|Year : 2013 | Volume
| Issue : 3 | Page : 170-174
Diagnostic dilemma in histopathology report following robot assisted laparoscopic prostatectomy: Tumour 'hide and seek'
TD Javali1, PM Dogra1, NP Gupta1, P Singh1, P Chatterjee2, AK Dinda2
1 Department of Urology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||23-Sep-2013|
P M Dogra
Department of Urology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Introduction: Widespread PSA (prostate specific antigen) screening has resulted in stage migration of prostate cancer. Smaller tumor volumes are being detected in radical prostatectomy specimens. This has coincided with increasing reports about the 'vanishing cancer phenomenon.' Aims: To analyse the cases of robot assisted laparoscopic prostatectomy (RALP) at our institute in which the pre operative prostate biopsy was positive for adenocarcinoma but no tumor could be identified in the final histopathology, and to review the literature for possible reasons for such a phenomenon. Materials and Methods: Nine patients were identified out of a total of 184 cases of RALP in which the final histopathology did not correlate with the initial biopsy report. The initial biopsy slides as well as the final histopathology slides were reviewed by a second pathologist. The specimens were processed in entirety and additional sections were taken until no tissue was left. Results: Two patients had cancer diagnosed on TURP (transurethral resection of prostate) chips, while the remaining patients had undergone TRUS biopsy for elevated PSA. The final histopathological diagnosis was benign prostatic hyperplasia in two patients, chronic prostatitis in four patients, and acute florid prostatitis in one patient, granulomatous prostatitis with glandulostromal hyperplasia in one patient and TCC (transitional cell carcinoma) of prostate in one patient. Conclusion: Most cases of pT0 are due to inability of routine histopathological analysis to identify minute tumor focus. Urologists need to be aware of this in view of the potential medico legal implications.
Keywords: Immunostaining, prostate cancer mimickers, vanishing cancer phenomenon
|How to cite this article:|
Javali T D, Dogra P M, Gupta N P, Singh P, Chatterjee P, Dinda A K. Diagnostic dilemma in histopathology report following robot assisted laparoscopic prostatectomy: Tumour 'hide and seek'. Indian J Cancer 2013;50:170-4
|How to cite this URL:|
Javali T D, Dogra P M, Gupta N P, Singh P, Chatterjee P, Dinda A K. Diagnostic dilemma in histopathology report following robot assisted laparoscopic prostatectomy: Tumour 'hide and seek'. Indian J Cancer [serial online] 2013 [cited 2020 Jan 24];50:170-4. Available from: http://www.indianjcancer.com/text.asp?2013/50/3/170/118719
| » Introduction|| |
Use of robotic surgery for prostate cancer along with the increasing importance given to functional outcome following radical prostatectomy has resulted in surgeons being very particular about case selection. Furthermore, with incorporation of PSA (prostate specific antigen) screening in many health programmes prostate cancer is now being detected at an earlier stage. This has coincided with the detection of smaller volume of cancer in radical prostatectomy specimens.  There have also been sporadic reports in literature about the 'vanishing cancer syndrome' - the phenomenon of not finding any cancer in the radical prostatectomy specimen, despite a positive needle biopsy. ,,,, This has important medico legal implications - both for the pathologist as well as the surgeon, keeping in mind the potential side effects of surgery. The patient may feel that surgery has been performed unnecessarily or worse still, that cancer has been left behind in the body.
The reported incidence of histopathological stage pT0 varies between 0.7 to 4.2% in various case series of open radical prostatectomy series. 
Many possible explanations may be put forward to explain the phenomenon of pT0 after a positive needle biopsy.
The cancer focus may be so minute that it may be completely removed by the initial diagnostic procedure, be it TURP or needle biopsy. Indeed, in the series reported by Herkommer et al.,  most of the men with pT0 had a previous TURP or open prostatectomy. Bostwick and Bostwick  reported more than ten-fold decline in the incidence of vanishing cancer in their series of 6843 radical prostatectomies over a 30 year period, from 1966 to 1995, which coincided with the decrease in use of TURP. However, aggressive PSA screening, the use of 12 core and extended core biopsies  and newer diagnostic modalities like magnetic resonance spectroscopy and other functional MRI (magnetic resonance imaging) techniques may reverse this trend by detecting low volume cancers.
Neoadjuvant androgen therapy may mask minute cancer foci. Kollermann et al.  reported a pT0 rate of 15% after prolonged neoadjuvant androgen deprivation in patients with stage T1-3N0M0 prostate cancer. Similarly, extensive inflammation, either non-specific or granulomatous, may obscure underlying prostate cancer.
