2021, Volume 37, Number 1, Page(s) 026-031
Stromal Lymphoid Response Status in Micropapillary Urothelial Carcinomas Diagnosed in Bladder Transurethral Resections and its Comparison with Conventional Urothelial Carcinomas
Ezgi HACIHASANOŠLU1, Ušur YÜCETAŽ2, Ošuzhan OKĒU3, Kemal BEHZATOŠLU4
1Department of Pathology, Yeditepe University Faculty of Medicine, ISTANBUL, TURKEY
2Department of Urology, University of Health Sciences, Istanbul SUAM, ISTANBUL, TURKEY
3Department of Pathology, Recep Tayyip Erdogan University, Faculty of Medicine, RIZE, TURKEY
4Acibadem Health Group, ISTANBUL, TURKEY
Keywords: Micropapillary urothelial carcinoma, Stromal lymphoid response, Transurethral resection, Urothelial carcinoma, Bladder
Micropapillary urothelial carcinoma is an aggressive variant of urothelial carcinoma. Evidence suggests that the relationship between
the tumor and inflammatory cells is important in tumor progression and the treatment response. We evaluated the stromal lymphoid response
in micropapillary urothelial carcinomas and compared it with conventional urothelial carcinomas.
Material and Method: Among bladder transurethral resection materials diagnosed as invasive urothelial carcinoma between January
2010-March 2017, cases with at least 5% micropapillary urothelial carcinoma were evaluated for age, gender, grade, stage, micropapillary
urothelial carcinoma percentage, presence/percentage of accompanying conventional urothelial carcinoma/urothelial carcinoma variants, in
situ urothelial carcinoma/micropapillary urothelial carcinoma, lymphovascular invasion, necrosis, and stromal lymphoid response. Stromal
lymphoid response was scored as 0-1-2-3. All parameters were evaluated in 50 pure conventional urothelial carcinomas.
Results: Among 47 micropapillary urothelial carcinomas, 41 were male. The mean age was 69 years. pT1/pT2 was 23/24. Six cases were pure
MPUC. Lymphovascular invasion was present in 8, necrosis in 9 cases. Stromal lymphoid response was present and scored as 1-2-3 in 32
micropapillary urothelial carcinomas (68.1%) and 48 conventional urothelial carcinomas (96%). Micropapillary urothelial carcinomas had
significantly higher lymphovascular invasion and pT2 rates and lower stromal lymphoid response.
Conclusion: Low stromal lymphoid response in micropapillary urothelial carcinomas can be responsible for the poor clinical outcome and
impaired response to treatment of these tumors. This is the first study in the English literature to demonstrate a lower stromal lymphoid response
rate in micropapillary urothelial carcinomas compared to conventional urothelial carcinomas.
Micropapillary urothelial carcinoma (MPUC) is an
aggressive variant of urothelial carcinoma (UC) described
by Amin et al. in 1994 1,2
. It is a rare variant with reported
incidence being 0.6-6% among UCs 1-4
. MPUC is more
frequently encountered in males and in the 6th and 7th
. MPUC is usually diagnosed at an advanced
. Microscopically the tumor is characterized by
tightly packed cell clusters without fibrovascular cores and
surrounding lacuna which resemble small dilated lymphatic
. Lymphovascular invasion is an early
finding in MPUCs and thus metastasis is more frequently
There is increasing evidence that the relationship between
tumor cells and inflammatory cells has great importance in
the development and progression of tumors 10,11. The
lymphoid response to the tumor has also been shown to
have an impact on the treatment response and survival in
various cancer types, including UC 10,12-15. The status
of the lymphoid response in the tumor stroma can be an
important factor responsible for poor clinical outcome and
impaired treatment response in MPUCs.
Our aim in this study was to document the stromal
lymphoid response and other histopathological features
of MPUCs diagnosed in bladder transurethral resection
(B-TUR) materials, and to compare these parameters with
The electronic database of a single center pathology
department was scanned for cases diagnosed as Invasive
urothelial carcinoma in B-TUR materials between January
2010-March 2017. All hematoxylin-eosin (H&E) stained
slides were retrieved from the archive and reviewed for
MPUC. There is no specified criterion for the cutoff
proportion of the micropapillary component to qualify as
MPUC, and 5% or 10% has been suggested as the lower limit
. Most series in the literature have included cases with
<10% micropapillary component and it is reported that any
amount of micropapillary component is associated with a
poor outcome 4,9,17
. In the light of this information,
cases with a minimum 5% micropapillary component were
included in the study. For patients with a MPUC diagnosis
in recurrent B-TURs, only the first B-TUR materials with
MPUC were included in the study. Demographic data of the
cases were obtained from the hospital electronic database.
