Human Kidney Injury Molecule-1 (hKIM- 1): A Useful Immunohistochemical Marker for Diagnosing Renal...
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Transcript of Human Kidney Injury Molecule-1 (hKIM- 1): A Useful Immunohistochemical Marker for Diagnosing Renal...
![Page 1: Human Kidney Injury Molecule-1 (hKIM- 1): A Useful Immunohistochemical Marker for Diagnosing Renal Cell Carcinoma and Ovarian Clear Cell Carcinoma Journal.](https://reader031.fdocument.pub/reader031/viewer/2022033105/56649d365503460f94a0e093/html5/thumbnails/1.jpg)
Journal Reading:Human Kidney Injury Molecule-1 (hKIM-Human Kidney Injury Molecule-1 (hKIM-1): A Useful Immunohistochemical Mark1): A Useful Immunohistochemical Marker for Diagnosing Renal Cell Carcinoma er for Diagnosing Renal Cell Carcinoma and Ovarian Clear Cell Carcinomaand Ovarian Clear Cell Carcinoma Am J Surg Pathol Volume 31, Number 3, March 2007
Fan Lin, MD, PhD,etc
From the Department of Laboratory Medicine, Geisinger Medical Center
Presented by Intern 賴妮均
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Introduction (1)
9th most Common malignant tumors in U.S. Notorious for distant metastasis
Lung, lymph node, liver, bone, and brain Subtypes:
Conventional; (clear cell) carcinoma Papillary carcinoma Chromophobe carcinoma
D/D with oncocytoma (benign) Collecting duct carcinoma Unclassified carcinoma
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Introduction (2)Immunostaining Markers in RCC
CD10 90% of RCCs
also detected in many hepatocellular carcinomas, prostatic carcinomas, and urothelial carcinomasPositive in normal renal tissue
RCC Ma (RCC marker)
84-92% of primary RCC and 67-84% 0f metastatic RCC
Positive in normal renal tissue
Coexpression of epithelial membrane antigen and vimentin
clear cell RCC
MN/CA9 (Carbonic anhydrase IX)
100% of clear cell RCC and papillary RCC
Also expressed in cervical dysplasia and carcinoma
P504S100% of papillary RCCs and some primary and metastatic clear cell RCC
marker for prostatic adenocarcinomaPositive in normal renal tissue
CD9/MPR1),Antimitochondrialantibody (113–1), E-cadherin and vinculin
high sensitivity for chromophobe RCC, papillary RCC, and oncocytoma
Osteonectin (SPARC) sarcomatoid RCC
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Introduction (3)B defensin-1 (+), parvalbumin (+), and vimentin (-)
100 % of Chromophobe RCC and oncocytoma
glutathione S-transferase-a and carbonic anhydrase II(CAII)
Clear cell RCC and chromophobe RCC
kidney-specific cadherin (Ksp-cadherin) andRon proto-oncogene
Majority of both chromophobe RCC and oncocytoma
frequently absent in clear cell RCC Ksp-cadherin :Positive in normal renal tissue
CD117 (c-kit)chromophobe RCC and some oncocytoma
frequently absent in clear cell RCC
S-100 protein70% of clear cell RCC and 90% of oncocytoma
only observed in 6% of chromophobe RCCPositive in normal renal tissue
none of the aforementioned markers is absolutely sensitive and specific for RCC
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Introduction (4)
Human kidney injury molecule-1 (hKIM-1)= TIM-1 (T cell immunoglobin domain andmucin domain protein 1)= HAVCR1 (hepatitis A virus cellular receptor 1)
Gene: located in human chromosome 5q Type I transmembranous glycoprotein containing an extracellular immunoglobulinlike domain topping a long mucinl
ike sequence As biomarker for regeneration of renal proximal tubules after tubular injury.3
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Material and Method (1)
Case Selection264 cases of renal epithelial neoplasmanonymous and disassociated from any
clinical data
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Material and Method (2) TMA sections
221 cases of nonrenal tumors from various organs to test the specificity of anti-hKIM-1 antibody
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Material and Method (3)
TMA constructionH&E stain sections were reviewedremove 1.0-1.5 mm tissue core from marked
area of paraffin block inserted into recipient paraffin block
(Beecher Instruments Inc, Sun Prairie, WI)
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Material and Method (4)
Immunohistochemistry Formalin-fixed and paraffin-embedded 4μm sections Antibody to hKIM-1
AKG7 monoclonal antibody Confirmed by ABE3 antibody in CCCO and uterus
Positive control: Kidney tissues with acute tubular necrosis
Negative control: replacement of the primary antibody with nonimmune mouse serum
Interpretation: 2 surgical pathologists indicates negative; 1+, <10%; 2+, 11% to 50%; 3+, >50%.
