Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions

Martignoni, Guido; Gobbo, Stefano; Camparo, Philippe; Brunelli, Matteo; Munari, Enrico; Segala, Diego; Pea, Maurizio; Bonetti, Franco; Illei, Peter B.; Netto, George J.; Ladanyi, Marc; Chilosi, Marco; Argani, Pedram

doi:10.1038/modpathol.2011.93

Cited by 103 publications

(85 citation statements)

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“…Along these lines, we previously noted that the ASPSCR1-TFE3 renal cell carcinomas tend to have higher nuclear grade and more voluminous cytoplasm than the PRCC-TFE3 renal cell carcinomas. 3,4 A further more objective difference between these neoplasms is their differential immunohistochemical expression of the cysteine protease cathepsin K. 50,51 We have previously shown that a majority (12 of 14, or 86%) of PRCC-TFE3 renal cell carcinomas diffusely express cathepsin K, whereas all eight ASPSCR1-TFE3 renal cell carcinomas tested have been negative for this immunohistochemical marker. As cathepsin K expression is typically driven by the transcription factor MITF, which is in the same family as TFE3 and TFEB, and has overlapping activity, our hypothesis has been that the PRCC-TFE3 fusion protein is better able to activate cathepsin K expression compared with the ASPSCR1-TFE3 fusion protein.…”

Section: Discussionmentioning

confidence: 99%

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage

et al. 2014

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Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P ¼ 0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up. Modern Pathology (2014) 27, 875-886; doi:10.1038/modpathol.2013; published online 6 December 2013Keywords: ASPSCR1; PRCC; renal cell carcinoma; Xp11 translocation carcinoma Xp11 translocation renal cell carcinomas are characterized by chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 transcription factor gene, which maps to this locus. 1,2 The most common subtypes of Xp11 translocation renal cell carcinomas are the ASPSCR1-TFE3 (also known as ASPL-TFE3) renal cell carcinomas resulting from a t(X;17)(p11;q25) translocation, 3 and the PRCC-TFE3 renal cell carcinomas, resulting from a t(X;1)(p11;q21) translocation. 4 As most cytogenetically or molecularly confirmed cases have been described in case reports or small series, a formal clinical comparison of these two subtypes of Xp11 translocation RCC has not been performed.We report two new genetically confirmed Xp11 translocation renal cell carcinomas, one with an ASPSCR1-TFE3 gene fusion and the other with a PRCC-TFE3 gene fusion. We review the literature for all published cases of ASPSCR1-TFE3 renal cell carcinomas (41 cases...

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Section: Discussionmentioning

confidence: 99%

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage

et al. 2014

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“…18 Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. 19 Cathepsin K is consistently and diffusely positive in ASPS (Figure 4). 19 Although these 2 immunohistochemical stains are highly sensitive, they are not entirely specific because other tumors also show positivity (described below).…”

Section: Microscopic Featuresmentioning

confidence: 99%

“…19 Cathepsin K is consistently and diffusely positive in ASPS (Figure 4). 19 Although these 2 immunohistochemical stains are highly sensitive, they are not entirely specific because other tumors also show positivity (described below). Often, ASPS is positive for desmin and muscle-specific actin.…”

Section: Microscopic Featuresmentioning

confidence: 99%

“…19 However, its role in differentiating ASPS from other potential mimickers is relatively limited because it is positive in melanoma, granular cell tumor, and other tumors 19 (Table). Therefore, the best practical application for cathepsin K in this setting is when the clinical, radiologic, histomorphologic, and immunohistochemical data are competing between ASPS and ASPCR1-TFE3 translocation RCC, where both will be positive for TFE3 immunohistochemical stain, whereas cathepsin K will show positivity in the former but not in the latter.…”

Section: Differential Diagnosismentioning

confidence: 99%

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Alveolar Soft Part Sarcoma

Jaber¹,

Kirby

2015

Archives of Pathology &Amp; Laboratory Medicine

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Alveolar soft part sarcoma is a rare neoplasm usually arising in the soft tissues of the lower limbs in adults and in the head and neck region in children. It presents primarily as a slowly growing mass or as metastatic disease. It is characterized by a specific chromosomal alteration, der(17)t(X:17)(p11:q25), resulting in fusion of the transcription factor E3 (TFE3) with alveolar soft part sarcoma critical region 1 (ASPSCR1) at 17q25. This translocation is diagnostically useful because the tumor nuclei are positive for TFE3 by immunohistochemistry. Real-time polymerase chain reaction to detect the ASPSCR1-TFE3 fusion transcript on paraffin-embedded tissue blocks has been shown to be more sensitive and specific than detection of TFE3 by immunohistochemical stain. Cathepsin K is a relatively recent immunohistochemical stain that can aid in the diagnosis. The recent discovery of the role of the ASPSCR1-TFE3 fusion protein in the MET proto-oncogene signaling pathway promoting angiogenesis and cell proliferation offers a promising targeted molecular therapy.

