vesicle invasion is defined by involvement of the muscular wall.7–9,17 At times, especially in needle biopsy specimens, it is difficult to distinguish between seminal vesicle and ejaculatory duct–type tissue. It is important not to overinterpret ejaculatory duct as seminal vesicle–type tissue. Ejaculatory duct epithelium is generally surrounded by loose fibrous connective tissue with abundant blood vessels, whereas the seminal vesicle epithelium is surrounded by smooth muscle bundles constituting its wall.Perineural invasion on core needle biopsies has been associated with a high risk of extraprostatic extension in some studies, although the exact prognostic significance remains to be determined.18–21 Perineural invasion has also been found to be an independent risk factor for predicting an adverse outcome in patients treated with external beam radiation.18 The value of perineural invasion as an independent prognostic factor, however, has been questioned in a multivariate analysis.22The diagnostic term prostatic intraepithelial neoplasia (PIN), unless qualified, refers to high-grade PIN.23 Low-grade PIN is generally not reported. The presence of PIN should be reported in all biopsy specimens, including those with carcinoma.9 High-grade PIN in a biopsy without evidence of carcinoma is a significant risk factor for the presence of carcinoma on subsequent biopsies.24,25 The reporting of high-grade PIN in prostatectomy specimens is optional.Specimens weighing less than 12 g should be submitted in their entirety, usually in 6 to 8 cassettes.26,27 For specimens greater than 12 g, the initial 12 g are submitted (6–8 cassettes), and 1 cassette for every additional 5 g may be submitted.In general, random chips are submitted; however, if some chips are firmer or have a yellow or orange-yellow appearance, they should be preferentially submitted.In radical prostatectomy specimens with no grossly visible tumor, the specimen may be submitted in its entirety or partially sampled in a systematic fashion. One method of partial sampling involves submitting the entire apical segment and bladder neck along with alternating posterior transverse sections. Two or three random blocks demonstrating the anterior surface are also submitted along with samples of each seminal vesicle, including their juncture with prostate proper.Extraprostatic extension is the preferred term for the presence of tumor beyond the confines of the prostate gland.8,28 Tumor abutting on or admixed with fat constitutes extraprostatic extension. Extraprostatic extension may also be reported when tumor involves perineural spaces in the neurovascular bundles, even in the absence of periprostatic fat involvement. In certain locations, such as the anterior prostate and bladder neck regions, there is a paucity of fat, and in these locations extraprostatic extension is determined when the tumor extends beyond the confines of the normal glandular prostate. Sometimes there is a distinct bulging tumor nodule that may be associated with a desmoplastic stromal reaction.The entire surface of the prostate should be inked to evaluate the surgical margins.29–36 Usually, surgical margins should be designated as “negative” if tumor is not present at the inked margin and as “positive” if tumor cells touch the ink at the margin. Positive surgical margins should not be interpreted as extraprostatic extension. If the surgical margin is positive, the pathologist should state this explicitly, although this finding is not relied on for pathologic staging. The specific locations of the positive margins should be documented, and there should be some indication (eg, number of positive blocks, linear extent in millimeters) of the extent of margin positivity.The apex should be closely examined because of its unusual susceptibility to positive margins.29–31 At the apex, tumor admixed with skeletal muscle elements does not constitute extraprostatic extension. The apical and bladder neck surgical margins should be sectioned entirely, preferably with a perpendicular orientation. Microscopic involvement of bladder neck muscle fibers in radical prostatectomy specimens should not be equated with a pT4 designation. The latter generally requires gross involvement of the bladder neck.The protocol recommends the use of the TNM Staging System for carcinoma of the prostate of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) as shown below.37,38By AJCC/UICC convention, the designation “T” of the TNM classification refers exclusively to the first resection of a primary tumor. The prefix symbol “p” refers to the pathologic classification of the TNM (pTNM), as opposed to the clinical classification. Pathologic classification is based on gross and microscopic examination. Therefore, 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.The absence or presence of residual tumor following preoperative, nonsurgical therapy (eg, chemotherapy and/or radiation treatment) may be described by the symbol “R” and classified as follows:RX Residual tumor cannot be assessedR0 No residual tumorR1 Microscopic residual tumorR2 Macroscopic residual tumorIf residual tumor is present, its extent may be documented by the TNM classification preceded by the symbol “y” (eg, ypT1).Local recurrence following a previous resection should be classified as listed above with the prefix “r” (eg, rpT1).Primary Tumor, Clinical (cT)TX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Clinically inapparent tumor not palpable or visible by imaging T1a Tumor incidental histologic finding in 5% or less of tissue resected T1b Tumor incidental histologic finding in more than 5% of tissue resected T1c Tumor identified by needle biopsy (eg, because of elevated prostate-specific antigen)T2 Tumor confined within the prostate* T2a Tumor involves one lobe T2b Tumor involves both lobesT3 Tumor extends through the prostatic capsule† T3a Extracapsular extension (unilateral or bilateral) T3b Tumor invades the seminal vesicle(s)T4 Tumor is fixed or invades adjacent structures other than the seminal vesicles, bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall* Tumor found in one or both lobes by needle biopsy, but that is not palpable or visible by imaging, is classified as T1c.† Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2. Tumor extension into periprostatic soft tissue, as opposed to organ-confined cancer (T2), is classified as T3.Primary Tumor, Pathologic (pT)pT2* Organ confined pT2a Unilateral pT2b BilateralpT3 Extraprostatic extension pT3a Extraprostatic extension pT3b Seminal vesicle extensionpT4† Invasion of bladder, rectum* There is no pathologic T1 category.† Invasion of bladder indicates direct spread into the wall of the urinary bladder. The basal prostatic stroma blends imperceptibly into the bladder neck musculature, and in most instances involvement of the bladder neck margin in a radical prostatectomy does not indicate that the tumor is pT4.Regional Lymph Nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in regional lymph node or nodesDistant Metastasis* (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis M1a Nonregional lymph node(s) M1b Bone(s) M1c Other site(s)* When more than 1 site of metastasis is present, the most advanced category (pM1c) is used.

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