Should Pathologists Diagnose ‘‘Adenocarcinoma’’When They Encounter a Single Small Atypical
Focus in a Prostate Biopsy?
In Response:
Both Letters to the Editor referring to our paper ‘‘Variability in diagnostic opinion among pathologists for
single small atypical foci in prostate biopsies’’ challenge its recommendation to obtain second opinion of a specialist pathologist before making a diagnosis of adenocarcinoma on a focus, comprising
5 or less atypical acini.4 Dr Dalton1 argues that the clinical outcome of men with these lesions, irrespective
of the diagnosis, is any how favorable.His view seems to be further corroborated by another paper recently published in this Journal5 on false negative prostate biopsies that is, biopsies where the diagnosis of prostate cancer was missed. The missed lesions were small foci of Gleason score 6 (3 +3) denocarcinomas in a single biopsy. Indeed,none of the men with a false-negative biopsy seemed to have a cancer advanced beyond the curable stage at the time of prostate cancer diagnosis 4 to 8 years later and the cancers did not differ from those found in men with a previous truly negative biopsy result.
To our opinion, the argument raised by Dr Dalton1 might be valid at a population level, but may not apply
for the individual man, in whom the small atypical focus could represent the tip of the iceberg, requiring
additional clinical investigations. As literature has shown that intercollegial consultation leads to more definite diagnoses of benign or cancer in prostate biopsies,3 we maintain our recommendation on this matter.The reason for the disagreement of Drs Gilks and Huntsmans2 with our position is the lack of consensus among the experts themselves. On account of this lack of agreement on the diagnosis
of such small foci, no individual expert can function as a ‘‘golden standard’’and therefore, they propose that pathologists should refrain from making a definite diagnosis of cancer when the number of atypical acini does not exceed a given number, for example, 10 acini. In contrast, we would argue that not all lesions with fewer than 6 atypical acini in our study suffered from a lack of consensus among experts, and in average the experts did better than the general pathologists of our study. The proportion
of consensus in these cases might in fact be higher in a real-life situation as compared with this virtual microscopy environment, for reasons outlined in the discussion of our paper. Thus, we do not agree with
a recommendation that would deny a pathologist’s right to render a definite diagnosis of adenocarcinoma when he would feel comfortable enough to do so. Obviously, we endorse the view
that the scientific community should continue to look for additional tools to reduce the diagnostic uncertainty on these small atypical foci. In the mean time, we would encourage pathologists
to seek advice from specialist pathologists to reduce the uncertainty of their diagnosis under these circumstances.

Theodorus H. Van der Kwast, MD,
PhD*
Jonathan I. Epstein, MD, PhDw
*Department of Pathology University
Health Network Toronto, Canada
wDepartment of Pathology
The Johns Hopkins Medical Institutions
Baltimore, MD

感谢各位网友非常有见地的剖析，收益匪浅，国内和国外一样到究竟是“小腺泡非典型增生”还是“腺癌”的争议仍在进行中，在“Variability in diagnostic opinion among pathologists for single small atypical foci in prostate biopsies ”发表后不久Am J Surg Pathol  Volume 34, Number 7, July 2010 又发表了一封读者来信“Diagnostic Uncertainty in the Interpretation of Small Atypical Acinar Lesions of Prostate”

To the Editor:

