










































Key Words Competing Interests Article Information

Kidney cancer, CD34, FSHR,  
tumor markers

None declared.

Funding Statement: Dr Giancarlo Marra’s 
work at Institut Mutualiste Montsouris and at 
Institut Curie has been funded by a grant from 
the European Urology Scholarship Programme 
(EUSP).

Received on August 22, 2021 
Accepted on January 15, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(3):132–143

DOI: 10.48083/RQBN1626

132 SIUJ  •  Volume 3, Number 3  •  May 2022 SIUJ.ORG

This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

ORIGINAL RESEARCH

CD34 and FSHR Expression to Differentiate  
Multiple Subtypes of Benign and Malignant  
Renal Neoplasms
Giancarlo Marra,1,2 Didier Meseure,3 Marine Lefèvre,2 Andre Nicolas,3 Laetitia Lesage,3  
Nicolae Ghinea,4 Marco Moschini,1 Caio Pasquali,1 Petr Macek,1 Claudia Filippini,2  
Paolo Gontero,2 Rafael Sanchez-Salas,1 Xavier Cathelineau1

1 Department of Urology, Institut Mutualiste Montsouris and Université Paris Descartes, Paris, France  2 Department of Urology and University of Turin, Turin, Italy  
3 Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie, Paris, France  4 Department of Pathology, Institut Mutualiste 
Montsouris, Paris, France

Abstract

Background Currently, no markers accurately differentiate benign from malignant renal masses. CD34 and FSHR 
are transmembrane proteins involved in neo-angiogenetic pathways and are differently expressed in several normal 
and cancerous tissues. However, little evidence exists on their distribution in different renal tumors. We aimed to 
evaluate their expressions in various renal tumors and adjacent normal tissue.

Methods We retrieved 810 histological samples from 26 patients who underwent surgery for suspected RCa. In each 
case a core of 10 × 1 mm was selected perpendicular to the tumor capsule between normal kidney and tumor. Within 
this core 30 regions of interest (ROI), each measuring 669 μm × 500 μm, were acquired at 20× magnification (n = 2 
adjacent normal tissue; n = 2 tumor capsule; n = 26 tumor). The surface area of FSHR and CD34 immunostaining was 
quantified in each ROI using number of stained pixels. The results were compared between RCa and normal kidney.

Results Immunostaining was significantly different in normal, tumor capsular, and tumor tissues (both CD34 and 
FSHR P < 0.0001), with overall highest expression in normal and lowest in tumor tissues, where CD34 and FSHR were 
differently expressed amongst different tumor subtypes (both P < 0.0001). CD34 and FSHR were more expressed in 
benign versus malignant (both P < 0.0001) and in chromophobe carcinoma versus oncocytoma tumor tissues (CD34 
P = 0.0003; FSHR P < 0.0001). The discriminating ability of FSHR alone for benign versus malignant (AUC 0.805; 
95% CI 0.771 to 0.837) and chromophobe carcinoma versus oncocytoma (AUC 0.973; 95% CI 0.939 to 0.991) was high. 
In both cases FSHR AUC was significantly higher than CD34 (both P < 0.0001) and equivalent to the combination 
of CD34 and FSHR (both P > 0.9). The correlation amongst levels of staining in tumor tissues and distance from the 
capsule were overall weak (Spearman coefficient CD34 to 0.0644; FSHR-0.16322).

Conclusion CD34 and FSHR are differentially expressed across renal tumor subtypes and between tumor and 
surrounding tissues. FSHR expression alone may be a useful tool to differentiate benign from malignant tumors and 
chromophobe carcinoma from oncocytoma.

Introduction 
Neo-angiogenesis is an important process for malignant and benign tumors growth and progression, allowing 
unrestricted expansion[1,2]. CD34 and follicle-stimulating hormone receptor (FSHR) are transmembrane proteins 
present in endothelial cells on the surface of blood vessels and differently expressed in several normal and cancerous 
tissues[2].

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CD34 is an intercellular adhesion and cell-sur-
face glycoprotein present in hematopoietic progenitor 
cells and endothelial vascular and lymphatic cells[2,3]. 
Although its specific function is not yet precisely char-
acterized, CD34 is a pan-endothelial marker, and 
anti-CD34 antibodies are highly sensitive for endo-
thelial differentiation. CD34 is differentially expressed 
in neoplastic and normal endothelium and/or may 
yield a prognostic value for several cancers including 
cervical[2], gastric[4] hepatoellular[5], prostate[6,7], 
kidney[8], bladder[9], and other neoplasms.

FSHR is a glycosylated transmembrane protein of the 
G protein receptors family, normally found in human 
testis Sertoli and ovarian granulosa cells[10,11]. Its 
presence has also been demonstrated in other tissues 
including osteoclasts, monocytes, endometrial cells, 
and the thyroid and the prostate glands, where, however, 
its expression is usually limited[11]. On the contrary, 
several malignancies—ovarian[12], prostate[13,14], 
breast[15], and others[15,16]—are found with FSHR 
expression. Although in cancer cells FHSR presence 
has been shown to vary depending on tumor type, its 
expression is constant in the endothelial cells within 
several cancers[11].

Kidney cancer is not infrequent, currently represent-
ing the sixth and eighth commonest cancer in men and 
women respectively, with more than 70 000 new cases 
detected yearly in the US[17]. In recent years, renal 
cancer (RCa) diagnosis has undergone a shift, with more 
than 60% of cases being diagnosed in the form of inci-
dental small renal masses when abdominal imaging 
is performed for other investigations[18]. These renal 
lesions can be benign or malignant, and the RCa can 
vary widely with respect to prognosis. Conventional 
imaging, including CT and/or mpMRI, despite being 
currently able to identify renal masses, cannot reliably 
distinguish benign angiomyolipoma (AML) with mini-
mal fat and oncocytoma from malignant lesions[19–21]. 
This diagnostic challenge holds even more true for 
oncocytoma as even when renal biopsies are performed, 
final histology of the surgical specimens confirms onco-
cytic neoplasms in only about 64.6% of cases, with the 
remaining tumors being mainly chromophobe carci-
noma (18.7%)[22].

Although several attempts have been made, to date 
no molecular markers are able to reliably differentiate 
benign from malignant renal lesions[23]. Some studies 
previously detailed CD34 and FSHR expression in renal 
tissues and renal cell carcinoma (RCC), but overall, little 
to no evidence exists on their distribution in different 
RCa[11,24]. Furthermore, as they are expressed in tumor 
endothelial cells and involved in neo-angiogenetic path-
ways at multiple levels, they represent a potential target 
for molecular imaging with specific contrast agents and 
for novel therapeutic agents[1,2,10,11].

