A UK-based investigation of inter- and intra-observer reproducibility of Gleason grading of prostatic biopsies.

AIMS: The frequency of prostatic core biopsies to detect cancer has been increasing with more widespread prostate specific antigen (PSA) testing. Gleason score has important implications for patient management but morphological reproducibility data for British practice are limited. Using literature-based criteria nine uropathologists took part in a reproducibility study. METHODS: Each of the nine participants submitted slides from consecutive cases of biopsy-diagnosed cancer assigned to the Gleason score groups 2-4, 5-6, 7 and 8-10 in the original report. A random selection of slides was taken within each group and examined by all pathologists, who were blind to the original score. Over six circulations, new slides were mixed with previously read slides, resulting in a total of 47 of 81 slides being read more than once. RESULTS: For the first readings of the 81 slides, the agreement with the consensus score was 78% and overall interobserver agreement was kappa 0.54 for Gleason score groups 2-4, 5-6, 7, 8-10. Kappa values for each category were 0.33, 0.56, 0.44 and 0.68, respectively. For the 47 slides read more than once, intra-observer agreement was 77%, kappa 0.66. The study identified problems in core biopsy interpretation of Gleason score at levels 2-4 and 7. Patterns illustrated by Gleason as 2 tended to be categorized as 3 because of the variable acinar size and unassessable lesional margin. In slides with consensus Gleason score 7, 13% of readings were scored 6 and in slides with consensus 6, 18% of readings were scored 7. CONCLUSIONS: Recommendations include the need to increase objectivity of the Gleason criteria but limits of descriptive morphology may have to be accepted.

A study of Gleason score interpretation in different groups of UK pathologists; techniques for improving reproducibility.

AIMS: To test the effectiveness of a teaching resource (a decision tree with diagnostic criteria based on published literature) in improving the proficiency of Gleason grading of prostatic cancer by general pathologists. METHODS: A decision tree with diagnostic criteria was developed by a panel of urological pathologists during a reproducibility study. Twenty-four general histopathologists tested this teaching resource. Twenty slides were selected to include a range of Gleason score groups 2-4, 5-6, 7 and 8-10. Interobserver agreement was studied before and after a presentation of the decision tree and criteria. The results were compared with those of the panel of urological pathologists. RESULTS: Before the teaching session, 83% of readings agreed within +/- 1 of the panel's consensus scores. Interobserver agreement was low (kappa = 0.33) compared with that for the panel (kappa = 0.62). After the presentation, 90% of readings agreed within +/- 1 of the panel's consensus scores and interobserver agreement amongst the pathologists increased to kappa = 0.41. Most improvement in agreement was seen for the Gleason score group 5-6. CONCLUSIONS: The lower level of agreement among general pathologists highlights the need to improve observer reproducibility. Improvement associated with a single training session is likely to be limited. Additional strategies include external quality assurance and second opinion within cancer networks.

Allelic imbalance and biochemical outcome after radical prostatectomy.

OBJECTIVE: To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment. PATIENTS AND METHODS: Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone radical prostatectomy. One group comprised men who developed biochemical recurrence within 2 years of surgery and one group were prostate-specific antigen (PSA) free for at least 3 years. Men were matched for Gleason grade, preoperative PSA and pathological stage. Analysis was performed by genotyping. RESULTS: Allelic imbalance was analysed using 30 markers, and was seen in at least one marker in 57 (92%) of the cases. Deletion at marker D10S211 (10p12.1) was significantly more common in the relapse group than the non-relapse group (35 vs 5%, P=0.03). CONCLUSIONS: This study demonstrates significant association between AI on chromosome 10 and biochemical progression after radical prostatectomy.

The feasibility and results of a population-based approach to evaluating prostate-specific antigen screening for prostate cancer in men with a raised familial risk.

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age < or =65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45-69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were > or =4 ng ml(-1) and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied.

Handling and reporting of biopsy and surgical specimens of testicular cancer.

This paper is the result of a meeting of the European Association of Pathologists, Uropathology Division in Florence 2003. The aims of this meeting were to establish: guidelines for specimen handling by urologists and minimum requirements for data accompanying testicular specimens submitted to pathologists; a consensus on techniques for processing specimens by pathologists; the essential information required from pathology reports; areas where our standard practice is traditional rather than evidence based and where further studies are required. The general aims of histopathology are to give or confirm a diagnosis; assess established prognostic markers; identify changes associated with treatment; provide information for audit (i.e. imaging, urology and pathology) and maintain a permanent record (slides/blocks).

A large prostate at radical retropubic prostatectomy does not adversely affect cancer control, continence or potency rates.

