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The Prostate 28359-363 (I996)
Microvascular Invasion of the Seminal Vesicles in
Adenocarcinoma of the Prostate
Sam D. Graham, Jr., Pave1 Napalkov, Lynda Watts, Diva Salomao, and
David G. Bostwick
Department of Surgery Division of Urology, Emory University School of Medicine, Atlanta,
Georgia (S.D.G., P.N., L W.); Department of Pathology, Mayo Clinic, Rochester,
Minnesota (D.S., D.G.B.)
ABSTRACT:
The objective of this article is to determine the relationship between microvascular invasion and seminal vesicle invasion in prostatic adenocarcinoma.Radical prostatectomies with seminal vesicle involvement were examined histologically and immunohistochemicallywith antibodies directed against S-100protein and factor WI. Microvascular
invasion of the seminal vesicles showed a positive correlation with microvascular and capsular invasion of the prostate (P= 0.006 and 0.048,respectively)and lymph node metastases.
Tumor progression was found in 8 of 14 (57%) patients with microvascular invasion of the
seminal vesicles, compared with 3 of 22 (14%) without microvascular invasion (P=O.OOl).
Microvascular invasion of the seminal vesicles is predictive of tumor progression and lymph
node metastases in prostatic adenocarcinoma. 0 1996 Wiley-Liss, Inc.
KEY WORDS:
Microvascular invasion, seminal vesicle, radical prostatectomy
INTRODUCTION
The prognosis of prostatic adenocarcinoma is determined by the extent of tumor at radical prostatectomy [1,2]. Seminal vesicle invasion carries a risk of
recurrence and/or progression of more than 50%
[3-51 and usually appears either as tumor surrounding the seminal vesicles or as stromal and muscular
invasion [6,7. The tissue around the seminal vesicles
is predominantly fat with a rich anastomosing network of small vessels [8]. This study was performed
to determine whether seminal vesicle invasion is
chiefly due to microvascular invasion and to investigate the relationship between microvascular or perineural invasion in the prostate and microvascular invasion of the periseminal vesicular tissue.
METHODS
Specimen Preparation
Prostates from radical prostatectomies were
painted with India ink and Bouin's solution upon receipt and then fixed in formalin. Sampling of the
prostate included sections of the distal urethral margin; then, representative sections were taken every
0 1996 Wiley-Liss, Inc.
2-3 mm, on both the right and left sides. Sections
were also taken of any suspiciously area. All specimens were examined by a single reference pathologist. Seminal vesicle invasion was defined as the
presence of adenocarcinoma within the muscular
wall of the seminal vesicle. Microvascular invasion of
the seminal vesicles included foci within the seminal
vesicles and the adjacent periseminal vesicular soft
tissue, which is in intimate association.
case selection
The study group consisted of 36 patients with prostatic adenocarcinoma involving the seminal vesicles
with a minimum of 2 years of follow-up selected from
201 radical prostatectomy specimens for clinically localized cancer performed at Emory University between 1979 and 1991. Patient medical records were
reviewed for evidence of tumor progression and re-
Received for publication November 18, 1994; accepted May 17,
1995.
Address reprint requests to Dr. Sam D. Graham, Jr., 1365 Clifton
Rd., NE, Atlanta, GA 30320.
360
Grahamet al.
TABLE 1. Patterns of Invasion of Prostatic
AdenouKinorna in the Prostate and Seminal Vesicles
Prostate
N
%
Microvascular and perineural 10 28
Microvascular only
0
0
Perineural only
23
64
Fibromuscular stromal only
3
8
Total
36 loo
Seminal vesicle
N
%
9
5
18
25
14
50
11
100
4
36
currence based upon followup digital rectal examination (DRE), serum prostate-specific antigen (PSA)
level, radionuclide bone scan, and/or repeat biopsies
when indicated.
Fig. I. Microvascular invasion (arrowhead) of prostatic adenocarcinoma in the seminal vesicle (immunoperoxidase staining with antibody to factor VIII. x 100).
lmmunohistochemistry
Tissue sections were obtained from formali-fixed
paraffin-embedded blocks of the prostate and seminal vesicles, cut at 7 pm, and placed on silanized or
poly-l-lysine coated slides. Routine indirect immunoperoxidase staining was performed on each specimen. Briefly, sections were deparaffinized in xylene
and rehydrated in alcohol. Endogenous peroxidase
activity was quenched with 3% hydrogen peroxide,
and the sections were incubated in stable 0.1% pepsin
solution with normal serum. Slides were incubated
with primary mouse monoclonal antibody (S-100,
Dako, Carpenteria, CA; or factor VIII-related antigen
Biogenix, San Ramon, CA) and processed with biotinylated streptavidin kit (Dako). Aminoethylcarbazole or diaminobenzidine were used as chromogenic
peroxidase substrates; the slides were counterstained
with Mayer's hematoxylin. Known positive and negative controls for each antibody were run in parallel
with each staining and gave appropriate results.
cular arteries, arterioles, venules, and small capillarylike spaces. The capillary-like structures were uniformly distributed throughout the smooth muscle
layer and in the mucosal folds of the normal seminal
vesicle, and represent either lymphatic channels, capillaries, and venules. In some sections, the number
of immunoreactive capillary-like structures was increased in areas with malignant glands in comparison
with normal tissue, although this was not quantified.
