Eric C. Belanger

Interobserver Variability Between Expert Urologic Pathologists for Extraprostatic Extension and Surgical Margin Status in Radical Prostatectomy Specimens

Accurate Gleason score, pathologic stage, and surgical margin (SM) information is critical for the planning of post-radical prostatectomy management in patients with prostate cancer. Although interobserver variability for Gleason score among urologic pathologists has been well documented, such data for pathologic stage and SM assessment are limited. We report the first study to address interobserver variability in a group of expert pathologists concerning extraprostatic soft tissue (EPE) and SM interpretation for radical prostatectomy specimens. A panel of 3 urologic pathologists selected 6 groups of 10 slides designated as being positive, negative, or equivocal for either EPE or SM based on unanimous agreement. Twelve expert urologic pathologists, who were blinded to the panel diagnoses, reviewed 40× whole-slide scans and provided diagnoses for EPE and SM on each slide. On the basis of panel diagnoses, as the gold standard, specificity, sensitivity, and accuracy values were high for both EPE (87.5%, 95.0%, and 91.2%) and SM (97.5%, 83.3%, and 90.4%). Overall κ values for all 60 slides were 0.74 for SM and 0.63 for EPE. The κ values were higher for slides with definitive gold standard EPE (κ=0.81) and SM (κ=0.73) diagnoses when compared with the EPE (κ=0.29) and SM (κ=0.62) equivocal slides. This difference was markedly pronounced for EPE. Urologic pathologists show good to excellent agreement when evaluating EPE and SM. Interobserver variability for EPE and SM interpretation was principally related to the lack of a clearly definable prostatic capsule and crush/thermal artifact along the edge of the gland, respectively.

Postoperative Radiotherapy for Prostate Cancer: A Comparison of Four Consensus Guidelines and Dosimetric Evaluation of 3D-CRT Versus Tomotherapy IMRT

PURPOSE Despite the benefits of adjuvant radiotherapy after radical prostatectomy, approximately one-half of patients relapse. Four consensus guidelines have been published (European Organization for Research and Treatment of Cancer, Faculty of Radiation Oncology Genito-Urinary Group, Princess Margaret Hospital, Radiation Therapy Oncology Group) with the aim of standardizing the clinical target volume (CTV) delineation and improve outcomes. To date, no attempt has been made to compare these guidelines in terms of treatment volumes or organ at risk (OAR) irradiation. The extent to which the guideline-derived plans meet the dosimetric constraints of present trials or of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) trial is also unknown. Our study also explored the dosimetric benefits of intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS A total of 20 patients treated with postoperative RT were included. The three-dimensional conformal radiotherapy (3D-CRT) plans were applied to cover the guideline-generated planning target volumes (66 Gy in 33 fractions). Dose-volume histograms (DVHs) were analyzed for CTV/planning target volume coverage and to evaluate OAR irradiation. The OAR DVHs were compared with the constraints proposed in the QUANTEC and Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trials. 3D-CRT plans were compared with the tomotherapy plans for the Radiation Therapy Oncology Group planning target volume to evaluate the advantages of IMRT. RESULTS The CTV differed significantly between guidelines (p < 0.001). The European Organization for Research and Treatment of Cancer-CTVs were significantly smaller than the other CTVs (p < 0.001). Differences in prostate bed coverage superiorly accounted for the major volumetric differences between the guidelines. Using 3D-CRT, the DVHs rarely met the QUANTEC or RADICALS rectal constraints, independent of the guideline used. The RADICALS bladder constraints were met most often by the European Organization for Research and Treatment of Cancer consensus guideline (14 of 20). The tomotherapy IMRT plans resulted in significant OAR sparing compared with the 3D-CRT plans; however, the RADICALS and QUANTEC criteria were still missed in a large percentage of cases. CONCLUSION Treatment volumes using the current consensus guidelines differ significantly. For the four CTV guidelines, the rectal and bladder DVH constraints proposed in the QUANTEC and RADICALS trials are rarely met with 3D-CRT. IMRT results in significant OAR sparing; however, the RADICALS dose constraints are still missed for a large percentage of cases. The rectal and bladder constraints of RADICALS should be modified to avoid a reduction in the CTVs.