OBJECTIVES: To determine the effect of a large prostate at radical retropubic prostatectomy (RRP) on the pathological outcome, biochemical recurrence rates, potency and continence. PATIENTS AND METHODS: From a database of 440 patients treated with RRP, retrospective information was obtained on prostate weights, patient and tumour characteristics, and follow-up. Potency and continence after RRP was obtained using a self-reported validated questionnaire. Patients with prostates of > 75 or < or = 75 g were compared. RESULTS: The median (range) prostate size was 87 (76-182) and 42 (4.1-75) g in the two groups. The response rate to the questionnaire was 78% (344 men). Patients with prostates of > 75 g were older, with a median (range) age of 65 (51-74) years, than the other group, at 61 (40-76) years (P = 0.01), and had higher initial prostate-specific antigen (PSA) levels, at 9.6 (3.4-37.8) and 7.6 (0.1-30.0) ng/mL, respectively (P = 0.001). Tumours within larger prostates were of a lower stage (P = 0.035), lower Gleason grade (median 6 and 7, P = 0.015), of smaller volume (median 1.0, 0.1-12.4; and 1.5, 0.1-21.1 mL; P = 0.04) and more often 'clinically insignificant' (23% and 6%, P = 0.001). There was no difference in the number or distribution of positive surgical margins. For a limited median follow-up of 20-25 months, patients with prostates of > 75 g were less likely to have biochemical recurrence (5% vs 24%, P < 0.001). Potency and continence rates were similar between the groups. CONCLUSIONS: Prostate size at RRP does not affect the risk of impotence or incontinence afterward. A prostate of > 75 g is associated with a lower likelihood of PSA-relapse, potentially as a result of lead-time bias. While an enlarged prostate may contraindicate other potentially curative cancer treatments, the outcomes of RRP appear to be unaffected.

Incidental findings in pelvic lymph nodes at radical prostatectomy.

AIMS: To assess the frequency and cause of incidental (non-metastatic) lymph node pathology discovered before or at radical prostatectomy. METHODS: Eight hundred and fifty four consecutive lymphadenectomies received between 1988 and 2001 were reviewed. All had been processed and stained routinely. Additional techniques, indicated by morphology, were then performed. RESULTS: Incidental pathology was found in 15 cases: florid sinus histiocytosis following prosthetic joint replacement (eight), non-caseating granulomas (three), small lymphocytic cell lymphoma (two), follicular lymphoma (one), and foreign body reaction (one). Incidental pathology was present in 1.8% of 854 patients who underwent pelvic lymphadenectomy during radical prostatectomy. CONCLUSION: Awareness of possible non-metastatic lymph node pathology aids histological diagnosis and may be clinically relevant.

Screening for prostatic cancer and its evolution within Britain.

The arguments for and against screening for prostatic cancer are frequently discussed (Albertsen PC. Screening for prostate cancer is neither appropriate nor cost-effective. Urol Clin North Am 1996; 23: 521-530; Schroder FH, Alexander FE, Bangma CH, Hugosson J, Smith DS. Screening and early detection of prostate cancer. Prostate 2000; 44: 255-263). In contrast, this paper outlines how screening became possible, why the decision was made not to initiate a national screening programme in Britain, the other pathways being pursued, and the current problems, in particular the issue of histopathology workload.

Anterior prostate cancer: is it more difficult to diagnose?

UNLABELLED: OBJECTIVE; To determine whether anterior prostatic tumours are adequately sampled using the Stamey sextant protocol, as a fifth of prostate cancers are anterior in distribution at radical prostatectomy. MATERIALS AND METHODS: All tumours (62) with an anterior distribution (>or=75% of the tumour anterior to the urethra) on radical prostatectomy whole-mounts, and in which the number and results of the sextant biopsies were available, were extracted from a prostate cancer database. Sixty-one posterior tumours (>or=75% of the malignant tissue posterior to the urethra) and their corresponding sextant biopsies were also retrieved for comparison. The number of biopsy sessions, the number of cores involved and the summated tumour length were recorded, together with the prostate gland weight, the tumour volume and the site of >or=75% of tumour in the superior-inferior axis. RESULTS: Anterior tumours required significantly more biopsy sessions to diagnose prostate cancer than posterior neoplasms (anterior, one set 47; > one set 15; posterior, one set 57; > one set, four, P=0.007). Anterior tumours had fewer cores with tumour involvement and less summated tumour length than had posterior cancers. The mean (sd) number of positive cores was; anterior 1.8 (1.01), posterior 2.50 (1.30) (P=0.001); the summated tumour length was; anterior 5.05 (4.10) mm, posterior 9.25 (7.80) mm (P<0.001). There was no significant difference in gland weight (mean anterior 43.8 g; posterior 48.3 g, P=0.3) or tumour volume (mean anterior 1.85 mL; posterior 1.49 mL, P=0.11) between the groups. There was no significant difference between the incidence of anterior and posterior neoplasms with respect to their position in the superior-inferior axis (P=0.96). CONCLUSIONS: Anterior prostate tumours account for 21% of all prostate cancers. They more often require multiple sets of sextant biopsies for diagnosis, and yield smaller areas of cancer on core biopsies than do posterior tumours in glands of similar weight and tumour volume. If prostate cancer is suspected clinically but biopsies are negative, targeting the anterior gland at subsequent prostatic biopsy should be considered.