During technical preparation of specimens, small cancer foci may get entrapped in paraffin. Furthermore, routine histologic sectioning may not evaluate the entire prostate volume. 
Specimen switching must be kept in mind if large volume or high grade cancer is detected in needle biopsy but no cancer in radical prostatectomy specimen. DNA identity analysis must be considered in such cases. 
There are many benign conditions of the prostate that may mimic prostate cancer and if the pathologist is not vigilant, may result in false positive reports in the initial biopsy. Benign atrophy, post-atrophic hyperplasia, atypical adenomatous hyperplasia, seminal vesicle-type tissue, Cowper's gland, and inflammatory processes like granulomatous prostatitis, xanthogranulomatous prostatitis and malakoplakia may be misinterpreted as adenocarcinoma.  In such cases use of immunohistochemical stains like p63, CAM 5.2, 34βE12 and AMACR may help in diagnosis. ,
A minute cancer focus, in the periphery of the gland may inadvertently be left behind, in an overzealous attempt to perform a nerve sparing procedure, resulting in a 'cancer sparing prostatectomy'. This is depicted in [Figure 1].
The purpose of this study was to analyze the possible reasons for vanishing cancer phenomenon in our case series of robot assisted laparoscopic prostatectomy (RALP).
| » Materials and Methods|| |
Between July 2006 and August 2010, 184 patients with clinically localized prostate cancer underwent RALP at our institute. A prospective database has been maintained which contains clinical, pathologic and operative details of all RALPs. We identified nine cases in which the final histopathology of radical prostatectomy did not correlate with the initial biopsy report. In eight of these patients, no tumor was identified in the radical prostatectomy specimen. The following details of these nine patients were extracted from the database: patients' age, PSA level, prostate weight, PSA density, history of TURP (transurethral resection of prostate) prior to the radical prostatectomy, history of neoadjuvant androgen deprivation therapy, digital rectal examination findings, gleason score on biopsy, number of cores positive for carcinoma, whether prostate cancer was detected on TURP chips or needle biopsy, whether the initial biopsy was performed at our institute or some other centre and the final histopathology report. All patients were prospectively followed up and the PSA levels at last follow up visit was noted. Radical prostatectomy was performed a minimum of 6 weeks after TRUS (Trans rectal ultrasound) guided biopsy and 12 weeks after TURP.
In none of the cases frozen section analysis of radical prostatectomy specimen for assessment of margin status was done. Processing of specimens was done as per standard guidelines. 
When cancer was not found after the initial histopathological examination, following procedures were undertaken to search for residual cancer.
Any suspicious appearing foci were evaluated by immunostaining with alpha-methylacyl-CoA racemase (AMACR).
- The initial biopsy slides were reviewed to rule out a false positive diagnosis. Unfortunately only three out of the nine patients had undergone biopsy at our institute [case no. 6, 7, and 8. [Table 1]] while in the remaining cases the outside biopsy slides were available for assessment by our pathologist. At this juncture note was also made as to which lobe of the prostate the positive cores were from.
- The final histopathology slides of the radical prostatectomy specimen were reviewed by a second pathologist to rule out a false negative diagnosis.
- The remaining prostate gland was processed in its entirety and additional deeper sections were taken after flipping the tissue in the paraffin block until no tissue was left.
| » Results|| |
Patient characteristics and clinical and biopsy details are given in [Table 1].
In two patients (Sl. Nos. 2 and 3) prostate cancer was diagnosed on TURP chips while the remaining patients had prostate cancer diagnosed on trans rectal ultrasound guided prostate biopsy. No patient had a palpable nodule on rectal examination. None of the patients had received hormonal therapy prior to radical prostatectomy. The mean PSA was 11.82 ng/ml (range 0.95 to 24.94 ng/ml). The mean prostate weight was 45.33 gms (range 20 to 93 gms).
The final report was signed out after being reviewed by two pathology consultants. The final histopathology (i.e. before applying AMACR stain) was benign prostatic hyperplasia in 2 patients, chronic prostatitis in 4 patients, granulomatous prostatitis with glandulostromal hyperplasia in 1 patient, florid acute prostatitis in 1 patient, and transitional cell carcinoma of prostate in 1 patient. The follow up of patients ranged from 6 to 42 months. All patients had undetectable PSA at the last follow up.