Oncocytic papillary renal cell carcinoma with solid architecture : Mimic of renal oncocytoma

Papillary renal cell carcinoma (PRCC) can display extensive areas of solid and non‐papillary architecture and extensive areas with oncocytic cytoplasm. Eleven oncocytic renal cell neoplasms (ORCN) with histopathological features posing a diagnostic problem between renal cell carcinoma (RCC) with oncocytic features and renal oncocytoma (RO) were identified. The neoplasms were well circumscribed or encapsulated tumors with solid and diffuse growth pattern. Very occasional papillae were seen in four and tumoral necrosis in two of 11. Six ORCN displayed a CD117+/progesterone receptor (PR)+ immunophenotype (feature shared by RO) and five tumors displayed a CD117–/PR– immunophenotype (feature shared by RCC). The CD117–/PR– ORCN also displayed α‐methylacyl‐coenzyme A racemase and RCC antigen reactivity as well as varying reactivity for cytokeratin 7, vimentin and CD10 (features of oncocytic PRCC). These five cases had tumor sizes ranging from 1 to 6 cm. Two patients in the latter group developed progression of the disease with metastases. In conclusion, oncocytic PRCC with solid architecture is a rare type of RCC. The carcinoma often poses differential diagnostic problems with RO and has similar immunohistochemical properties to the common type of PRCC. Cytogenetic and molecular studies have not been performed yet for this variant of RCC.

Renal cell carcinoma with mixed features of papillary and clear cell cytomorphology: a fluorescent in situ hybridization study

We performed fluorescent in situ hybridization (FISH) to investigate the numeric change of chromosomes 7, 17, and Y and loss of chromosome 3p in “papillary renal cell carcinomas (RCC) with extensive clear cell changes (CCC).” Consecutive cases of RCC over a 12-year period were reviewed to identify “papillary RCC with extensive CCC.” Immunostaining for cytokeratin 7 and alpha-methylacyl-CoA racemase (AMACR) and FISH for chromosomes 7, 17, Y, and 3p were applied. Of the total of 521 RCC retrieved, there were 49 RCC with papillary architecture and clear cell areas that could be divided into: Group 1 (12 cases), typical clear cell RCC with focal areas of papillary formation; Group 2 (28 cases), focal typical papillary RCC having papillary architecture with extensive CCC; and Group 3 (nine cases), RCC with an admixture of eosinophilic/clear cytoplasm and solid/papillary architecture. Group 1 showed negative immunoreactivity for CK7 and AMACR and absence of numeric chromosomal gain or loss of chromosomes 7/17 and Y. Groups 2 and 3 showed variable reactivity for CK7 and AMACR. Tumors in group 2 and five in group 3 showed trisomies of chromosomes 7 and/or 17 with or without loss of chromosome Y. Loss of small arm 3p was observed in groups 1 and 3 but not in group 2 tumors. In conclusion, papillary RCC may show phenotypical CCC mimicking clear cell RCC. In a small number of cases with mixed histopathological features, FISH is helpful in subtyping RCC.

Utility of cytokeratin 5/6, cytokeratin 20, and p16 in the diagnosis of reactive urothelial atypia and noninvasive component of urothelial neoplasia.

Background:The utility of cytokeratin (CK)5/6 in distinguishing reactive urothelial atypia (RA) from urothelial carcinoma in situ (CIS) and from noninvasive component of high-grade papillary urothelial carcinoma (PUC) is unknown. Design:Twenty RA with or without papillary hyperplasia and 90 noninvasive components of neoplastic urothelial lesions were submitted for immunostaining with CK5/6, CK20, and p16. Results:Diffuse and strong reactivity involving the full or nearly full thickness of urothelium was observed with CK5/6 in 90% of RA cases. CK20 and p16 were negative in 90% and 85% of the RA cases, respectively. For CIS and noninvasive components of high-grade PUC without squamous differentiation, there was no CK5/6 staining or reactivity in the basal layer only. CK20 and p16 showed strong positivity in full thickness of urothelium in 75% to 85% of cases. CIS with weak/focal or negative reactivity for p16 or CK20 exhibited moderate cytologic atypia. Low-grade PUC displayed variable reactivity for CK5/6, CK20, and p16. Urothelial lesions with squamoid or basaloid features showed positive reactivity for CK5/6. Urothelial lesions with glandular differentiation showed negative reactivity for CK5/6. Conclusions:Diffuse CK5/6 reactivity in RA and negative CK5/6 reactivity in CIS and PUC may be helpful in distinguishing between these 2 entities.