The role of the histopathologist in the management of testicular germ cell tumour in adults.

In the last 20--30 years the availability of effective chemotherapy and more accurate clinical staging has greatly improved the prognosis for patients with testicular germ cell tumours. Initially, such treatment appeared to diminish the role of histopathology to the distinction between seminoma and nonseminomatous germ cell tumour (NSGCT) in the primary specimen. However, histopathology has evolved as a prognostic tool indicating the risk of relapse in various defined clinical contexts thereby facilitating therapeutic decisions. The clinical emphasis has been on quality of life and reduction of therapy both in terms of the number of patients treated and the number of chemotherapy courses given to each patient. The treatment of adult testicular germ cell tumours may differ between countries but protocols are established. Therefore it is appropriate to discuss the role of histopathology during this era of relative therapeutic stability.

Prognostic markers in clinically localised prostate cancer.

The prognostic value of immunohistochemical staining of P53, BCL-2, p27kip1, PSA, AR and MIB-1 was compared with that of established prognostic variables (Gleason score, surgical margins, tumour volume) following radical prostatectomy. Five groups were selected: negative margins with stable serum PSA (n=11), negative margins with rising serum PSA (n=7), positive margins with stable serum PSA (n=7), positive margins with rising serum PSA (6) and patients with micrometastatic disease diagnosed in lymph nodes removed during radical prostatectomy (n=8). Gleason score and tumour volume were of prognostic significance and immunohistochemical staining for MIB-1 and BCL-2 showed added independent prognostic significance in multivariate analysis.

Accuracy and cost of intraoperative lymph node frozen sections at radical prostatectomy.

AIM: To assess the value of intraoperative diagnostic examination of frozen sections of lymph nodes removed during radical prostatectomy. METHODS: Pelvic lymph nodes from patients with prostatic carcinoma were obtained (1) as frozen sections during radical prostatectomy, to exclude patients from non-curative surgery, and (2) as paraffin sections postoperatively from lymphadenectomy performed at radical prostatectomy, to stage the tumour and assess need for adjuvant treatment. Findings from the two approaches were used to assess the accuracy and cost of frozen section diagnosis, and to judge the results of omitting intraoperative diagnosis. RESULTS: In 82 patients frozen section revealed metastasis in six (7.3%), and metastases were found in a further four (4.9%) on paraffin sections (false negatives). Of the 195 patients undergoing staging lymphadenectomy (without frozen section), metastatic cancer was seen in nine cases (4.6%). The frozen section cost of metastatic cancer detection per patient was calculated as 7516 Pounds (550 Pounds x 82/6), with an associated false negative rate of 33%. CONCLUSIONS: Frozen section diagnosis of metastatic carcinoma in pelvic lymph nodes before radical prostatectomy has a high false negative rate and is costly. It may not be justified with the observed low incidence of lymph node metastasis.

Clinical aspects associated with Sertoli-cell-only histology.

OBJECTIVE: To assess the clinical features found in infertile men in whom the histological diagnosis of Sertoli-cell-only (SCO) was made on testicular biopsy. PATIENTS AND METHODS: A retrospective review was carried out of the seminal fluid analysis, testis size and follicle-stimulating hormone (FSH) levels of 72 men who had bilateral testicular biopsies due to infertility when one (30) or both (42) of bilateral testicular biopsies showed tubules containing only Sertoli cells. In a subgroup of 15 men, the biopsies were re-examined to correlate the morphological features with the plasma FSH level. RESULTS: When both biopsies showed bilateral SCO the patient had azoospermia (86%) or oligozoospermia (14%); the testicular size was normal in 36% and the FSH level was normal (43%), raised (21%) or grossly elevated (more than twice normal, 36%). When one biopsy showed SCO, the opposite testis showed appearances which varied from grossly impaired spermatogenesis to almost normal spermatogenesis. The clinical findings were also very variable. CONCLUSIONS: The clinical features associated with the histological diagnosis of SCO are extremely variable. Biopsy evidence of bilateral SCO cannot be relied upon to indicate a total absence of spermatogenesis in the testes.

Postchemotherapy residual masses in germ cell tumor patients: content, clinical features, and prognosis. Medical Research Council Testicular Tumour Working Party.