After AMACR staining became available at our institute, the above cases were reviewed. AMACR staining was applied to 2 cases (case nos. 6 and 9), in which a suspicious focus was identified on re-evaluation of the slides. AMACR stain was positive in case no. 6 and negative in case no. 9 [Figure 2], [Figure 3], [Figure 4] and [Figure 5]. After AMACR staining the diagnosis of case 6 was changed to chronic prostatitis with areas of high grade PIN (prostatic intraepithelial neoplasia).
|Figure 2: TRUS biopsy showing adenocarcinoma prostate Gleason Score 3 + 3 = 6 (case no. 9)|
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|Figure 3: Final histopathology slides of radical prostatectomy specimen of same patient (case no. 9), showing no tumor|
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|Figure 5: Positive AMACR staining of a small suspicious focus in case no. 6|
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| » Discussion|| |
The pT0 rate in our series was 3.8%. Keeping in mind the fact that none of our patients had received neoadjuvant androgen deprivation therapy; this is higher than that reported in all previous series. ,,,,, There has been recent literature suggesting that prostatic carcinomas in Asian patients have a low incidence and low prostatic volume as compared to the Western countries. Asians also have a high grade (Gleason score above 7) prostate cancer. , Moreover, while all published literature on 'vanishing cancer syndrome' have come from open radical prostatectomy series, ours is the first RALP series to comment on this entity. Laurent Salomon et al.  reported 30 cases of pT0 among 7,693 radical prostatectomy specimens in a multicentre study. At a median of 82 months follow up there was no biochemical progression. They questioned the practice of extensive specimen processing to identify a tumor focus, as it did not change patient prognosis. However, medico legal implications justify extensive specimen analysis.
As we were hindered by the non-availability of basal cell markers like 34βE12 and immuno-stains for cytokeratin CAM 5.2 and for p63, we can only conjecture as to the plausible reasons for pT0 in our patient series.
None of the specimens submitted had any evidence of capsular incision or any gross morphological features to suggest that complete oncological extirpation had not been done.In case numbers 1 and case 5 the Gleason grade for the needle biopsy was 1 and 2 respectively. In the present scenario low Gleason's score prostatic adenocarcinomas are questionable entities. However, in the initial studies by Gleason it was described that specimens where only one grade was present, it was doubled to produce a score. This practice is followed by many pathologists till date. There have been many studies to indicate that the diagnosis of Gleason's 2 (1 + 1) is not viable in biopsy material and should be limited to TURP and radical prostatectomy specimens.  The incidence of Gleason's 2 (1 + 1) is fairly low and there no studies which highlight the survival statistics of this grade tumors.The presence of these tumors should be confirmed with appropriate immunohistochemistry. Since the blocks were not available for these cases only slide review was done.
In case number 5 there was only one core positive for the tumor which could indicate an extremely low volume prostate cancer. The radical prostatectomy specimen of both the cases (1 and 5) did not show any residual tumor.
In case number 2 a TURP was performed and this could have removed a small tumor focus. Post TURP radical prostatectomy specimens are known to have a higher incidence of pT0. 
In case no. 4 again there was only one core positive (out of 12 cores) which indicates a small tumor focus and furthermore the radical prostatectomy specimen showed florid acute prostatitis which can mask a small focus of malignancy.
Case no. 8 had a final biopsy report of granulomatous prostatitis with glandulostromal hyperplasia, which is a known mimicker of prostate cancer.
Case no. 7 also had only 2 positive cores which may have been 'lost' during technical preparation of the slides. Only a small fraction of tissues is examined histologically, even when the entire prostate has been embedded. It is estimated that total embedding of the prostate samples only about 1% of evaluable surface areas of the prostate, so it is possible that small cancers will remain embedded in paraffin. One study showed that at least 2678 histologic sections would have to be generated if the entire prostate was embedded and each block was serially sectioned. 
Although AMACR staining did ultimately change the diagnosis in case no. 6 the wide discrepancy in TRUS biopsy finding and final histopathology in this patient, as well as in case 9 (in which AMACR was negative), is difficult to explain. Although we had no reason to suspect specimen switching, DNA identity analysis is indicated in such cases. It is to be highlighted that in all these cases the radical prostatectomy specimens were processed in entirety and the blocks corresponding to the positive cores were also processed in entirety. However the use of immuno stains like 34βE12, CAM 5.2 and p63 may have helped in identifying the elusive tumor foci in these cases.
| » Conclusion|| |
Based on the above experience, we now routinely review all outside biopsy slides before subjecting patients to radical prostatectomy. Patients with low volume cancers who opt for surgery are forewarned about the possibility of pT0. Immunohistochemistry markers are being used to distinguish prostatic cancer variants from benign mimickers. Urologists need to be aware of the vanishing cancer phenomenon as the incidence of this may increase in the future as a result of increasing detection of low volume cancers.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]