Microvascular invasion was defined as transmural invasion of vascular structures by malignant glands
(Fig. 1). Frequently, immunoreactive spaces were
compressed by adjacent malignant glands; when
there was no definite luminal invasion, this was not
considered evidence of invasion (Fig. 2).
S-100 protein immunoreactivity was identified in
large and small nerves throughout the prostate. Perineural invasion varied from rare neoplastic glands
abutting nerves to massive circumferential and intraneural invasion (Fig. 3).
RESULTS
Seminal Vesicle Involvement
Seminal vesicle involvement was microvascular in
14 cases (39%),perineural in 27 (82%),and confined
to the fibromuscular stroma in 4 (11%).Nine cases
(25%)showed both perineural and microvascular invasion, and 23 (64%)had stromal invasion associated
with either microvascular (5)or perineural (18) invasion (Table I).
lmmunohistochemical Studies
There was intense cytoplasmic reactivity for factor
VIII-related antigen in endothelial cells of large mus-
Correlation of Seminal Vesicle and Prostatic
Microvascular Invasion
Ten patients (28%) had microvascular invasion of
the prostate; 8 of these had concurrent microvascular
invasion of the seminal vesicles (Table 11, P = 0.003);
33 of the 36 patients (92%) in the study group had
perineural invasion in the prostate confirmed by
S-100 staining, and 27 (82%) also had perineural invasion of the seminal vesicles (Table 111, P = 0.01). Of
10 patients who had both perineural and microvascular invasion of the prostate, 5 had both in the seminal vesicles.
Microvascular Invasion of Seminal Vesicles in Prostatic Adenocarcinoma
36I
TABLE II. Relationship of Microvascular Invasion in the
Prostate to Microvascular Invasion in the Seminal
Vesicles in Adenocarcinoma of the Prostate*
Prostate
Positive
Negative
Total
Seminal vesicles
N
%
N
%
N
%
Positive
Negative
Total
8
2
10
80
20
100
6
20
26
23.1
76.9
14
22
36
38.9
61.1
100
100
*P= 0.0029; Fisher's exact test.
Fig. 2. lmmunoreactive microvascular space in the seminal vesicle compressed by the malignant glands of prostatic adenocarcinoma (immunoperoxidase staining with antibody to kctor VIII,
x 100.)
TABLE 111. Relationship of Perineural Invasion in the
Prostate to Perineural Invasion in the Seminal Vesicles
in Adenocarcinoma of the Prostate*
Prostate
Positive
Negative
Total
Seminalvesicles
N
%
N
%
N
%
Positive
Negative
27
6
33
81.8
18.2
100
0
3
3
0
100
100
27
9
36
75
25
100
Total
*P= 0.0117; Fisher's exact test.
Fig. 3. Perineural invasion (arrowheads) of prostatic adenocarcinoma in the seminal vesicle (immunoperoxidase staining with antibody to S-I OO, X I OO).
Correlation of Microvascular Invasion and
Tumor Progression
Eight of the 36 (22%) patients with seminal vesicle
involvement had lymph node metastases at radical
prostatectomy. Of these, 5 (63%)had microvascular
involvement of the seminal vesicle, 4 (50%) had microvascular invasion of the prostate, and l had neither microvascular nor perineural invasion. In patients with microvascular invasion of the seminal
vesicles, 5 (36%) had lymph node metastases, compared with 8 (22%)in the entire study group.
Median follow-up was 43 months, with a range of
24-136 months. 11 patients experienced tumor progression as defined by elevation of PSA >0.5 n g / d
(n = ll), positive DRE (n = 2), abnormal radionuclide
bone scan (n=6), and/or positive biopsy (n=4). Of
the 17patients who progressed, 8 had only microvas-
cular invasion of the seminal vesicle, 6 had both microvascular and perineural invasion of the seminal
vesicle, and 5 had lymph node metastases. Tumor
progression was found in 8 of 14 (57%)patients with
microvascular invasion compared with 3 of 22 (14%)
without microvascular invasion of the seminal vesicles (Fig. 4).