Histological grading and staging were done according to
World Health Organization (WHO) 2016 Classification
of Urogenital Tumors 1. All cases were evaluated in
terms of age, sex, histological grade, stage, MPUC percent,
accompanying conventional UC and other UC variants,
in situ UC, in situ MPUC, lymphovascular invasion, and
necrosis. Lymphoid response in the tumor stroma was
assessed in H&E stained slides, with a methodology similar
to that used in the study by Klintrup et al. in colorectal
carcinomas 18. The tumor stroma was evaluated with
the x10 objective, and a four-degree scale of 0-1-2-3 was
used for scoring. A score of 0 was given when there were
no/hardly any mononuclear inflammatory cells identified.
A score of 1 was given when mild and patchy infiltration
of mononuclear inflammatory cells were spotted. Score
2 was given when there was widespread mononuclear
inflammatory cell infiltration but the stromal fibrous
tissue was also recognizable in the background. Score 3
denoted very extensive mononuclear inflammatory cell
infiltration so that the background fibrous tissue could
not be distinguished. The inflammatory response score
was independently assessed by three pathologists. When
two or all the pathologists had the same score, that score
was accepted as the final score. If all three pathologists had
different scores, the final score was given after a consensus
evaluation. For the facilitation of the statistical analysis, the
four-degree scale was reduced to a two-degree scale: score
0 was accepted as negative for stromal lymphoid response,
and scores 1, 2 and 3 were combined and regarded as
positive for stromal lymphoid response.
All these parameters were also evaluated in 50 cases
of randomly selected invasive conventional urothelial
carcinoma cases diagnosed in B-TUR materials between
January 2010-March 2017.
IBM SPSS Statistics for Windows, version 22.0 (IBM Corp.,
Armonk, N.Y., USA), was used in the statistical analysis.
The Kolmogorov-Smirnov test was used to assess whether
a variable followed a normal distribution or not. The
independent samples t-test and the Mann-Whitney U test
were used in the analysis of quantitative independent data.
The chi-square test was used in the analysis of qualitative
independent data. P values of less than 0.05 were regarded
as statistically significant.
Among 1440 B-TUR materials with an invasive urothelial
carcinoma diagnosis between January 2010- March 2017,
59 cases (4.1%) had more than 5% MPUC component.
Twelve patients had more than one B-TUR material with
MPUC component. Only the first B-TUR materials for these
patients were taken into consideration and the following
biopsies were excluded. Thus, a total of 47 MPUC cases
were included in the study. Distributions of the MPUC cases
and conventional UC cases were not significantly different
(p>0.05). Demographic and histopathological features
of the MPUC and conventional UC cases and statistical
comparison of the findings between the two groups are
summarized in Table I.
Click Here to Zoom
|Table I: Comparison of demographic and histopathological findings between conventional UC and MPUC cases.
Demographic and Histopathological Findings in
Forty-one cases were male and 6 were female. The age
range was 43-89, with a mean age of 69 and a median of
69 years. Twenty-three cases were stage pT1 and 24 cases
were pT2. All cases had high grade histological features.
The percentage of MPUC component in the cases were
between 5-100%, with a mean of 37.8%. Six cases had
pure micropapillary morphology. In 41 cases, MPUC
was accompanied by conventional UC. One or more UC
variant other than MPUC was present in 13 cases (27.6%).
The most common UC variant accompanying MPUC was
the nested variant (6 cases). Other accompanying variants
were as follows: poorly differentiated variant (3 cases),
sarcomatoid variant (1 case), lipid-rich variant (1 case), and
pseudoangiomatous variant (1 case). Areas of glandular
differentiation were seen in 7 cases. Squamous and
trophoblastic differentiation was present in 2 cases, each.