Our aim was to perform a preliminary evaluation of 
CD34 and FSHR expression in surgical specimens of 
different types of benign and malignant renal neoplasms 
and surrounding normal tissues and to detail their abil-
ity to differentiate amongst different subtypes of renal 
neoplasms.

Materials and Methods 
Patients and tissue analysis 
We retrieved histological samples from 26 patients 
who underwent surgical removal of a renal tumor 
including chromophobe RCC (n = 4), type 1 papillary 
RCC (pRCC1; n = 3), type 2 papillary RCC (pRCC2;  
n = 3), clear cell RCC (ccRCC; n = 9), oncocytoma (n = 6), 
and AML (n = 1). Paraffin-embedded tissue blocks 
were retrieved from the archives of the Department of 
Biopathology, Institut Mutualiste Montsouris, Paris, 
France.

Immunohistochemistry 
Immunohistochemistry assay was performed using 
FSHR-A02 antibodies (homemade antibody, mouse 
monoclonal, at 0.2µg/mL for 30min at RT) and CD34 
antibodies (DAKO ref:M7165, mouse monoclonal 
Qbend-10, at 1/200 for 30min at RT).

All immunostainings were processed using a Leica 
BOND R X research automated immunostaining 
device. Heat induced antigen retrieval was performed 
using citrate pH6 buffer (FSHR) and EDTA pH9 buffer 
(CD34). Immunodetection was performed using Leica 
Bond Polymer Refine detection kit according to the 
manufacturer’s instructions. Antibodies specificity was 
confirmed on a panel of human testis tissue.

Quantitative analysis 
FSHR and CD34 labeled whole slides were scanned with 
the Perkin Elmer Vectra 3 scanner at ×10 magnification. 
Sections of 3 µm were cut with a microtome perpen-
dicularly from the paraffin-embedded tissue block, 
including samples from the normal kidney, the tumor 
capsular zone, if present, and the kidney tumor. In 
each case, a core of 10 mm (depth) × 1 mm (width) was 
selected perpendicular to the capsule between normal 

Abbreviations 
AML angiomyolipoma
ChC chromophobe carcinoma
FSHR follicle-stimulating hormone receptor
RCa renal cancer
RCC renal cell carcinoma

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kidney and tumor to simulate a biopsy core. Within 
this core, 30 regions of interest (ROI), each measuring 
669 μm × 500 μm, were acquired at 20× magnification. 
Two ROI were analyzed from normal kidney, 2 from 
the tumor capsular zone, when present, and 26 from 
the tumor (Figure 1). These ROI were then analyzed 
using the Perkin Elmer inForm software, which made 
it possible to determine the number of positive pixels 
for the DAB and thus to know the percentage of FSHR 
and CD34 labeled surface. Recorded variables included 
FSHR and CD34 staining, distance from the capsule 
and/or normal tissue, and tumor type. Figure 2 and 
Figure 3 display examples for the different tumors that 
were assessed according to ROI type for CD34 and 
FSHR immunostaining, respectively.

Study aims 
Our primary aim was to evaluate expression of CD34 
and FSHR in different ty pes of renal neoplasms 
including surrounding normal tissues, tumor capsular 
tissue, and tumor tissue.

Secondar y aims were to eva luate whether CD34 
and FSHR are differentially expressed in and can 
discriminate between (1) malignant versus benign 
renal tumor; (2) oncocy toma versus chromophobe 
carcinoma.

Statistical analysis  
Su mma r y data were presented as media n a nd 
interquartile range for continuous variables and as 
frequency and percentages for categorical variables. In 
univariate analysis, continuous variables were compared 
with the use of Wilcoxon-Mann-Whitney or Kruskal-
Wallis test as appropriate. Spearman’s coefficient was 
used to evaluate correlation between CD34 and FSHR 
immunostaining in cancerous tissues depending on the 

distance from the capsule. To investigate the ability of 
biomarkers to discriminate benign from malignant 
t u mor s  a nd  onc o c y tom a  f rom  c h romophob e 
carcinoma, CD34 and FSHR immunostaining values 
in cancerous tissues and the combination of both 
were used to perform different receiver-operating 
characteristics curves (ROC). Results are given as area 
under the curve (AUC) and 95% confidence interval 
(CI). Comparison between AUC was perform using 
DeLong’s test. All tests were two-tail, and the level of 
statistical significance was set at 0.05. All the analyses 
were performed with SAS software, version 9.4 (SAS 
Institute Inc., Cary, US).

Results 
Baseline analysis 
We a na ly zed 810 t issue sa mples, i nclud i ng 210 
(26%) benign a nd 60 0 (74%) ma ligna nt tumors. 
The majority of samples were from tumor tissues 
(n = 702) and a minority from tumor capsular (n = 54) 
or normal (n  =  54) tissue surrounding the cancer. 
Immunostaining values for CD34 and FSHR stratified 
by tumor subtype and tissue source (normal adjacent 
tissue, tumor capsule or tumor) are displayed in 
Figure 4A-B.

Overall distribution of CD34 and FSHR in 
normal, capsular, and tumor tissues 
Table 1 displays immunostaining values of CD34 and 
FSHR depending on tumor subtypes and malignant or 
benign diseases. Overall, we observed immunostaining 
was slightly but statistically significantly different in 
normal, tumor capsular, and tumor tissues (both CD34 
and FSHR P < 0.0001), with overall highest expression 
in normal tissues and lowest expression in cancerous 
tissues. Expression was always higher in normal 
and tumor capsular tissues compared with tumor 
tissues with the exception of CD34 for chromophobe 
carcinoma.

Overall, capsular CD34 and FSHR did not yield 
significant differences amongst different tumors with 
CD34 ranging from 4.47 for pRCC2 to 11.16 for pRCC1 
(P = 0.1450) and FSHR ranging from 1.05 for AML to 
5.25 for oncocytoma (P = 0.14). CD34 expression was 
different amongst normal adjacent tissue from differ-
ent tumors (range 6.98 for ccRCC to 13.33 for AML;  
P = 0.0196) while FSHR did not yield any significant 
differences (range 0.92 for AML to 4.65 for oncocytoma; 
P = 0.1120). CD34 and FSHR were significantly differ-
ently expressed across the different tumor tissues (both  
P < 0.0001). The range was relatively wide for CD34 (from 
1.45 for pRCC1 to 8.72 for chromophobe carcinoma), 
whereas FSHR always had a mean staining percentage 
< 0.9 with the exception of oncocytoma (4.28).