Chi-square analysis of variance was used to test
the predictive value of microvascular invasion in the
seminal vesicle, the combination of microvascular
and perineural invasion in the seminal vesicle, and
lymph node metastases for tumor progression. In
all groups, the predictive values were significant
(P=O.O09, P=O.OlO, and P=O.O40, respectively). Microvascular invasion in the seminal vesicles alone was
the best single predictor (P= 0.03, standard error (SE)
= 0.866), as compared with lymph node metastases
(P= 0.02, SE = 0.956). The combination of microvascular invasion and perineural invasion of the seminal
vesicles was a stronger predictor of tumor progression than lymph node metastases (P= 0.01, SE = 0.934
and P=0.05, SE -0.934, respectively), but its predictive value was not as sigruficant as that of microvascular invasion alone (Fig. 4). No correlation was
found between perineural invasion alone and tumor
362
Graham et al.
Fig. 4. Correlation between progression rate and invasion of the
seminal vesicles. There was a significant correlation between progression rate compared to microvascular invasion (P=O.Ol). microvaxular and perineural invasion (P=O.OI), and lymph node
metastases (P=O.OI). Of 36 patients in the study group, I I progressed and 25 were free of tumor (median follow-up, 43 months).
All P-values based on Fisher’s exact test.
progression, probably because perineural invasion of
the prostate and seminal vesicles were found in almost all of the patients in this study.
DISCUSSION
Seminal vesicle invasion is one of the most sigruficant predictors of failure of radical prostatectomy in
prostatic adenocarcinoma, accounting for progression rates of 51-64% [4,5,9]. It usually involves the
fibromuscular stroma or the adjacent soft tissue [6,7l,
which are rich in microvascular channels and may be
a pathway for tumor spread to the obturator lymph
nodes [ l q .
We found a high incidence of microvascular and
perineural invasion in the seminal vesicles, similar to
that seen in the prostate, and there was a positive
trend with nodal metastases (63% vs. 32%). Five
cases showed stromal invasion and microvascular invasion of the seminal vesicles, but we could not determine whether the microvascular invasion was secondary to stromal invasion. Since the seminal vesicles
were step sectioned at 3mm levels, our findings may
underestimate the incidence of microvascular and
perineural invasion due to sampling error.
Microvascular invasion by tumors in other organs
is predictive of tumor progression and lower cancerspecific survival, including transitional cell carcinoma
of the bladder and testicular carcinoma, probably due
to access to the systemic vasculature for metastasis
[lo-121. If tumor cells are to gain access to the systemic lymphatics, as is currently evaluated surgically
by obturator node sampling, microvascular invasion
of the seminal vesicle may represent the first level of
lymphatic invasion. Perineural invasion may also
play a role in metastatic spread [13,14]. Vessels and
nerves are closely aligned anatomically, and it is
likely that there is crossover invasion. In mapping
studies, McNeal and colleagues [7,15,16] showed that
the neurovascular pedicles of the prostate at the apex
and base provide paths of egress for carcinoma to the
periprostatic soft tissues; however, these investigators did not evaluate the incidence of microvascular
invasion.
Rare studies have looked at the intraprostatic or
periprostatic microlymphatic architecture [17-191. Using light and electron microscopy, Furusato and
Mostofi [20] demonstrated lymphatics in the stroma
and small capillaries in the stroma and perineural
spaces. We identified factor VIII-related antigen-immunoreactive capillary-like structures in the stroma
of the prostate, seminal vesicles, and periseminal vesicular fat. In most of the sections of the prostate and
seminal vesicles stained for factor VIII-related antigen, the number of reactive capillaries appeared to be
increased in foci of invasive carcinoma, as compared
with the adjacent benign tissue, indicative of tumor
neo-angiogenesis. Recent studies indicate that angiogenesis plays a role in prostate cancer [21,22].
Our findings indicate that microvascular invasion
of the seminal vesicles by prostatic adenocarcinoma is
predictive of tumor progression. Perineural invasion
of the prostate was present in virtually all cases, limiting its usefulness. Patients with microvascular involvement of the prostate had similar involvement in
the seminal vesicles; this correlated with tumor progression. We found a sigruficant positive correlation
between lymph node metastases, microvascularinvasion, and microvascular with perineural invasion and
tumor progression; microvascular invasion in the
seminal vesicles was the strongest predictor of progression. The freely anastomosing microvascular
channels in the fibromuscular stroma and fat adjacent
to the seminal vesicles may represent a sigruficant
pathway by which prostatic adenocarcinoma disseminates. Identification of microvascular and perineural
invasion at this site appears to be prognostically useful.
ACKNOWLEDGMENTS
The authors acknowledge the help of Helen M.
Hamson, Division of Urology, Emory University,
and of Ted Gansler, Department of Pathology, Emory
University, for their assistance in this paper.
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