The recently published article by Van der Kwast et al1 presents interesting and important data on diagnosis of small atypical foci on prostate needle biopsies. The authors show that these small foci are not reliably diagnosed by community
pathologists (k—0.21), with only slightly better performance by recognized
experts in the field (k—0.39).Not surprisingly, the results are worse (ie, consensus is particularly evasive)for the smallest foci under consideration,consisting of 5 or fewer acini.The authors are to be commended for a carefully designed study with the participation of leading experts in prostate pathology. We write, however,to take strenuous issue with the conclusion as stated in the abstract;the authors ‘‘encourage pathologists to obtain intercollegial consultation of a specialist pathologist for these lesions before a carcinoma diagnosis.’’Why? This conclusion is not supported by their data. Even if shown to an expert, the diagnosis would depend on which expert one chose as a consultant, and we have no way of knowing which consultant is right in a given case. We would interpret their results as follows: (1)small foci of 5 or fewer glands cannot be reproducibly diagnosed as benign versus malignant, even by experts,and therefore (2) major treatment decisions should not be made based on such small foci, given the lack of reproducibility of diagnosis. We see
no benefit to the patient of obtaining an expert opinion in such a case.The underlying issue is how reproducible the diagnosis of a given histopathologic variable must be to use it to guide therapy. We are not aware of this being formally discussed or rigorously examined, yet it is critical. It is a highly complex issue,requiring consideration of the nature of the treatment options, but a few recent examples are available for consideration. In the case of administration of adjuvant therapy in breast cancer, American Society of Clinical Oncology/College of American Pathologists guidelines call for test accuracy (agreement with independent reference method) of 95% for HER2 testing. Frozen section has an acceptable accuracy of greater than 98%.The diagnosis of single small atypical acini on prostate biopsies falls well short of these standards. As we move to evidence-based treatment  ecisions,greater reproducibility will be expected of pathologists. We should be prepared to state when we are not able to render reproducible diagnoses,as our opinions remain critical in treatment planning, and our credibility is eroded if we pretend all diagnoses are equal, in terms of reproducibility.The authors have clearly identified a circumstance where a diagnosis of carcinoma is not possible with certainty,an important step forward.We should now search for tools that will objectively predict patient outcome in such cases, and not fall back on reliance on subjective expert opinion for these small atypical acinar lesions.

C. Blake Gilks, MD, FRCPC
David G. Huntsman, MD
Department of Pathology
Vancouver General Hospital and British
Columbia Cancer Agency
Canada

谢谢王主任的关注，在回答问题之前让我们共同学习一下有关内容：

Variability in Diagnostic Opinion Among Pathologists
for Single Small Atypical Foci in Prostate Biopsies

(Am J Surg Pathol 2010;00:000–000)

Abstract: Pathologists are increasingly exposed to prostate
biopsies with small atypical foci, requiring differentiation
between adenocarcinoma, atypical small acinar proliferation
suspicious for malignancy, and a benign diagnosis. We studied
the level of agreement for such atypical foci among experts in
urologic pathology and all-round reference pathologists of the
European Randomized Screening study of Prostate Cancer
(ERSPC). For this purpose, we retrieved 20 prostate biopsies
with small (most <1 mm) atypical foci. Hematoxylin and eosinstained
slides, including 10 immunostained slides were digitalized
for virtual microscopy. The lesional area was not marked.
Five experts and 7 ERSPC pathologists examined the cases.
Multirater k statistics was applied to determine agreement and
significant differences between experts and ERSPC pathologists.
The k value of experts (0.39; confidence interval, 0.29-0.49) was
significantly higher than that of ERSPC pathologists (0.21;
confidence interval, 0.14-0.27). Full (100%) agreement was
reached by the 5 experts for 7 of 20 biopsies. Experts and
ERSPC pathologists rendered diagnoses ranging from benign
to adenocarcinoma on the same biopsy in 5 and 9 biopsies,
respectively. Most of these lesions comprised between 2 and 5
atypical glands. The experts diagnosed adenocarcinoma (49%)
more often than the ERSPC pathologists (32%) (P<0.001). As
agreement was particularly poor for foci comprising <6 glands,
we would encourage pathologists to obtain intercollegial consultation
of a specialized pathologist for these lesions before a
carcinoma diagnosis, whereas clinicians may consider to perform
staging biopsies before engaging on deferred or definite therapy.
Key Words: prostate cancer, prostate biopsy, pathology,
diagnostics, interobserver variation, virtual microscopy