FIGURE 1. 

Tissue sampling methodology for CD34 and FSHR 
quantification  

For each case acquisition of 30 zones of 669 µm x 500 µm  
(10 mm depth x 1 mm width) was performed.
Red: normal surrounding tissue; blue: capsular tissue;  
green: tumor tissue.

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FIGURE 2.

CD34 immunostaining in adjacent normal, tumor 
capsular and tumor tissue in different types of renal 
neoplasms 

FIGURE 3. 

FSHR immunostaining in adjacent normal, tumor 
capsular and tumor tissue in different types of renal 
neoplasms 

Malignant versus benign renal cancers 
Immunostaining values for CD34 and FSHR stratified 
by cancer subtype and location (normal adjacent tissue, 
tumor capsule or tumor) are displayed in Figure 4C-D 
and Table 1.

CD34 expression was highest in normal tissue, 
followed by tumor capsular and tumor tissues both for 

malignant and benign neoplasms (P = 0.0301 amongst 
benign and P < 0.0001 for malignant lesions) but no rele-
vant differences were found between expression in the 
tumor capsule and normal tissue of benign versus malig-
nant diseases (both P > 0.2). However, CD34 was slightly 
but statistically significantly more highly expressed in 
benign (5.69, IQR 3.5 to 7.3) versus malignant tumor 
tissues (4.92, IQR 1.7 to 7.1, P < 0.0001).

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TABLE 1. 

Immunostaining values of CD34 and FSHR stratified by tumor type and site 

CD34 % staining (IQR)

All ccRCC Cromophobe  Carcinoma pRCC1 pRCC2 Oncocytoma AML P value

Normal 8.58   (5.9–11.0) 6.98    (4.5–9.8) 9.84  (8.3–10.8) 10,24    (10.0–10.5) 11.49    (11.0–12.2) 7.57  (5.8–8.3) 13.33    (9.4–17.2)* 0.0196

Capsule 6.12   (2.7–8.6) 3.97    (1.8–5.8) 7.53  (5.3–9.5) 11.16 (3.8–18.9) 4.47 (1.2–8.0) 6.83  (5.3–8.8) 5.31 (1.4–9.2)* 0.1450

Tumor 5.10   (2.0–7.2) 5.42   (2.7–7.3) 8.72  (5.2–12.2) 1.45 (0.9–2.0) 2.09 (1.5–2.5) 6.27  (4.5–7.7) 3.05  (2.2–3.5) <0.0001

P <0.0001 0.0399 0.6131 <0.0001 0.0002 0.4914 0.0663

All 5.41  (2.63–7.42) 8.69  (5.3–12.2) 2.33 (1.0–2.2) 2.96 (1.5–3.0) 6.43  (4.7–7.8) 3.89  (2.1–4.4) <0.0001

Benign Malignant

Normal     8.39 (5.9–9.4) 8.67   (6.9–11.0) 0.4274

Capsule    6.61  (5.1–9.0)  5.93 (2.3–8.1) 0.2275

Tumor 5.69   (3.5–7.3)   4.92  (1.7–7.1) <0.0001

P 0.0301 <0.0001

All    5.98 (3.7–7.7) 5.20   (1.8–7.6) <0.0001

Chromophobe Oncocytoma

Normal 9.84   (8.3–10.8) 7.57    (5.8–8.3) 0.0678

Capsule   7.53 (5.3–9.5) 6.83    (5.3–8.8) 0.6160

Tumor 8.72   (5.2–12.2) 6.27    (4.5–7.7) 0.0003

P 0.6131 0.4914

All 8.69   (5.3–12.2) 6.43   (4.67–7.8) <0.0001

FSHR % staining (IQR)

All ccRCC Cromophobe  Carcinoma pRCC1 pRCC2 Oncocytoma AML P value

Normal 2.22  (0.7–2.7) 2.03   (0.5–2.3) 3.12   (2.6–3.7) 1.29  (1.3–1.3) 1.35   (2.2–2.5) 4.65   (3.8–5.7) 0.92 (0.8–1.1) 0.1120

Capsule 2.49   (2.7–8.6) 1.94   (0.2–3.2) 1.47   (0.4–1.7) 1.63  (0.5–2.5) 3.44   (0.8–5.0) 5.25   (3.3–6.3) 1.05   (1.0–1.1) 0.1400

Tumor  1.28  (0.03–1.8) 0.82   (0.01–1.1) 0.08   (0.02–0.1) 0.29   (0.0–0.3) 0.82   (0.2–1.3) 4.28   (2.2–5.1) 0.02  (0–0.01) <0.0001

P <0.0001 0.0002 <0.0001 0.0005 0.0691 <0.0001 0.0059

All 0.98   (0.02–1.4) 0.32   (0.02–0.2) 0.41 (0.06–0.43) 1.07   (0.18–1.6) 4.35   (2.2–5.2) 0.15   (0–0.02) <0.0001

Benign Malignant

Normal 3.41   (1.2–5.1) 1.99   (0.5–2.6) 0.1932

Capsule 4.32   (1.1–4.9)  2.05  (0.4–3.4) 0.0500

Tumor 3.50   (1.5–4.5) 0.61    (0.02–0.65) <0.001

P 0.7875 <0.0001

All 3.55   (1.35–4.8) 0.80   (0.03–1.072) <0.001

Chromophobe Oncocytoma

Normal 3.12  (2-6–3.7)  4.65   (3.8–5.7) 0.4705

Capsule 1.47   (0.4–1.7)   5.25   (3.3–6.3) 0.0268

Tumor 0.08   (0.02–0.1)   4.28   (2.2–5.1) <0.0001

P <0.0001 <0.0001

All  0.32  (0.02–0.2)   4.35 (2.2–5.2) <0.0001

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TABLE 1. 