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Material and Method (5)
Western Blot 4 cases of renal tumor with different subtypes Normal renal tissue from a clear cell RCC case
Frozen tissue blocksLysed tissue homogenatws Electrophoresed on 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) Transferred onto polyvinyl diflouride membranes Incubated with AKG7 monoclonal antibody
Evenness of the protein loading: antibody to β-actin
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Material and Method (6)
Gene Expression Microarray tissues were frozen promptly after surgery an
d stored at -80 .℃hKIM-1 mRNA level
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Results (1) Non-neoplastic renal tissue
Negative: Glomeruli, vessels, inflammatory cells, interstitialcells, lymphoid aggregatesinterstitial tissues
Positive immunoreactivity was observed in proximal tubules, with a cytoplasmic / membranous staining pattern during acute tubular necrosis
2 of 20 case in TMA showed focal immunostaining occasional proximal tubules
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Result (2)
Renal Epithelial Neoplasm
(2/15) in TMA
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Result (3)Clear cell RCC, Papillary RCC
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Result (4)
Chromophobe RCC
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Result (5) Diffuse immunoreactivity was more frequently observed in high-grad
e clear cell RCC (56%) than in low-grade clear cell
2/2 sacromatoid RCC were positive 1 case of Wilms tumor and no immunoreactivity was observed (data not shown)
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Result (6)
Metastatic clear cell RCC The percentages of positive c
ases were not significantly different among theseanatomic sites.
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Result (7) Non-renal Neoplasms
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Result (8) CCCO
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Result (9) Clear cell carcinoma of uterus Adenocarcinoma of the colon
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Result (10)
Western Blot
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Result (11) hKIM-1 mRNA in Renal Tumors From Affy
metrix Microarrays
0
-131
537
285
-126
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Discussion
Do we really need another immunohistochemical marker?
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Discussion
Differentiated from normal renal tissue The previously reported biomarkers are expressed in normal renal tissue Murine KIM-1 expressed in actived T cells and linked to air hypersensitivity, but h
KIM-1 does not
Negative staining in: Non-neoplastic renal tissues Transplanted renal biopsy with acute cellular rejection
Positive staining in: (1) proximal tubules adjacent to renal tumors (2) proximal and distal tubules in the tumorous kidney, probably secondary to tumor ob
struction and compression (3) atrophic renal tubules; (4) proximal tubules associated with tubular injury,such as hypoxia, ischemia, toxin, inf
ection, etc
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Discussion
More specific to clear cell RCC and papillary RCC Oncocytoma: only 4 of 41 (9.8%) with focally positive stained Chromophobe RCC: all negative
CD-10 also expressed in oncocytoma RCC Ma also expressed in chromophobe RCC P504S also expressed in both oncocytoma and chromophobe
RCC S-100 also expressed in >90% oncocytoma
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Discussion
More specific to metastatic RCC Han et al: only 1 of 450 nonrenal tumor was positive
(HCC) CD10, RCC Ma, S-100, P504S, glutathione S-transfer
ase-a, CD117: well-documented in other nonrenal tumors
Why higher positive reaction than previoud Han’s study?
CCCO and uterus were not included The previous study only checked TMA
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Discussion
What are the unique features and utility of this antibody?
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Discussion
Expression of hKIM-1 in CCCO (93.8%) Both ovary and uterus serous carcinoma and endometroid carcinoma la
cked hKIM-1 expression Dent and coworkers: gene amplification in CCCO was most common at
chromosome 3 Von Hippel-Lindau tumor-suppressor genes:
located at the chromosome 3p25; and the von Hippel-Lindau tumorsuppressor
closely linked to the tumorigenesis of both sporadic and hereditary clear cell RCC
hKIM-1 had similar role in both clear cell RCC and CCCO? Anti-hKIM-1Ab may be used in targeted cancer therapy for CCCO?
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Discussion
clear cell carcinoma of the uterusonly 33% expressed hKIM-1not related to chromosome 3 alternation
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Clear cell carcinoma of uterus Adenocarcinoma of the colon
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Discussion
Focal positive staining in adenocarcinoma of the colon 5 of 40 cases Pattern: apical portions of neoplastic glands
Only in well and moderately differentiatied colonic adenocarcinoma
the AKG7 anti-hKIM-1 monoclonal antibody:against the extracellular mucin domaincross reaction
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Disscusion
Conventional RCC S-100+/hKIM-1+/MSH2-/CK7-
Chromophobe RCC MSH2+ (cytoplasmic staining) /CK7+/S-100-/hKIM-1-
Oncocytoma S-100+/MSH2+ (apical and nuclear staining) /hKIM-1-/CK7-or fo
cal +
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Conclusion
HKIM-1 is a relatively sensitive and specific marker for confirming the diagnosis of papillary RCC, cle
ar cell RCC, and metastatic RCCdistinguishing clear cell RCC from chromopho
be RCC and oncocytoma identifying CCCO
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Thanks for your attention !