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“…ASPSCR1-TFE3), in contrast to the absence of staining in the conventional clear cell, papillary, chromophobe RCCs or oncocytomas, or in any adjacent nonneoplastic renal tissue. 11,12 Outcome data on this entity are still relatively premature and highly variable, with some patients having an extremely aggressive course and others a relatively indolent one. Overall, survival is similar to that seen in patients with clear cell RCC, and among patients with PRCC-TFE3 RCC and ASPSCR1-TFE3 RCC, only advanced stage and older age at diagnosis independently predicted death in a multivariate analysis of the 2 tumors.…”

Section: Xp11 Translocation-associated Renal Cellmentioning

confidence: 99%

Biomarker, Molecular, and Technologic Advances in Urologic Pathology, Oncology, and Imaging

Ellis

Harik

Cohen

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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Urologic pathology is evolving rapidly. Emerging trends include the expanded diagnostic utility of biomarkers and molecular testing, as well as adapting to the plethora of technical advances occurring in genitourinary oncology, surgical practice, and imaging. We illustrate those trends by highlighting our approach to the diagnostic workup of a few selected disease entities that pathologists may encounter, including newly recognized subtypes of renal cell carcinoma, pheochromocytoma, and prostate cancer, some of which harbor a distinctive chromosomal translocation, gene loss, or mutation. We illustrate applications of immunohistochemistry for differential diagnosis of needle core renal biopsies, intraductal carcinoma of the prostate, and amyloidosis and cite encouraging results from early studies using targeted gene expression panels to predict recurrence after prostate cancer surgery. At our institution, pathologists are working closely with urologic surgeons and interventional radiologists to explore the use of intraoperative frozen sections for margins and nerve sparing during robotic prostatectomy, to pioneer minimally invasive videoscopic inguinal lymphadenectomy, and to refine image-guided needle core biopsies and cryotherapy of prostate cancer as well as blue-light/fluorescence cystoscopy. This collaborative, multidisciplinary approach enhances clinical management and research, and optimizes the care of patients with urologic disorders. (Arch Pathol Lab Med. 2017;141:499-516; doi: 10.5858.arpa.2016-0263-SA) I n this review, we summarize the effect of a number of biomarker, molecular, and technologic advances in urologic pathology, oncology, and imaging on routine, day-to-day practice and research at our institution. The objective of this review is not to cover the entire gamut of all advances that we have and use at our institution but, rather, to highlight a few pertinent concepts in our field. Topics that will be covered include biomarkers, molecular testing of selected malignancies (eg, transcription factor E3 [TFE3]/ Xp11.2 translocation-associated renal cell carcinoma; p63, high-molecular-weight cytokeratin and racemase cocktail [PIN4]/phosphatase and tensin homolog [PTEN] for some cases of intraductal carcinoma of the prostate; and succinate dehydrogenase subunit B in renal cell carcinoma and pheochromocytoma), amyloidosis of the genitourinary tract, and workup of neoplastic needle core kidney biopsies. In addition, we will report the effect of pathologic, oncologic, and radiologic technologic advances (ie, global transcriptome analysis and RNA biomarkers of prostate cancer; robotic-assisted radical prostatectomy; minimally invasive videoscopic inguinal lymphadenectomy; targeted magnetic resonance imaging [MRI]-guided prostate needle core biopsies; anti-1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid in prostate cancer; cryotherapy for prostate cancer; and blue-light/white-light cystoscopy for bladder lesions) performed at our institution.

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Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions

Cited by 103 publications

References 24 publications

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage

Alveolar Soft Part Sarcoma

Biomarker, Molecular, and Technologic Advances in Urologic Pathology, Oncology, and Imaging

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