Immunostaining values of CD34 and FSHR stratified by tumor type and site 

CD34 % staining (IQR)

All ccRCC Cromophobe  Carcinoma pRCC1 pRCC2 Oncocytoma AML P value

Normal 8.58   (5.9–11.0) 6.98    (4.5–9.8) 9.84  (8.3–10.8) 10,24    (10.0–10.5) 11.49    (11.0–12.2) 7.57  (5.8–8.3) 13.33    (9.4–17.2)* 0.0196

Capsule 6.12   (2.7–8.6) 3.97    (1.8–5.8) 7.53  (5.3–9.5) 11.16 (3.8–18.9) 4.47 (1.2–8.0) 6.83  (5.3–8.8) 5.31 (1.4–9.2)* 0.1450

Tumor 5.10   (2.0–7.2) 5.42   (2.7–7.3) 8.72  (5.2–12.2) 1.45 (0.9–2.0) 2.09 (1.5–2.5) 6.27  (4.5–7.7) 3.05  (2.2–3.5) <0.0001

P <0.0001 0.0399 0.6131 <0.0001 0.0002 0.4914 0.0663

All 5.41  (2.63–7.42) 8.69  (5.3–12.2) 2.33 (1.0–2.2) 2.96 (1.5–3.0) 6.43  (4.7–7.8) 3.89  (2.1–4.4) <0.0001

Benign Malignant

Normal     8.39 (5.9–9.4) 8.67   (6.9–11.0) 0.4274

Capsule    6.61  (5.1–9.0)  5.93 (2.3–8.1) 0.2275

Tumor 5.69   (3.5–7.3)   4.92  (1.7–7.1) <0.0001

P 0.0301 <0.0001

All    5.98 (3.7–7.7) 5.20   (1.8–7.6) <0.0001

Chromophobe Oncocytoma

Normal 9.84   (8.3–10.8) 7.57    (5.8–8.3) 0.0678

Capsule   7.53 (5.3–9.5) 6.83    (5.3–8.8) 0.6160

Tumor 8.72   (5.2–12.2) 6.27    (4.5–7.7) 0.0003

P 0.6131 0.4914

All 8.69   (5.3–12.2) 6.43   (4.67–7.8) <0.0001

FSHR % staining (IQR)

All ccRCC Cromophobe  Carcinoma pRCC1 pRCC2 Oncocytoma AML P value

Normal 2.22  (0.7–2.7) 2.03   (0.5–2.3) 3.12   (2.6–3.7) 1.29  (1.3–1.3) 1.35   (2.2–2.5) 4.65   (3.8–5.7) 0.92 (0.8–1.1) 0.1120

Capsule 2.49   (2.7–8.6) 1.94   (0.2–3.2) 1.47   (0.4–1.7) 1.63  (0.5–2.5) 3.44   (0.8–5.0) 5.25   (3.3–6.3) 1.05   (1.0–1.1) 0.1400

Tumor  1.28  (0.03–1.8) 0.82   (0.01–1.1) 0.08   (0.02–0.1) 0.29   (0.0–0.3) 0.82   (0.2–1.3) 4.28   (2.2–5.1) 0.02  (0–0.01) <0.0001

P <0.0001 0.0002 <0.0001 0.0005 0.0691 <0.0001 0.0059

All 0.98   (0.02–1.4) 0.32   (0.02–0.2) 0.41 (0.06–0.43) 1.07   (0.18–1.6) 4.35   (2.2–5.2) 0.15   (0–0.02) <0.0001

Benign Malignant

Normal 3.41   (1.2–5.1) 1.99   (0.5–2.6) 0.1932

Capsule 4.32   (1.1–4.9)  2.05  (0.4–3.4) 0.0500

Tumor 3.50   (1.5–4.5) 0.61    (0.02–0.65) <0.001

P 0.7875 <0.0001

All 3.55   (1.35–4.8) 0.80   (0.03–1.072) <0.001

Chromophobe Oncocytoma

Normal 3.12  (2-6–3.7)  4.65   (3.8–5.7) 0.4705

Capsule 1.47   (0.4–1.7)   5.25   (3.3–6.3) 0.0268

Tumor 0.08   (0.02–0.1)   4.28   (2.2–5.1) <0.0001

P <0.0001 <0.0001

All  0.32  (0.02–0.2)   4.35 (2.2–5.2) <0.0001

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AML Oncocyt Cromoph RCC TPP T1 TPP T2 AML Cromoph Oncocyt RCC TPP T1 TPP T2

20,00

15,00

0000

5,00

0,00

A B

C
D

34

FS
H

R

20,00

25,00

15,00

10,00

5,00

0,00

Capsule Normal tissue Tumor Capsule Normal tissue Tumor

A. CD34 stratified per tumor subtype; B. FSHR stratified by tumor subtype; C. CD34 stratified by malignant versus benign tumor; D. FSHR stratified by 
malignant versus benign tumor; AML: angiomyolipoma; chromoph: chromophobe carcinoma; pRCC: papillary renal cell carcinoma; ccRCC: clear cell  
renal cell carcinoma.

FIGURE 4. 

CD34 and FSHR immunostaining in adjacent normal, tumor capsular and tumor tissue amongst different types of 
renal neoplasms

C D

Capsule Normal tissue Tumor Capsule Normal tissue Tumor

C
D

34

FS
H

R

20,00

15,00

10,00

5,00

0,00

25,00

20,00

15.00

10,00

5,00

0,00
Benign MalignantBenign Malignant

FSHR was expressed similarly in normal, tumor 
capsular, and benign tumor tissues and no relevant 
differences with corresponding sites related to malig-
nant tumors were noted (normal tissue P = 0.19 and 
tumor capsule P = 0.05). However, FSHR expression 
was significantly greater in benign (3.55, IQR 1. 5 to 4.5) 
versus malignant tumor tissues (0.15, IQR 0.02 to 0.65, 
P < 0.0001).

ROC curves are displayed in Figure 5A. The highest 
AUC in differentiating malignant from benign tumors 
was for FSHR (AUC 0.805; 95% CI 0.771 to 0.837). The 
discriminating ability of FSHR alone was comparable 
to the use of the combination of FSHR and CD34 (AUC 
0.805; 95% CI 0.770 to 0.837, P = 0.9920) and superior 
to CD34 alone (AUC 0.630; 95% CI 0.589 to 0.669, 
P <0.0001).

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Oncocytoma versus chromophobe carcinoma 
CD34 expression was overall not significantly different 
amongst different sites within oncocy tomas and 
chromophobe subtypes (both P > 0.4). Similarly, no 
significant staining differences were observed between 
tumor capsular and normal tissues of oncocytomas 
versus chromophobe carcinomas (both P > 0.05). 
Nonetheless, CD34 was present at higher levels in 
chromophobe carcinoma (8.72; IQR 5.3 to 12.2) 
versus oncocytoma tumor tissues (6.27, IQR 4.5 to 7.8, 
P = 0.0003).

FSHR was expressed differently in normal, capsular, 
and tumor tissues both for chromophobe carcinomas 
and oncocytomas (both P < 0.0001). FSHR was signifi-
cantly higher in capsular sections related to oncocytoma 
compared with chromophobe carcinoma (5.25, IQR 
3.3 to 6.3 versus 1.47, IQR 0.4-1.7; P = 0.0268) and even 
more markedly expressed in tumor tissue from oncocy-
toma (4.28, IQR 2.2 to 5.1) compared with chromophobe 
carcinoma, where the FSHR was almost not expressed 
(0.08, IQR 0.02 to 0.1; P < 0.0001).