Sporadic clear cell renal cell carcinoma with diffuse cytokeratin 7 immunoreactivity

Aims: Clear cell renal cell carcinoma (CRCC) with diffuse immunoreactivity for CK7 is described. Methods: All cases of CRCC, measuring 20 mm or less in diameter over a period of 10 years, were examined. Areas of regenerative epithelial cell nests (REC) were also examined. Results: Fifteen specimens containing 29 nodules were diagnosed as CRCC due to the characteristic clear cytoplasm. Of these 29 nodules, 21 showed diffuse CK7 positivity while eight showed CK7 negativity. The CK7 positive CRCC measured less than 16 mm and contained varying proportions of tumour cells with chromophil cytoplasm. Architecturally, CK7 positive CRCC consisted of cysts and solid cell nests with tubulo‐acinar formations or papillary formations. Immunostaining for AMACR, CD10 and RCC showed negative or focal reactivity in the CK7 positive CRCC, frequently positive reactivity in CK7 negative CRCC and negative reactivity in REC which also displayed strong CK7 reactivity. The ten patients with 21 CK7 positive CRCC developed no metastatic disease over a follow up time that ranged from 1 to 10 years (mean of 3 years). Conclusions: CRCC characterised by diffuse CK7 positivity represents a distinct type of CRCC with characteristic histopathological and immunohistochemical features.

Perivascular epithelioid cell tumour (PEComa) of the soft tissue

Aims: PEComa is a rare tumour developing from perivascular epithelioid cells (PEC) and is characterised by positive immunoreactivity for HMB45. Since PEComas are tumours having both a spindle cell component and an epithelioid and giant cell component, as seen in many sarcomas, as well as having a wide distribution in various organs and soft tissue, we reviewed cases originally diagnosed as sarcomas of the soft tissue in our institution and screened them by immunostaining for HMB45. Methods: Consecutive soft tissue sarcomas (31 tumours) retrieved from the Surgical Pathology file at our institution for a period of 3 years were submitted for immunostaining for HMB45. Cases with positive HMB45 immunostaining were submitted for further immunostaining for MART1, CD68, S100 protein, cytokeratin AE1/3, EMA, vimentin, MSA and CD117. Results: Of 31 sarcomas, three tumours in the group of 11 malignant fibrous histiocytomas (MFH) and unclassified sarcomas showed positive immunoreactivity for HMB45 and MART1 in 1–25% of tumour cells. The three tumours were located in the lower extremities and measured 8, 11 and 12 cm in diameter. Patient gender male:female was 2:1 and ages were 46, 56 and 60 years. Microscopically, the tumours were composed of a variable proportion of spindled cells, multinucleated cells and epithelioid cells disposed in diffuse sheets or nests. Mitotic figures and necrosis were frequent. The immunoreactivity was diffuse for CD68, focal for AE3 and EMA, negative or focal for MSA and CD117, and negative for S100 and AE1. All three patients developed lymph node or distant metastases and died of the disease within 1–2 years. Conclusions: PEComa re‐screened from the group of high grade sarcomas without definite differentiation range from pleomorphic to monomorphic cytohistopathological features. Immunostaining for HMB45 of unclassified sarcomas is useful for the classification of these tumours. They occur preferentially in the lower extremities and have a high malignant potential when associated with large size, tumoural necrosis and high mitotic activity.