BACKGROUND: In a retrospective study that included a detailed histopathologic review, the clinicopathologic features of patients with germ cell tumors (GCT) and resectable residual masses after chemotherapy were assessed. METHODS: Histologic material from 153 patients was available for review. Recorded details included primary histologic diagnosis, location, size and number of metastases, marker levels before and after chemotherapy, and completeness of surgical excision. A median of seven histologic sections per resection were reviewed by two pathologists independently (and together when disagreement occurred). In each case, details were recorded regarding fibrosis, necrosis, hemorrhage, embryonal carcinoma (undifferentiated teratoma), yolk sac tumor, choriocarcinoma (trophoblastic tumor), differentiated teratoma (mature and immature), dysplasia in somatic tissues, and non- germ cell tumor (GCT) malignancies. The percentage of the sample that each of these components comprised was also estimated. RESULTS: The median postchemotherapy follow-up time was 7 years, and 38 of 153 patients (25%) experienced disease progression. In a multivariate analysis, incomplete resection of all residual masses (in 38 patients) and the presence of malignant elements (in 23 patients) were independent risk factors for progression. In the subset of patients in whom all masses were completely resected, the presence of embryonal carcinoma (undifferentiated teratoma) was the single most significant risk factor for progression. Seven percent of patients had this factor, which was associated with a 2-year progression free survival rate of 12.5%, compared with 88.0% where this component was absent. CONCLUSIONS: Progression free survival can be predicted well by the completeness of excision of residual masses and the presence of malignant germ cell elements. The latter confers a relatively poor prognosis even if all of these elements are completely resected.

Intratubular germ cell neoplasia of the contralateral testis in testicular cancer: defining a high risk group.

PURPOSE: We define a group of testis cancer patients who are at high risk for carcinoma in situ of the contralateral testis and, therefore, a second germ cell tumor. MATERIALS AND METHODS: The histology was reviewed in 186 testis cancer patients who underwent contralateral testicular biopsy either because of a history of testicular maldescent or an atrophic contralateral testis (defined as a volume of 12 ml. or less). Testicular volume, semen analysis, serum gonadotropin levels, serum testosterone and estradiol levels were assessed in the majority of patients. RESULTS: Univariate analyses identified contralateral testicular atrophy, low sperm density, young age at presentation and low Johnsen score as factors associated with increased risk of a positive biopsy. A history of maldescent in the absence of atrophy was associated with carcinoma in situ prevalence of only 4%. Multivariate analysis identified only testicular atrophy and age at presentation as independent determinants of a positive biopsy. Testis cancer patients with a small contralateral testis had a 20% and those presenting at age 30 years or younger had a 34% prevalence, respectively, of carcinoma in situ on contralateral testis biopsy (95% confidence interval 20 and 46%, respectively). CONCLUSIONS: Testis cancer patients with an atrophic contralateral testis who present before the age of 31 years are at high risk for carcinoma in situ of the contralateral testis and, therefore, a second germ cell tumor. It is estimated that this group comprises 6% of all testis cancer patients. We predict that a policy of performing contralateral testicular biopsy will produce positive results for carcinoma in situ in a third of these patients and will detect contralateral carcinoma in situ in approximately 40% of all testis cancer patients.

Histological changes associated with long-term urethral stents.

OBJECTIVE: To assess the histological changes found in patients with long-term external sphincter, prostatic and urethral stents. PATIENTS AND METHODS: Eighteen patients with long-term stents (mean time since insertion 3.5 years) were investigated. Three had external sphincter stents for detrusor-sphincter dyssynergia secondary to spinal injury, eight had prostatic stents for obstruction secondary to benign prostatic hyperplasia and seven had urethral stents for recurrent strictures. Nine stents were occluded at investigation, of which seven were entirely removed. The mucosae overlying the remaining two were biopsied, as were mucosae over the nine patent stents, at urethroscopy. RESULTS: The changes observed included polypoid hyperplasia (11 of 18 patients) between and around the stent mesh wires, nonkeratinizing squamous metaplasia (two) or hyperkeratotic squamous metaplasia (seven), chronic inflammation (15) with prominent plasma cell infiltrates (11), variable foreign-body granuloma (two) and microabscess formation (five), usually associated with clefts formed around the stent wires (three of five). CONCLUSION: Stents become incorporated into the urethral wall by a process of polypoid hyperplasia through the stent mesh, with at least focal covering of the stent in most cases, and with variable inflammatory infiltrates, most of which are rich in plasma cells. The urothelial and connective tissue proliferation resulted in obstruction of the stent lumen in nine of the patients studied. Further long-term study is necessary to exclude the development of carcinoma in patients with keratinizing squamous metaplasia, although no malignancy was seen in this study.