Case 3 -
Transition Zone-directed Biopsy Showing Adenocarcinoma, Gleason Score 3+3=6 with Clear Cell Morphology, Involving 7% of Needle Core Tissue and Measuring 1.2 Mm in Length
Memorial Sloan Kettering Cancer Center
New York, NY
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51 year old male with a history of a 3 cm, organ-confined clear cell renal cell carcinoma in 1998.
Over a four year period the patient's PSA rose from 1.71 to 3.28 prompting a systematic prostate needle biopsy.
Case 3 - Slide 1
Transition Zone-directed Biopsy Showing Adenocarcinoma, Gleason Score 3+3=6 with Clear Cell Morphology, Involving 7% of Needle Core Tissue and Measuring 1.2 Mm in Length
Evolving Clinical, Pathologic and Molecular Evaluation of Transition Zone Tumors
In a series of studies from the late 1980's and early 1990's examining the zonal origin of prostate
cancer, a number of investigators argued that transition zone (TZ) tumors could be identified using
distinctive histological criteria characterized by McNeal and colleagues. Descriptions encompassed a
range of findings, including well-differentiated glands of variable size and contour, composed of tall
cuboidal to columnar cells with basally-oriented nuclei and occasional eosinophilic luminal secretions.
Some variability was noted in both the cytoplasm (clear to pale pink) and nuclei (minimally atypical to
enlarged and hyperchromatic with prominent nucleoli) of such glands. In 1988, McNeal et al further
demonstrated that two-thirds of 21 TZ-dominant cancers and nearly 75% of 29 "incidental" smaller TZ
tumors initially diagnosed on transurethral resection showed >60% of this morphology and were
associated with a high percentage of Gleason pattern 1-2 cancer foci. They concluded that this "clear
cell" appearance was a marker of TZ tumors and more globally, of low grade lesions.
In subsequent years, many reports claimed that TZ tumors should be considered separately from
peripheral zone (PZ) tumors since they have a more indolent course, higher cure rate, and overall more
favorable prognosis. While TZ tumors may be of larger volume and associated with higher serum PSA values
than PZ tumors, most reports have maintained that TZ tumors show lower GS, often retaining a Gleason
pattern 2. In 2003, Shannon et al in examining 76 cases from each zone found that TZ tumors had
significantly lower GS and lower % Gleason pattern 4/5 when compared with PZ tumors of similar volumes.
Following the lead of McNeal, classification of TZ cancers in many studies was founded upon recognizing
the specialized "clear cell" morphologic features described above. Few studies however, had compared TZ
tumors with anterior PZ tumors (i.e. tumor in the anterolateral "horns" of the prostate).
Among multiple changes to the diagnostic armamentarium for prostate cancer over the past two decades,
systematic sextant needle biopsies, initially 6-core and now routinely 12-core, combined with aggressive
PSA screening protocols have been increasingly successful in early detection of low-volume posterior
tumors. Consequently, in recent years we and others have reported a trend towards an increasing number
of dominant anterior prostatic tumors. A significant percentage of these cancers are located in the
prostatic transition zone and are typically more difficult to detect by digital rectal examination and
poorly visualized on imaging.
In a recent series of studies, we have examined the anatomy of the anterior prostate, compared
pathologic variables between TZ and anterior PZ tumors, assessed for McNeal's "clear cell" morphology in
tumors of both zones and retrospectively determined the accuracy with which transition zone-directed
needle biopsies detect clinically relevant TZ tumors. This case presentation will highlight some of
these results as well as recent work quantifying the incidence of the novel TMPRSS2-ERG gene fusion in transition versus peripheral zone tumors.
In a detailed histopathologic analysis of 197 anterior dominant tumors emphasizing the variability in
anterior prostatic anatomy from apex through base to determine zone of origin and pathological staging,
Al-Ahmadie et al showed that the majority of anterior dominant tumors in the prostate are actually of
anterior PZ origin. Specifically 97/197 (49%) were designated as anterior peripheral zone, 70/197 (36%)
transition zone, 14 (7%) involved both zones, while 16 (8%) were of indeterminate zone. Comparing the
first two groups – anterior PZ and TZ – of anterior dominant tumors, no significant differences in
Gleason scores, incidence of extraprostatic extension (EPE) or overall surgical margin positivity rate
were observed. Given these similarities and in contrast to prior studies which most often compared TZ
tumors with the more common posterior peripheral zone tumors, long term clinical outcomes and future
molecular analyses will be necessary to assess whether true differences in biology and behavior exist
between tumors of TZ and anterior PZ origin.
While McNeal and others used "clear cell" morphology as a marker of cancers with transition zone
origin, Garcia et al have revealed another angle of McNeal's work which was previously under-recognized.
In a study focused on dominant lesions in radical prostatectomy specimens, we have demonstrated that
while this tumor appearance is present in the overwhelming majority of TZ tumors and is more commonly
predominant in TZ tumors than in PZ tumors (ratio > 5:1), it occurs as the predominant (>50%)
morphology in only 49% of transition zone-dominant tumors. A careful look at McNeal's original work
reveals that while only 3% of peripheral zone-dominant tumors showed >60% "clear cell" histology, 34
of 67 (51%) PZ-dominant tumors exhibited some of this morphology, with 7 of 34 (21%) showing
>20%. We likewise found that though only 4% of PZ tumors display >50% "clear cell"
appearance, 35% of PZ tumors with any such histology showed >25%.