ROC curves are displayed in Figure 5B. FSHR expression 
in tumor tissues was able to accurately differentiate 
oncocytomas from chromophobe carcinomas (AUC 
0.973; 95% CI 0.939 to 0.991). The discriminating ability 
of FSHR alone was comparable to the combination of 
FSHR and CD34 (AUC 0.973; 95% CI 0.939 to 0.991, 
P = 0.9875) and superior to that of CD34 alone (AUC 
0.666; 95% CI 0.595 to 0.731; P < 0.0001).

Capsular distance in cancerous tissue
The correlation amongst levels of staining in tumor 
tissues and distance from the capsule were overall 
weak (Spearman’s coefficient CD34 -0.0644; FSHR-
0.16322) and different amongst different cancer 
subtypes (Supplementary Table S1). Lowest and highest 
correlation for CD34 were with tpRCC2 (0.01529) and 
chromophobe carcinoma (0.18685), respectively and for 
FSHR with chromophobe carcinoma (0.01521) and AML 
(−0.349949), respectively.

Discussion
In the current study, we assessed CD34 and FSHR 
expression in different renal cancer subtypes, including 
benign and malignant neoplasms and cancerous and 
non-cancerous surrounding tissues. To our knowledge, 
this is the first work to detail CD34 and FSHR expression 
in this context. Several findings of our work are of 
interest.

First, we found both markers can vary widely 
amongst different subtypes of renal cancers. This holds 
true especially for the expression of CD34 and FSHR 
in cancerous tissues, but differences amongst cancer 
subtypes in normal surrounding tissues and in the 

capsule are less marked. A limited number of stud-
ies investigated immunostaining levels depending on 
kidney cancer histology for CD34[25,26], suggesting 
different levels of expression, and no studies assessed 
FSHR. Immunostaining differences need to be further 
explored to determine the possible roles of these mole-
cules in different types of carcinogenetic pathways 
according to the corresponding cancer subtypes.

Second, within the same renal cancer subtype, 
CD34 and FSHR also vary significantly, depending on 
whether we analyzed the normal peri-tumoral tissue, 
the capsule, or the cancer. Some cancers, as for TPP1 and 
TPP2 for CD34, have markedly higher staining outside 
the cancerous areas, and others, like oncocytomas, 
have similar levels of expression throughout different 
sites. Indeed, patterns of expression of these molecules, 
whether they are more or less present towards the 
cancerous or non-cancerous tissues or whether they are 
more or less uniform throughout different sites, also 
mandate further assessment as they may help in recog-
nizing different renal cancers and in clarifying different 
molecular carcinogenetic pathways.

An increased staining at the level of the cancer 
surface may suggest increased angiogenesis and inva-
sive and metastatic potential for cancer cells, through 
newly formed vessels deriving from FSHR pathway acti-
vation[27]. Similarly, previous authors suggested VEGF-
mediated downregulation of CD34 adhesion molecule 
may constitute a tumor-mediated escape mechanism 
from immune surveillance[28].

In this context, it was interesting to note there were 
only weak correlations/changes in CD34 and FSHR 
expression depending on the depth within the cancerous 
tissues. Others detailed a shell type distribution of the 
FSHR receptor, reaching the highest level of expression 
at the border between normal and cancerous tissues and 
then gradually decreasing inside and outside the cancer. 
This finding was noted for all the 11 different cancers 
analyzed, except for renal cell carcinoma, where, as 
in our work, only mild differences between cancerous 
and non-cancerous tissues and overall weak correlation 
of FSHR and CD34 expression and distance from the 
capsule were highlighted[15]. Whether these findings 
may be related to different angiogenetic molecular path-
ways in kidney neoplasms and/or linked to the relatively 
high radiation and drug resistance of kidney neoplasms 
remains to be understood[29].

Third, CD34 and FSHR may help in differentiating 
benign and malignant renal cancers as, especially when 
looking at cancerous areas, they are both more expressed 
in benign tumors. Importantly, this difference, although 
being statistically significant, remains weak for CD34 
and possibly not clinically meaningful. By contrast, 
the expression difference of FSHR between benign and 

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CD34 and FSHR Expression to Differentiate Multiple Subtypes of Benign and Malignant Renal Neoplasms

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malignant renal cancers is more pronounced. In fact, if 
used as a diagnostic test, FSHR has acceptable to excel-
lent ability in discriminating between benign and malig-
nant lesions. Not only is the FSHR discriminating ability 
superior to that of CD34 alone, but it does not signifi-
cantly increase if used in combination with CD34.

Fourth, CD34 and FSHR may also be useful in distin-
guishing oncocytoma from chromophobe carcinoma. 
Again, while CD34 staining differs little between tumor 
types, FSHR is expressed at very low levels in chromo-
phobe carcinoma and at a high level in oncocytoma. As 
such, FSHR has an outstanding discriminating ability 
in differentiating these 2 tumor types, with an AUC of 
0.973 (95% CI 0.939 to 0.991).

Currently, relatively poor evidence is present for 
diagnostic biomarkers and for the ability of differen-
tiating amongst different renal cancer subtypes over-
all. Several molecules have been tested in a diagnostic 
setting. However, even the most promising ones, includ-
ing PAX2 and PAX8, vimentin, cytokeratine 7 and other 
subtypes, and c-kit, have a limited diagnostic ability 
and/or show relevant limitations such as negativizing 
in high-grade tumors, or not staining in some of the 
commonest renal malignancies[30]. Contrarily, a recent 
meta-analysis highlighted several promising molecules 
that may help to differentiate ChC from oncocytomas, 
warranting future comparisons with our results[24].

Several groups already showed FSHR expression 
in different cancerous tissues[15]. Nonetheless, FSHR 

FIGURE 5.  
ROC analysis and respective AUC values to differentiate amongst subtype of kidney tumor

Se
ns

iti
vi

ty

100-Speci�city

Speci�city Benign versus Malignant

0

100

20 40 60 80 100 0 20 40 60 80 100

    80

60

40

          20

0

Se
ns

iti
vi

ty

100-Speci�city

Speci�city Oncocytoma versus ChromophobeBA

100

    80

60

40

          20

0

  CD34   FSHR CD34 - FSHR   CD34   FSHR CD34 - FSHR

A. Benign versus malignant tumors; CD34 cut-off for malignant tumor ≤ 2.6136% - Youden index 0.2740; FSHR cut-off for oncocytoma identification 
≤ 1.6025% - Youden index 0.6223. B. Oncocytoma versus chromophobe carcinoma; CD34 cut-off for oncocytoma identification ≤ 9.2097% - Youden index 
0.3661; FSHR cut-off for oncocytoma identification > 0.5421% - Youden index 0.9176.