In situ UC was present in 32 cases and in situ MPUC in
2 cases. Lymphovascular invasion was detected in 8 cases.
Necrosis was seen in 9 cases.
Evaluation of the stromal lymphoid response was done
independently by three pathologists. In 36 cases, all three
pathologists had the same score. In 7 cases, two pathologists
had the same opinion and that was decided as the final
score. In 4 cases, a consensus meeting was held for the
final score. In all four of these cases, the given scores by the
pathologists before the consensus meeting were 0, 1, and 2.
The common property of these cases was the heterogeneity
of stromal lymphoid infiltration. After the consensus
meeting, 2 cases were assessed as score 1 and 2 cases were
assessed as score 2. As a result, and according to the fourdegree
scale evaluation of stromal lymphoid response as
0-1-2-3, 15 cases did not show a lymphoid response (score
0) whereas 18 cases had a score of 1, 9 cases had a score of
2 and 5 cases had a score of 3 for the lymphoid response.
Among the 6 pure MPUC cases, the stromal lymphoid
response score was 0 in 4 cases and 1 in 2 cases (Figure 1AC).
Click Here to Zoom
|Figure 1: Stromal lymphoid response scoring. A) Score 1
lymphoid response was defined as mild and patchy infiltration
of mononuclear cells (H&E; x10). B) Score 2 lymphoid response
was defined as widespread mononuclear inflammatory cell
infiltration with the stromal fibrous tissue still recognizable in
the background (H&E; x10). C) Score 3 lymphoid response was
defined as very extensive inflammatory infiltration so that the
background fibrous tissue could not be distinguished (H&E; x10).
Demographic and Histopathological Findings in
Conventional UC Cases
In 50 conventional UC cases, the age range was 48-89
years, with a mean of 66.9 and median of 66 years. Fortythree
patients were male and 7 were female. All cases were
invasive UC cases with high grade nuclear features. Fortyfive
and 5 cases were pT1 and pT2, respectively. In situ
UC was present in 30 of the control cases (60%). Necrosis was detected in 8 cases, whereas none of the cases had
Evaluation of the stromal lymphoid response was done
independently by three pathologists. All three pathologists
had the same score in 33 cases. In 12 cases, two pathologists
had the same opinion and that was decided as the final
score. In 5 cases, the final score required a consensus
meeting. The given scores by the pathologists in these
cases were 0, 1 and 2. Similar to what was encountered in
the MPUC cases, the common property of these cases was
the heterogeneity of stromal lymphoid infiltration. Three
cases were given a score of 1 and 2 cases were given a score
of 2 after the consensus meeting. Consequently, stromal
lymphoid response was scored as 0 in 2 cases, 1 in 33 cases,
2 in 11 cases and 3 in 4 cases.
Statistical Analysis of the Findings Between Two Groups
Statistical analysis showed no significant difference in terms
of patient age and sex between MPUC cases and control
cases. Also, no statistically significant difference was seen
between the two groups in terms of in situ UC and necrosis.
The ratio of pT2 was significantly higher in the MPUC
group (p<0.001). The lymphovascular invasion rate of
MPUC cases was also significantly higher than in the
control group (p<0.05). In order to make the scoring system more reproducible and to facilitate the analysis, the fourdegree
scale was converted to a two-degree scale. Score 0
was accepted as negative for stromal lymphoid response,
and scores 1, 2, and 3 were combined and regarded as
positive for a stromal lymphoid response. Stromal lymphoid
response presence was significantly lower in the MPUC
group than the control group (p<0.001).