The presence of non-focal "clear cell" morphology in greater than 20% of all tumors in our series is
relevant to assignment of zonal origin to some anterior prostatic tumors. As per above, the variability
of anterior prostatic anatomy and specifically, the impact of the proportions of PZ and TZ present in
this region in determining zone of origin has been recently highlighted. Especially in cases where
anatomic complexity makes this assessment difficult, the present data suggests that finding 25-50%
(non-focal) "clear cell" histology in an anterior tumor will not help establish its zonal origin.
Similarly, these observations are pertinent in assessment of tumor location detected by needle
biopsy. Given the difficulties in detecting anterior prostatic tumors on clinical examination, imaging
studies and needle biopsy, a number of investigators have examined the value of transition zone-directed
needle biopsies in prostate cancer detection, with conflicting results. While some have found utility
for such biopsies in patients with previous negative biopsy sessions or 'gray-zone' PSA levels, with few
exceptions, most authors have argued against using TZ-directed biopsies in routine protocols.
Surprisingly however, few studies have correlated the cancer seen in these needle biopsies with that seen
in prostatectomy specimens and/or the clinical relevance of these tumors.
McNeal and Noldus determined that TZ-directed biopsies were useful in identifying tumors >5.0 cc,
but could miss anterior tumors in the 2.0 to 5.0 cc range, while Pelzer et al showed that these biopsies
very rarely detected solitary TZ cancer. Haarer et al, working in an institution which routinely samples
the transition zone in needle biopsy sessions, compare d prostate cancers detected in transition
zone-directed needle biopsies with those seen in corresponding radical prostatectomy specimens with
surprising results. Among 61 patients (25 /61 (41%) left, 23/61 (38%) right, and 13/61 (21%) bilateral
transition zone) in whom cancer was present on a transition zone-directed needle biopsy , we found that
at prostatectomy, 24/61 (39.5%) cases had no tumor in the transition zone whatsoever. An additional
24/61 (39.5%) cases showed non-dominant TZ cancer with only 13/61 (21%) displaying a dominant TZ lesion.
Similarly, 18/38 (47%) and 17/36 (47%) cases with cancer in left or right transition zone-directed needle
biopsy, respectively, showed either no TZ tumor or tumor in the contralateral TZ only at radical
prostatectomy. In 8 cases, the transition zone-directed core was the only needle core with cancer and
2/8 (25%) such cas es showed dominant TZ cancer at prostatectomy.
Hence, cancers identified on transition zone-directed needle biopsy cores were either not from the
transition zone or did not reflect a dominant TZ lesion in nearly 80% of cases. Furthermore, cancer
identified in a left or right-sided transition zone-directed needle biopsy did not predict ipsilateral TZ
cancer in almost 50% of cases. These collective findings suggest that : a) the presence of "clear cell"
morphology on needle biopsy should not be used in determining whether one has actually sampled the
transition zone; b) transition zone-directed needle biopsies do not adequately characterize transition
zone tumors and therefore care should be taken in their interpretation.
Over the past five years, numerous studies have shown TMPRSS2-ETS family
gene fusion and specifically TMPRSS2-ERG gene rearrangement to be a common
and recurrent genetic event in prostate cancer. While a wide variety of cohorts have been studied,
yielding incidences between 30-70%, zonal differences in the incidence of TMPRSS2-ERG gene fusion have only recently been considered.
Guo et al reported on 30 cases for which matched transition zone and peripheral zone tumor foci from
the same prostate and representing the largest tumor foci in the respective specimen were available for
analysis. They found TMPRSS2-ERG rearrangement in 43% of peripheral zone
tumor foci but in none of the transition zone tumor foci. In a response to a comment by Bismar and
Trpkov noting some of the manuscript's limitations, Guo et al acknowledged that their study was not
designed to evaluate the overall heterogeneity of TMPRSS2-ERG fusion among
all tumor foci of all zones in the 30 specimens. They also noted that a number of abstracts documenting
gene rearrangement in transition zone tumors had recently shown that a very small number of TZ tumors
display this fusion compared with the rates reported for peripheral zone tumors across series. Falzarano
et al evaluated tissue microarrays from 62 cases with dominant transition zone tumors of which 46 also
showed a tumor focus in the peripheral zone. Among interpretable cases, 12% of transition zone tumors
and 34% of peripheral zone tumors revealed TMPRSS2-ERG rearrangement,
showing definitively that gene fusion does occur in a minority of dominant transition zone.
Using our well-characterized cohort of anterior tumors, we also analyzed anterior peripheral zone and
transition zone prostate cancers arrayed in TMAs for TMPRSS2-ERG
rearrangement status and correlated it with the presence of "clear cell" histology. Significantly fewer
TZ cancers were found to have a rearrangement (4/58; 6.9%) than anterior PZ cancers (18/ 71; 25%).
Interestingly, these incidences of rearrangement are lower than that previously reported in radical
prostatectomy-based series largely derived from posterior PZ tumors. "Clear cell" histology was present
in 13% of anterior PZ tumors and 36% of TZ tumors, while 5% of cancers with and 17% without this
morphology had TMPRSS-ERG rearrangement, regardless of zone of origin.
Taken together, these three studies suggest that gene fusion is significantly less common in tumors of
transition zone origin, a phenomenon that bears further study.
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