AUC 95% CI

FSHR 0.805 (0.771–0.837)

CD34 0.630 (0.589–0669)

FSHR+CD34 0.805  (0.770–0.837)

AUC 95% CI

FSHR 0.973 (0.939–0991)

CD34 0.666 (0.595–0731)

FSHR+CD34 0.973 (0.770–0991)
 

140 SIUJ  •  Volume 3, Number 3  •  May 2022 SIUJ.ORG

ORIGINAL RESEARCH

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expression in renal neoplasms has been explored in only 
a few reports limited to renal cell carcinoma.

From a clinical perspective FSHR may have import-
ant implications in a diagnostic setting. Cancer misclas-
sification on biopsy specimens is not infrequent overall 
and as many as 1 in 3 oncocytomas detected on biopsy 
are found to be chromophobe carcinoma on examina-
tion of the surgical specimen[22]. Considering the global 
increase in the use of renal biopsy and the diagnostic 
shift towards small renal masses[18,31], the ability of 
FSHR to rule out malignant disease and chromophobe 
carcinomas urgently requires further investigation. If 
confirmed, FSHR use may have a relevant impact on 
clinical decision-making.

Another potential application may be represented by 
in vivo diagnostic imaging. Radu et al. proved intrave-
nous accessibility of the FSHR using gold-labeled-an-
tibodies in prostate cancer xenograft mouse models. 
Furthermore, distribution in normal organs was low[15]. 
Recently, Ingels and colleagues showed in vivo ultra-
sound with targeted FSHR microbubbles may correlate 
with sunitinib treatment response in mouse renal cell 
carcinoma[32]. If confirmed in patients, FSHR-based 
imaging could be used to identify renal tumor subtype, 
which would dictate which lesions require further inves-
tigation and possibly intervention.

In a prognostic setting, the value of FSHR remains 
unknown. Given our initial findings on its ability to 
discriminate between malignant and benign diseases 
and the findings of other studies detailing its ability in 
predicting treatment response[29], it is our intent to clar-
ify their prognostic abilities within malignant diseases 
in the near future. Similarly, previous reports found 
possible prognostic value for CD34, depending on its 
immunostaining pattern for renal cell carcinoma[8].

From a research perspective, further efforts should 
be made to elucidate possible roles of FSHR and CD34 
in kidney cancer pathways. CD34 may play a role in 
cancer immune escape but its role overall remains 
largely unknown[28]. On the contrary, amongst its 
several functions, the FSH/FSHR axis has been shown 
to increase angiogenesis through the HIF-1 and VEGF 
pathway[33], with FSHR overexpression promoting 

VEGF/VEGF-receptor binding, and, thus, angiogenesis. 
Furthermore, the pathway also promotes activation of G 
proteins in endothelial cells with activate VEGF recep-
tor in the absence of VEGF, possibly inducing prolifer-
ation and migration independent of VEGF[34,35]. Not 
surprisingly, some authors have speculated that block-
ing FSH-receptor may represent a valid antitumor strat-
egy, inhibiting angiogenesis. Furthermore, FSHR is 
expressed on the luminal surface of endothelial cells, 
thus being an ideal target for ligands to induce peritu-
moral vascular infarction[36].

In this sense, our work also clarifies FSHR may 
have a limited interest as a direct binding site for ther-
apeutic drugs. Others have hypothesized FSHR may 
represent an important target because its expression is 
higher in cancerous than in normal Sertoli and granu-
losa cells[15]. In the context of kidney cancer, we found 
FSHR is more highly expressed in benign tumors and 
associated normal tissue than in malignant tumors and 
associated normal tissue. Nonetheless, we sampled only 
normal tissue surrounding the cancer, possibly includ-
ing areas where molecular alterations may be more 
reflective of tumor microenvironment than unaltered 
normal tissues, which calls for further analysis.

Our work has some limitations. We included a rela-
tively small number of cases and, as a consequence, we 
did not perform multivariable analysis adjusting for 
patient features and/or investigating possible roles in 
patient prognosis. Nonetheless, our aim was to perform 
a preliminary analysis. On the basis of our present 
results, we are in the process of increasing the number of 
patients to confirm our preliminary findings.

Conclusion   
From our preliminary analysis of CD34 and FSHR 
in different subtypes of renal neoplasms, we found 
they are differently expressed in renal tumors and/or 
surrounding tissues depending on the Ca histology. 
FSHR expression alone may be a useful tool to 
differentiate amongst benign and malignant subtypes 
and chromophobe carcinomas and oncocy tomas. 
Larger studies are needed to confirm our findings and to 
evaluate their potential applications.

141SIUJ.ORG SIUJ  •  Volume 3, Number 3  •  May 2022

CD34 and FSHR Expression to Differentiate Multiple Subtypes of Benign and Malignant Renal Neoplasms

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References

1. Folkman J, Watson K , Ingber D, Hanahan D. Induction of 
angiogenesis during the transition from hyperplasia to neoplasia. 
Nature.1989;339:58–61. https://doi.org/10.1038/339058a0

2. Vieira SC, Silva BB, Pinto GA, Vassallo J, Moraes NG, Santana 
JOI, et al. CD34 as a marker for evaluating angiogenesis in cervical 
cancer. Pathol Pract.2005;201:313–318. https://doi.org/10.1016/j.
prp.2005.01.010

3. Fiedler U, Christian S, Koidl S, Kerjaschki D, Emmett MS, Bates DO, 
et al.The sialomucin CD34 is a marker of lymphatic endothelial cells 
in human tumors. Am J Pathol.2006;168:1045–1053. https://doi.
org/10.2353/ajpath.2006.050554

4. Tenderenda M, Rutkowski P, Jesionek-Kupnicka D, Kubiak R. 
Expression of CD34 in gastric cancer and its correlation with histology, 
stage, proliferation activity, p53 expression and apoptotic index. Pathol 
Oncol Res.2001;7:129–134. https://doi.org/10.1007/BF03032579

5. Coston WMP, Loera S, Lau SK, Ishizawa S, Jiang Z, Wu C-L, et 
al. Distinction of hepatocellular carcinoma from benign hepatic 
mimickers using glypican-3 and CD34 immunohistochemistr y. 
Am J Surg Pathol.2008;32:4 33 – 4 4 4. ht tps://doi.org/10.1097/
PAS.0b013e318158142f