MPUC is a rare histological variant of UC with aggressive
clinical outcome and poor prognosis 1,19
. In our series,
4.1% of all UC cases had a micropapillary component,
consistent with the reported incidence of 0.6-8% among
. The age range was 43-89, with a mean age of 69,
similar to the literature 1,2,5
. MPUC is known to show a
male predominance 1,2,7
. The male/female ratio was 6.8:1
in our study. MPUC usually presents with high stage disease
and shows high grade histology 1-3,19
. In this study, 23
cases were stage pT1 and 24 cases were pT2. All cases had
high grade histological features. Lymphovascular invasion
is a frequent finding in MPUCs; very high lymphovascular
invasion rates were reported by Amin et al., Alvarado-
Cabrero et al. and Johansson et al., respectively, 100%, 89%
and 75% 2,3,7
. The lymphovascular invasion rate was
17% in our study, relatively low compared to the literature,
but it was significantly higher than the conventional UC
It has been showed in many studies that the immune system
can provide a defense system against cancer in tumorigenesis
process, but it may also facilitate cancer development 11,20,21. As in many other types of malignancies, chronic
inflammation takes place in the pathogenesis of the
urothelial carcinoma and it has a double-sided role 22. On
one side, chronic inflammation is a well-known risk factor
for bladder carcinoma development. The best example for
this can be Schistosoma haematobium infection in bladder
carcinogenesis 1. On the other hand, inflammation is
induced by intravesical Bacillus Calmette-Guerin therapy
in bladder cancer treatment and cancer recurrence is
An inflammatory response is developed against UC, as with
many other cancers in the human body 10. Several studies
report that some cancers which have an inflammatory
response developed against them have better outcomes
and are associated with longer patient survival 18,23-25.
In a recent study by Liu et al., higher numbers of tumor
infiltrating lymphocytes was found to be related with longer
survival in bladder urothelial carcinoma 26. Lymphocyte
infiltration in the tumor has also shown to be associated
with the chemotherapy response 27. The mechanisms behind the association between lymphoid response and
survival and the therapy response have not been fully
In our study, the rate of stromal lymphoid response was
96% in conventional UCs and 68.1% in MPUCs, and
the difference between the two groups was statistically
significant. This finding can be explained by several
probable reasons. One of them can be the rapid progression
of MPUC so as not to allow development of lymphoid
response in the tumor. Another reason can be the possible
secretion of special chemical or immune mediators from
MPUC in order to inhibit the lymphoid response in the
stroma. Lower lymphoid response in MPUCs can also be
related to their lower response to standard UC therapy.
Regardless of the mechanism behind this, these tumors are
more aggressive than conventional UCs and their survival
rates are lower.
To the best of our knowledge, there are no studies in the
English literature investigating the relationship between
MPUC and stromal lymphoid response. This is the first
study to demonstrate a lower stromal lymphoid response
rate in MPUCs compared to conventional UCs. The
findings of our study need to be supported or opposed by
other studies. This area requires further research with more
CONFLICT of INTEREST
The authors declare no conflict of interest.
The authors received no financial support for the research,
authorship, and/or publication of this article.
Concept: EH, KB, Design: EH, KB, Data collection or
processing: EH, UY, OO, KB, Analysis or Interpretation:
EH, UY, OO, KB, Literature search: EH, UY, OO, KB,
Writing: EH, KB, Approval: EH, UY, OO, KB
1) Moch H, Humphrey PA, Ulbright TM, Reuter V. WHO
classification of tumours of the urinary system and male genital
organs. 4th ed. Lyon: IARC; 2016.
2) Amin MB, Ro JY, el-Sharkawy T, Lee KM, Troncoso P, Silva EG,
Ordóńez NG, Ayala AG. Micropapillary variant of transitional
cell carcinoma of the urinary bladder. Histologic pattern
resembling ovarian papillary serous carcinoma. Am J Surg Pathol.
3) Alvarado-Cabrero I, Sierra-Santiesteban FI, Mantilla-Morales
A, Hernandez-Hernandez DM. Micropapillary carcinoma of the
urothelial tract. A clinicopathologic study of 38 cases. Ann Diagn
4) Alkibay T, Sozen S, Gurocak S, Isik Gonul I, Poyraz A,
Ure I. Micropapillary pattern in urothelial carcinoma: A
clinicopathological analysis. Urol Int. 2009;83:300-5.
5) Kamat AM, Gee JR, Dinney CP, Grossman HB, Swanson DA,
Millikan RE, Detry MA, Robinson TL, Pisters LL. The case
for early cystectomy in the treatment of nonmuscle invasive
micropapillary bladder carcinoma. J Urol. 2006;175:881-5.
6) Siriaunkgul S, Tavassoli FA. Invasive micropapillary carcinoma of
the breast. Mod Pathol. 1993;6:660-2.
7) Johansson SL, Borghede G, Holmang S. Micropapillary bladder
carcinoma: A clinicopathological study of 20 cases. J Urol.