Postoperative Radiotherapy in Prostate Cancer: The Case of the Missing Target

PURPOSE Postoperative radiotherapy (XRT) increases survival in high-risk prostate cancer patients. Approximately 50% of patients on long-term follow-up relapse despite adjuvant XRT and the predominant site of failure remains local. Four consensus guidelines define postoperative clinical target volume (CTV) in prostate cancer. We explore the possibility that inadequate CTV coverage is an important cause of local failure. This study evaluates the utility of preoperative magnetic resonance imaging (MRI) in defining prostate bed CTV. METHODS AND MATERIALS Twenty prostate cancer patients treated with postoperative XRT who also had preoperative staging MRI were included. The four guidelines were applied and the CTVs were expanded to create planning target volumes (PTVs). Preoperative MRIs were fused with postoperative planning CT scans. MRI-based prostate and gross visible tumors were contoured. Three-dimensional (3D) conformal four- and six-field XRT plans were developed and dose-volume histograms analyzed. Subtraction analysis was conducted to assess the adequacy of prostate/gross tumor coverage. RESULTS Gross tumor was visible in 18 cases. In all 20 cases, the consensus CTVs did not fully cover the MRI-defined prostate. On average, 35% of the prostate volume and 32% of the gross tumor volume were missed using six-field 3D treatment plans. The entire MRI-defined gross tumor volume was completely covered in only two cases (six-field plans). The expanded PTVs did not cover the entire prostate bed in 50% of cases. Prostate base and mid-zones were the predominant site of inadequate coverage. CONCLUSIONS Current postoperative CTV guidelines do not adequately cover the prostate bed and/or gross tumor based on preoperative MRI imaging. Additionally, expanded PTVs do not fully cover the prostate bed in 50% of cases. Inadequate CTV definition is likely a major contributing factor for the high risk of relapse despite adjuvant XRT. Preoperative imaging may lead to more accurate CTV definition, which should result in further improvements in survival for patients with high-risk prostate cancer.

Epithelioid angiomyolipoma of the kidney mimicking renal sarcoma

1. Banerjee SS, Verma S, Shanks JH. Morphologic variants of plasma cell tumours. Histopathology 2004; 44; 2–8. 2. Igel TC, Engen DE, Banks PM, Keeney GI. Renal plasmacytoma: Mayo Clinic experience and review of the literature. Urology 1991; 37; 385–389. 3. Aoki T, Okita H, Kayano H et al. Anaplastic plasmacytoma with malignant pleural effusion lacking evidence of monoclonal gammopathy. Virchows Arch. 2002; 441; 154–158. 4. Strojan P, Soba E, Lamovec J, Munda A. Extramedullary plasmacytoma: clinical and histopathologic study. Int. J. Radiat. Oncol. Biol. Phys. 2002; 53; 692–701.

Management of small cell carcinoma of the bladder: Consensus guidelines from the Canadian Association of Genitourinary Medical Oncologists (CAGMO).

Small cell carcinomas (SCC) most commonly arise from the lung.1 These tumours are aggressive, present with early metastasis and are associated with a poorer prognosis compared to non-small cell lung cancer.2,3 Extra-pulmonary SCC was first described by Duguid and Kennedy in 19304 and subsequently has been reported in the gastrointestinal tract,5 head and neck6 and genitourinary (GU) system.7 SCC of the GU system (SCCGU) are uncommon, but can occur in the kidneys,8 renal pelvis,9 ureter,10 bladder,7 urachus,11 urethra12 and prostate.13 Although rare, these cancers are not insignificant. SCC accounts for 0.5% to 0.7% of all bladder cancers diagnosed.14,15 SCCGU also behaves more aggressively than typical GU histological counterparts.16 There is little medical literature to guide the optimal management of SCCGU malignancies and therefore treatment paradigms have by default mirrored those of the more common small cell carcinoma of the lung. Given the rarity of SCCGU tract and the lack of good clinical guidelines, it was clear that a guideline to help Canadian physicians and surgeons manage these patients with SCCGU was needed. This document achieves that goal for small cell carcinoma of the bladder (SCCB).