Understanding the Attributes of Papillary Renal Cell Carcinoma subtypes: Molecular Analysis, Biomarker Discovery and Implications to Therapy

Papillary renal cell carcinomas (PRCCs) are tumors that arise from the renal tubules. They are the 2nd most common of that group of tumors. They are classified histologically, based on a number of morphological criteria, into two subtypes. The PRCC1 and PRCC2 tumors differ considerably in clinical behavior, where type 2 tends to be more aggressive. This body of work attempted to answer a few dilemmas that hinder the PRCC clinical management. The first question is the proper subtyping of PRCCs, as about half the PRCC cases fail to conform histologically to one defined entity type; and there are no reliable markers to differentiate between the subtypes. The current work initially assessed a PRCC cohort of 317 patients, elucidating unique genomic signatures and molecular pathways characteristic of the two classical PRCC subtypes. The comprehensive transcriptomic analysis uncovered potential discriminating markers, and these were further validated in a 2nd PRCC cohort (108 patients). The results pointed towards a potentially new biological classification of PRCC tumors that stratifies patients into clinically relevant subgroups. Another dilemma we attempted to solve is the complete lack of an evidence-based therapy for metastatic PRCCs. A problem that is further confounded by the failure of clinical trials to segregate between the PRCC subtypes. Specific PRCC2 pathways were targeted both in-vitro and in-vivo (in xenograft mouse models) which showed a significant response to these specific therapies in comparison to other treatment modalities. Our new proposed therapies show promise and also highlight the need for personalized tumor treatment modalities that take into account each tumor’s specific biology. Lastly, we studied PRCC precursor lesions to uncover some of the events that underlie the PRCC pathogenesis and development. That revealed knowledge that can potentially be translated into PRCC early prevention and treatment.Ph.D

Glomus tumor of the rectum: A case report

Glomus tumors are mesenchymal tumors composed of modified smooth muscle cells representing a neoplastic counterpart of the perivascular glomus bodies. They are most common in the skin and subcutaneous tissue, but also occur in the viscera. In the gut, they are almost exclusively found in the stomach. There have been only seven previous cases reported in the literature of glomus tumor in the colon, 3 of which were in the anorectal area. We report the fourth case of glomus tumor in the anorectum, and 7th in the colon. A 68 year old female was referred for abdominal–perineal resection of a locally advanced rectal carcinoma after neo-adjuvant chemotherapy/radiation. The tumor showed marked therapy response with minimal residual tumor. From the pericolonic fat, a small nodule, 0.3 cm, was found, considered to be a lymph node. On histologic examination, this nodule was composed of a vascular lesion, where dilated blood vessels were associated with small collections of bland cells. The morphology and immunohistochemistry were consistent with a glomus tumor.Glomus tumors are generally benign, though rare cases have resulted in metastasis and death: histological features such as cellular atypia, mitosis and lymphovascular invasion do not predict malignant behavior. Keywords: Malignant glomus, Colon glomus, Gastrointestinal glomu

Urachal xanthogranuloma: a rare but important case presenting as a urachal mass

Abstract Background A urachal mass is a relatively rare presentation to the urologists’ practice, often requiring radical surgical excision for a definitive diagnosis. Xanthogranulomatous inflammation of the urachus is an extremely rare entity with few cases reported worldwide, and to the best of our knowledge, no cases reported in the western world. Case presentation In this case, a 55-year-old male patient presented with bothersome lower urinary tract symptoms and computed tomography findings demonstrating a urachal mass that was worrisome for urachal carcinoma. Following surgical intervention, histopathology revealed urachal xanthogranuloma. Post-operatively, the patient recovered well, and eventually, he had symptomatic and radiologic improvement. Conclusion This case brings awareness to a rare presentation of a urachal mass—urachal xanthogranuloma. While operative intervention was both diagnostic and therapeutic, we highlight the challenge in differentiating between benign and malignant processes for urachal masses. Herein, we show the importance of including urachal xanthogranuloma in the differential diagnosis of a urachal mass to prevent further morbidity associated with the treatment of this disease

Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

Papillary renal cell carcinoma (PRCC) is the most common nonclear cell RCCs and is known to comprise two histological subtypes. PRCC2 is more aggressive and is molecularly distinct from the other subtypes. Despite this, PRCCs are treated together as one entity, and they show poor response to the current therapies that do not target pathways implicated in their pathogenesis. We have previously detected ABCC2 (an ABC transporter), VEGF, and mTOR pathways to be enriched in PRCC2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC2. Twenty RCC cell lines from the Cancer Cell Encyclopedia were compared to the Cancer Genome Atlas PRCC cohort (290), to identify representative PRCC2 cell lines. Cell lines were further validated in xenograft models. Selected cell lines were treated in vitro and in vivo (mice models) under five different conditions, untreated, anti‐VEGF (sunitinib), ABCC2 blocker (MK571), mTOR inhibitor (everolimus) and sunitinib + MK571. Sunitinib +ABCC2 blocker group showed a significant response to therapy compared to the other treatment groups both in vitro (P ≤ 0.0001) and in vivo (P = 0.0132). ABCC2 blockage resulted in higher sunitinib uptake, both in vitro (P = 0.0016) and in vivo (P = 0.0031). Everolimus group demonstrated the second best response in vivo. The double‐treatment group showed the highest apoptotic rate and lowest proliferation rate. There is an urgent need for individualized therapies of RCC subtypes that take into account their specific biology. Our results demonstrate that combined targeted therapy with sunitinib and ABCC2 blocker in PRCC2 has therapeutic potential. The results are likewise potentially significant for other ABCC2 high tumors. However, the results are preliminary and clinical trials are needed to confirm these effects in PRCC2 patients