6. Foroozan M, Roudi R, Abolhasani M, Gheytanchi E, Mehrazma 
M. Clinical significance of endothelial cell marker CD34 and 
mast cell marker CD117 in prostate adenocarcinoma. Pathol Res 
Pract.2017;213:612–618. https://doi.org/10.1016/j.prp.2017.04.027

7. Nassif A E, Filho R T. Immunohistochemistr y expression of 
tumor markers CD34 and P27 as a prognostic factor of clinically 
localized prostate adenocarcinoma after radical prostatectomy. 
Rev Col Bras Cir.2010;37:338 – 3 4 4. ht tps://doi.org /10.1590/
s0100-69912010000500006

8. López JI, Erramuzpe A, Guarch R, Cortés JM, Pulido R, Llarena R, et 
al. CD34 immunostaining enhances a distinct pattern of intratumor 
angiogenesis with prognostic implications in clear cell renal cell 
carcinoma. APMIS.2017;125:128 –133. ht tps://doi.org/10.1111/
apm.12649

9. Ajili F, Kacem M, Tounsi H, Darouiche A, Enayfer E, Chebi M, et al. 
Prognostic impact of angiogenesis in nonmuscle invasive bladder 
cancer as defined by Microvessel density after immunohistochemical 
staining for CD34. Ultrastruct Pathol.2012;36:336–342. https://doi.org/
10.3109/01913123.2012.672847

10. Sprengel R, Braun T, Nikolics K, Segaloff DL, Seeburg PH. The testicular 
receptor for follicle stimulating hormone: structure and functional 
expression of cloned cDNA. Mol Endocrinol.1990;4:525–530. https://
doi.org/10.1210/mend-4-4-525

11. Papadimitriou K, Kountourakis P, Kottorou AE, Antonacopoulou AG, 
Rolfo C, Peeters M, et al. Follicle-stimulating hormone receptor (FSHR): 
a promising tool in oncology? Mol Diagnosis Ther.2016;20:523–530. 
https://doi.org/10.1007/s40291-016-0218-z

12. Zhang Z, Jia L, Feng Y, Zheng W. Overexpression of follicle-stimulating 
hormone receptor facilitates the development of ovarian epithelial 
cancer. Cancer Lett.2009;278:56 – 64. https://doi.org/10.1016/j.
canlet.2008.12.024

13. Mariani S, Salvatori L, Basciani S, Arizzi M, Franco G, Petrangeli E, et 
al. Expression and cellular localization of follicle-stimulating hormone 
receptor in normal human prostate, benign prostatic hyperplasia and 
prostate cancer. J Urol.2006;175:2072–2077. https://doi.org/10.1016/
S0022-5347(06)00273-4

14. Ben-Josef E, Yang SY, Ji TH, Bidart JM, Garde SV, Chopra DP, et al. 
Hormone-refractory prostate cancer cells express functional follicle- 
stimulating hormone receptor (FSHR). J Urol.1999;161:970 –976. 
https://doi.org/10.1016/S0022-5347(01)61831-7

15. Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, et al 
Expression of follicle-stimulating hormone receptor in tumor blood 
vessels. N Engl J Med.2010 Oct 21;363(17):1621-1630. doi: 10.1056/
NEJMoa1001283.

16. Siraj A, Desestret V, Antoine M, Fromont G, Huerre M, Sanson M, et 
al. Expression of follicle-stimulating hormone receptor by the vascular 
endothelium in tumor metastases. BMC Cancer.2013;13:246. https://
doi.org/10.1186/1471-2407-13-246

17. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J 
Clin.2020;70:7–30. https://doi.org/10.3322/caac.21590

18. Marra G, Oderda M, Allasia M, Munegato S, Joniau S, Gontero P. A 
review on the management of small renal masses: active surveillance 
versus surgery. Anticancer Agents Med Chem.2018;18:940–950. 
https://doi.org/10.2174/1871520617666171113123443

19. Rosenkrantz AB, Hindman N, Fitzgerald EF, Niver BE, Melamed J, 
Babb JS. MRI features of renal oncocytoma and chromophobe renal 
cell carcinoma. Am J Roentgenol.2010;195(6):W421-7. doi: 10.2214/
AJR.10.4718

20. Hindman N, Ngo L, Genega EM, Melamed J, Wei J, Braza JM, et 
al. Angiomyolipoma with minimal fat: can it be differentiated from 
clear cell renal cell carcinoma by using standard MR techniques? 
Radiology.2012;265:468–477. https://doi.org/10.1148/radiol.12112087

21. Richard PO, Jewett MAS, Bhatt JR, Evans AJ, Timilsina N, Finelli 
A. Active surveillance for renal neoplasms with oncocytic features 
is safe. J Urol.2016;195(3):581-586. doi: 10.1016/j.juro.2015.09.067. 
Epub 2015 Sep 24.

22. Patel HD, Druskin SC, Rowe SP, Pierorazio PM, Gorin MA, Allaf ME. 
Surgical histopathology for suspected oncocytoma on renal mass 
biopsy: a systematic review and meta-analysis. BJU Int.2017;119:661–
666. doi: 10.1111/bju.13763. Epub 2017 Feb 27.

23. Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, 
Fernández-Pello S, et al. European Association of Urology guidelines 
on renal cell carcinoma: the 2019 update. Eur Urol.2019;75:799–810. 
https://doi.org/10.1016/j.eururo.2019.02.011

142 SIUJ  •  Volume 3, Number 3  •  May 2022 SIUJ.ORG

ORIGINAL RESEARCH

https://doi.org/10.1038/339058a0
https://doi.org/10.1016/j.prp.2005.01.010
https://doi.org/10.1016/j.prp.2005.01.010
https://doi.org/10.2353/ajpath.2006.050554
https://doi.org/10.2353/ajpath.2006.050554
https://doi.org/10.1007/BF03032579
https://doi.org/10.1097/PAS.0b013e318158142f
https://doi.org/10.1097/PAS.0b013e318158142f
https://doi.org/10.1016/j.prp.2017.04.027
https://doi.org/10.1590/s0100-69912010000500006
https://doi.org/10.1590/s0100-69912010000500006
https://doi.org/10.1111/apm.12649
https://doi.org/10.1111/apm.12649
https://doi.org/10.3109/01913123.2012.672847
https://doi.org/10.3109/01913123.2012.672847
https://doi.org/10.1210/mend-4-4-525
https://doi.org/10.1210/mend-4-4-525
https://doi.org/10.1016/j.canlet.2008.12.024
https://doi.org/10.1016/j.canlet.2008.12.024
https://doi.org/10.1016/S0022-5347(06)00273-4
https://doi.org/10.1016/S0022-5347(06)00273-4
https://doi.org/10.1016/S0022-5347(01)61831-7
https://doi.org/10.1186/1471-2407-13-246
https://doi.org/10.1186/1471-2407-13-246
https://doi.org/10.3322/caac.21590
https://doi.org/10.2174/1871520617666171113123443
https://doi.org/10.1148/radiol.12112087 
https://doi.org/10.1016/j.eururo.2019.02.011
http://SIUJ.org