8) Heudel P, El Karak F, Ismaili N, Droz JP, Flechon A. Micropapillary
bladder cancer: A review of Leon Berard Cancer Center
experience. BMC Urol. 2009;9:5.
9) Comperat E, Roupret M, Conort P, Chartier-Kastler E, Bitker
MO, Richard F, Capron F, Haertig A, Cussenot O, Camparo P.
Aurora-A/STK-15 is differentially expressed in the micropapillary
variant of bladder cancer. Urol Int. 2009;82:312-7.
10) Huang HS, Su HY, Li PH, Chiang PH, Huang CH, Chen CH,
Hsieh MC. Prognostic impact of tumor infiltrating lymphocytes
on patients with metastatic urothelial carcinoma receiving
platinum based chemotherapy. Sci Rep. 2018;8:7485.
11) de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the
immune system during cancer development. Nat Rev Cancer.
12) Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman
LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood
WC, Davidson NE, Sledge GW, Sparano JA, Badve SS. Prognostic
value of tumor-infiltrating lymphocytes in triple-negative breast
cancers from two phase III randomized adjuvant breast cancer
trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32:2959-
13) Bremnes RM, Busund LT, Kilvaer TL, Andersen S, Richardsen
E, Paulsen EE, Hald S, Khanehkenari MR, Cooper WA, Kao
SC, Dųnnem T. The role of tumor-infiltrating lymphocytes in
development, progression, and prognosis of non-small cell lung
cancer. J Thorac Oncol. 2016;11:789-800.
14) Webb JR, Milne K, Watson P, Deleeuw RJ, Nelson BH. Tumorinfiltrating
lymphocytes expressing the tissue resident memory
marker CD103 are associated with increased survival in highgrade
serous ovarian cancer. Clin Cancer Res. 2014;20:434-44.
15) Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanismdriven
biomarkers to guide immune checkpoint blockade in
cancer therapy. Nat Rev Cancer. 2016;16:275-87.
16) Kwon GY, Ro JY. Micropapillary variant of urothelial carcinoma.
Adv Urol. 2011;2011:217153.
17) Samaratunga H, Khoo K. Micropapillary variant of urothelial
carcinoma of the urinary bladder; A clinicopathological and
immunohistochemical study. Histopathology. 2004;45:55-64.
18) Klintrup K, Makinen JM, Kauppila S, Vare PO, Melkko J,
Tuominen H, Tuppurainen K, Mäkelä J, Karttunen TJ, Mäkinen
MJ. Inflammation and prognosis in colorectal cancer. Eur J
19) Watts KE, Hansel DE. Emerging concepts in micropapillary
urothelial carcinoma. Adv Anat Pathol. 2010;17:182-6.
20) Avramoiu I, Petrescu IO, Ciurea ME, Bold A, Silosi I, tanTu
MM, Niculescu M, Savciu REA, Mogoantă SŽ. Peritumoral
inflammatory reaction in non-melanoma skin cancers -
histological and immunohistochemical study. Rom J Morphol
21) Hanahan D, Coussens LM. Accessories to the crime: Functions
of cells recruited to the tumor microenvironment. Cancer Cell.
22) Nesi G, Nobili S, Cai T, Caini S, Santi R. Chronic inflammation in
urothelial bladder cancer. Virchows Arch. 2015;467:623-33.
23) Grivennikov SI, Greten FR, Karin M. Immunity, inflammation,
and cancer. Cell. 2010;140:883-99.
24) Cai T, Nesi G, Boddi V, Mazzoli S, Dal Canto M, Bartoletti R.
Prognostic role of the tumor-associated tissue inflammatory
reaction in transitional bladder cell carcinoma. Oncol Rep.
25) Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related
inflammation. Nature. 2008;454:436-44.
26) Liu K, Zhao K, Wang L, Sun E. The prognostic values of
tumor-infiltrating neutrophils, lymphocytes and neutrophil/
lymphocyte rates in bladder urothelial cancer. Pathol Res Pract.
27) Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al.
Prognostic and predictive value of tumor-infiltrating lymphocytes
in a phase III randomized adjuvant breast cancer trial in nodepositive
breast cancer comparing the addition of docetaxel to
doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.
J Clin Oncol. 2013;31:860-7.