The Impact of Modifying Sunitinib Treatment Scheduling on Renal Cancer Tumor Biology and Resistance

With sunitinib treatment of metastatic renal cell carcinoma, most patients end up developing resistance over time. Recent clinical trials have shown that individualizing treatment protocols could delay resistance and result in better outcomes. We developed an in vivo xenograft tumor model and compared tumor growth rate, morphological, and transcriptomic differences between alternative and traditional treatment schedules. Our results show that the alternative treatment regime could delay/postpone cancer progression. Additionally, we identified distinct morphological changes in the tumor with alternative and traditional treatments, likely due to the significantly dysregulated signaling pathways between the protocols. Further investigation of the signaling pathways underlying these morphological changes may lead potential therapeutic targets to be used in a combined treatment with sunitinib, which offers promise in postponing/reversing the resistance of sunitinib

Reassessment of p53 immunohistochemistry thresholds in invasive high grade bladder cancer shows a better correlation with TP53 and FGFR3 mutations

FGFR3 mutations are frequently mutually exclusive of TP53 mutations in invasive high grade urothelial carcinoma (HGUC) and p53 immunohistochemistry is often used as a surrogate for TP53 mutations. A 10 % staining cut off has been used in HGUC for designation as p53 positive or negative however, a novel contemporary method we have previously proposed (0% or 50 % abnormal vs. 1-49 % wild type) has shown significant correlation with oncologic outcome as well. We aimed to compare how a >= 10 % vs. 0 % and >= 50 % cut off p53 assessment method correlates with TP53 and FGFR3 mutation status. Tissue microarrays created from three retrospective cohorts (two cystectomy cohorts (cohort A, n = 206 and cohort B, n = 91; one T1 transurethral resection cohort (cohort C, n = 47)) were stained with p53 and scored by two blinded reviewers using both p53 scoring schemes. 50 cases from cohort A were assessed for TP53 and FGFR3 mutation status using next generation sequencing and FGFR3 mutation status was separately assessed in cohorts B and C using SNaPshot methodology. 202 (58.7 %) and 142 (41.3 %) cases showed abnormal and wild type p53 staining, respectively. Using the 10 % cut off, 254 cases were positive (73.8 %) and 90 cases were negative (26.2 %). 27 (14.4 %) and 15 (30 %) assessed cases demonstrated FGFR3 and TP53 mutations, respectively; 19/27 FGFR3 mutated showed a wild type pattern of p53 expression while 15/15 TP53 mutated tumours showed an abnormal pattern of p53 expression. There was a significant correlation between the contemporary p53 scoring scheme and TP53 and FGFR3 mutations (p < 0.0001 and p = 0.002, respectively). Improved sensitivity, specificity, positive predictive value, and negative predictive value for TP53 mutation was also seen compared to the 10 % cut off; specifically, the sensitivity and negative predictive value were 100 %. These findings might be of clinical relevance in the era of precision medicine

Recurrent KRAS mutations are early events in the development of papillary renal neoplasm with reverse polaritu

We evaluated the clinicopathologic and molecular characteristics of mostly incidentally detected, small, papillary renal neoplasms with reverse polarity (PRNRP). The cohort comprised 50 PRNRP from 46 patients, divided into 2 groups. The clinically undetected (\u3c5 \u3emm) neoplasms (n = 34; 68%) had a median size of 1.1 mm (range 0.2-4.3 mm; mean 1.4 mm), and the clinically detected (≥5 mm) neoplasms (n = 16; 32%) which had a median size of 13 mm (range 9-30 mm; mean 16 mm). Neoplasms were positive for GATA3 (n = 47; 100%) and L1CAM (n = 34/38; 89%) and were negative for vimentin (n = 0/44; 0%) and, to a lesser extent, AMACR [(n = 12/46; 26%; weak = 9, weak/moderate = 3)]. KRAS mutations were found in 44% (n = 15/34) of the clinically undetected PRNRP and 88% of the clinically detected PRNRP (n = 14/16). The two clinically detected PRNRP with wild-type KRAS gene were markedly cystic and contained microscopic intracystic tumors. In the clinically undetected PRNRP, the detected KRAS mutations rate was higher in those measuring ≥1 mm vs[n = 14/19 (74%) vs n = 1/15 (7%)]. Overall, the KRAS mutations were present in exon 2-codon 12: c.35 G \u3e T (n = 21), c.34 G \u3e T (n = 3), c.35 G \u3e A (n = 2), c.34 G \u3e C (n = 2) resulting in p.Gly12Val, p. Gly12Asp, p.Gly12Cys and p.Gly12Arg, respectively. One PRNRP had a G12A/V/D complex mutation. Twenty-six PRNRP were concurrently present with other tumors of different histologic subtypes in the ipsilateral kidney; molecular testing of 8 of the latter showed wild-type KRAS gene despite the presence of KRAS mutations in 5 concurrent PRNRP. On follow up, no adverse pathologic events were seen (range 1-160 months; mean 44 months). In conclusion, the presence of KRAS mutations in small, clinically undetected PRNRP provides a unique finding to this entity and supports its being an early event in the development of these neoplasms