24. Ng KL, Morais C, Bernard A, Saunders N, Samaratunga H, Gobe G, et 
al. A systematic review and meta-analysis of immunohistochemical 
biomarkers that differentiate chromophobe renal cell carcinoma 
from renal oncocytoma. J Clin Pathol.2016;69:661–671. https://doi.
org/10.1136/jclinpath-2015-203585

25. Dekel Y, Koren R, Kugel V, Livne PM, Gal R. Significance of angiogenesis 
and microvascular invasion in renal cell carcinoma. Pathol Oncol 
Res.2002;8:129–132. https://doi.org/10.1007/BF03033722

26. Yilmazer D, Han Ü, Önal B. A comparison of the vascular density of 
VEGF expression with microvascular density determined with CD34 
and CD31 staining and conventional prognostic markers in renal 
cell carcinoma. Int Urol Nephrol.2007;39:691– 698. https://doi.
org/10.1007/s11255-006-9123-4

27. Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, et al. 
Relationship of endothelial cell proliferation to tumor vascularity in 
human breast cancer. Cancer Res.1993;53(18):4161-4163.

28. Hellwig SMM, Damen CA, Van Adrichem NPH, Blijham GH, 
Groenewegen G, Griffioen AW. Endothelial CD34 is suppressed in human 
malignancies: role of angiogenic factors. Cancer Lett.1997;120:203–
211. https://doi.org/10.1016/S0304-3835(97)00310-8

29. Siraj MA, Pichon C, Radu A, Ghinea N. Endothelial follicle stimulating 
hormone receptor in primary kidney cancer correlates with subsequent 
response to sunitinib. J Cell Mol Med.2012;6:2010–2016. https://doi.
org/10.1111/j.1582-4934.2011.01495.x

30. Farber NJ, Kim CJ, Modi PK, Hon JD, Sadimin ET, Singer EA. Renal 
cell carcinoma: the search for a reliable biomarker. Transl Cancer 
Res.2017;6:620–632. https://doi.org/10.21037/tcr.2017.05.19

31. Perera M, Papa N, Ischia J, Christidis D, Bolton D, Lawrentschuk N, 
et al. Trends in percutaneous renal biopsy: the evolving diagnostic 
pathway for the small renal mass. Urol Ann.2018;10(3):237-239. 
https://doi.org/10.4103/0974-7796.236516

32. Ingels A, Leguerney I, Cournède PH, Irani J, Ferlicot S, Sébrié C, et al. 
Ultrasound molecular imaging of renal cell carcinoma: VEGFR targeted 
therapy monitored with VEGFR1 and FSHR targeted microbubbles. 
Sci Rep.2020;10:1–8. https://doi.org/10.1038/s41598-020-64433-2

33. Alam H, Weck J, Maizels E, Park Y, Lee EJ, Ashcroft M, et al. Role 
of the phosphatidylinositol-3-Kinase and extracellular regulated 
kinase pathways in the induction of hypoxia-inducible factor (HIF)-1 
activity and the HIF-1 target vascular endothelial growth factor in 
ovarian granulosa cells in response to follicle-stimulating hormone. 
Endocrinology.2009;150(2):915-928. doi.org/10.1210/en.2008-0850

34. Castro-Fernández C, Maya-Núñez G, Méndez JP. Regulation of follicle-
stimulating and luteinizing hormone receptor signaling by “regulator of 
G protein signaling” proteins. Endocrine 2004;25:49–54. https://doi.
org/10.1385/ENDO:25:1:49

35. Zeng H, Zhao D, Yang S, Datta K, Mukhopadhyay D. Heterotrimeric  
Gαq /Gα 11 proteins function upstream of vascular endothelial growth 
factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability 
factor/ VEGF signaling. J Biol Chem.2003;278:20738–20745. https://
doi.org/10.1074/jbc.M209712200

36. Ghinea N. Vascular endothelial FSH receptor, a target of interest for 
cancer therapy. Endocrinology.2018;159:3268–3274. https://doi.
org/10.1210/en.2018-00466

SUPPLEMENTARY TABLE S1. 

Spearman’s coefficient for correlation amongst levels 
of staining in tumor tissue and distance from the tumor 
capsule overall and amongst different tumor subtypes 

Kidney Cancer Subtype Spearman’s Coefficient

CD34 FSHR

All −0.0644 −0.16322

AML 0.03701 −0.34994

Chromophobe carcinoma 0.18685 0.01521

Oncocytoma −0.16441 0.17977

Clear cell renal cell carcinoma −0.09991 −0.19721

Papillary renal cell carcinoma 
type 1

−0.01529 0.23871

Papillary renal cell carcinoma 
type 2

−0.21508 0.11991

Negative correlation: bold; positive correlation: underscored.

143SIUJ.ORG SIUJ  •  Volume 3, Number 3  •  May 2022

CD34 and FSHR Expression to Differentiate Multiple Subtypes of Benign and Malignant Renal Neoplasms

https://doi.org/10.1136/jclinpath-2015-203585
https://doi.org/10.1136/jclinpath-2015-203585
https://doi.org/10.1007/BF03033722
https://doi.org/10.1007/s11255-006-9123-4
https://doi.org/10.1007/s11255-006-9123-4
https://doi.org/10.1016/S0304-3835(97)00310-8
https://doi.org/10.1111/j.1582-4934.2011.01495.x
https://doi.org/10.1111/j.1582-4934.2011.01495.x
https://doi.org/10.21037/tcr.2017.05.19
https://doi.org/10.4103/0974-7796.236516
https://doi.org/10.1038/s41598-020-64433-2
https://doi.org/10.1385/ENDO:25:1:49
https://doi.org/10.1385/ENDO:25:1:49
https://doi.org/10.1074/jbc.M209712200
https://doi.org/10.1074/jbc.M209712200
https://doi.org/10.1210/en.2018-00466
https://doi.org/10.1210/en.2018-00466
http://SIUJ.org

