Tumors containing elements of both papillary thyroid carcinoma (PTC) and squamous cell carcinoma (SCC) are rare but well documented. When they present initially as metastatic disease in an organ that ...can harbor a primary SCC, the possibility of a tumor to tumor metastasis (TTM) must be considered. The aim of this case study is to illustrate how
BRAF
mutational analysis can be used to help differentiate between these two diagnoses. We report a 63-year-old male with a longstanding history of PTC metastatic to the brain and lymph nodes who presented to our institution with a right lower lobe lung mass after a 2-year recurrence-free interval. Histopathologic and immunohistochemical analysis revealed a composite neoplasm with distinct elements of both PTC and SCC. We performed
BRAF
V600E
(c.1799 T > A) mutational analysis to help elucidate the origin of each component. This is the first time that
BRAF
sequencing has been used to discriminate between dedifferentiated PTC and TTM, to the best of our knowledge. In the context of metastatic PTC with SCC dedifferentiation, the presence of the identical
BRAF
V600E
(c.1799 T > A) mutation in both components might help rule out tumor to tumor metastasis.
Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their ...clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. In this study, we used next-generation DNA and RNA sequencing to profile 25 primary prostatic mesenchymal neoplasms of possible specialized prostatic stromal origin, including cases originally diagnosed as PSS (11) and STUMP (14). Morphologically, the series comprised 20 cases with solid architecture (11 PSS and 9 STUMP) and 5 cases with phyllodes-like growth pattern (all STUMP). Combined DNA and RNA sequencing results demonstrated that 19/22 (86%) cases that underwent successful sequencing (either DNA or RNA) harbored pathogenic somatic variants. Except for TP53 alterations (6 cases), ATRX mutations (2 cases), and a few copy number variants (−13q, −14q, −16q and +8/8p), the findings were largely nonrecurrent. Eight gene rearrangements were found, and 4 (NAB2-STAT6, JAZF1-SUZ12, TPM3-NTRK1 and BCOR-MAML3) were useful for reclassification of the cases as specific entities. The present study shows that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous and include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, including soft tissue and the uterus. These data suggest that tumors of purported specialized prostatic stromal origin may perhaps not represent a single diagnostic entity or specific disease group and that alternative diagnoses should be carefully considered.
Since its reported discovery in 1994, maspin (mammary serine protease inhibitor) has been characterized as a class II tumor suppressor by its ability to promote apoptosis and inhibit cell invasion. ...Maspin is highly expressed in normal mammary epithelial cells but reduced or absent in aggressive breast carcinomas. However, despite efforts to characterize the mechanism(s) by which maspin functions as a tumor suppressor, its molecular characterization has remained somewhat elusive. Therefore, in an attempt to identify maspin-interacting proteins and thereby gain insight into the functional pathways of maspin, we employed a maspin-baited yeast two-hybrid system and subsequently identified Interferon Regulatory Factor 6 (IRF6) as a maspin-binding protein. IRF6 belongs to the IRF family of transcription factors, which is best known for its regulation of interferon and interferon-inducible genes following a pathogenic stimulus. Although many of the IRF family members have been well characterized, IRF6 remains poorly understood. We report that IRF6 is expressed in normal mammary epithelial cells and that it directly associates with maspin in a yeast two-hybrid system and in vitro. The interaction occurs via the conserved IRF protein association domain and is regulated by phosphorylation of IRF6. We have shown that, similar to maspin, IRF6 expression is inversely correlated with breast cancer invasiveness. We further demonstrated that the transient re-expression of IRF6 in breast cancer cells results in an increase of N-cadherin and a redistribution of vimentin commensurate with changes in cell morphology, suggestive of an epithelial-to-mesenchymal transition event. Concomitantly, we showed that maspin acts as a negative regulator of this process. These findings help to elucidate the molecular mechanisms of maspin and suggest an interactive role between maspin and IRF6 in regulating cellular phenotype, the loss of which can lead to neoplastic transformation.
Ovarian cancer (OVCA) patients often develop tolerance to standard platinum therapy that accounts for extensive treatment failures. Cisplatin resistant OVCA cells (cis-R) display enhanced survival ...mechanisms to cope with therapeutic stress. In these cells, increased autophagy process assists in chemoresistance by boosting the nutrient pool under stress. To improve the treatment response, both protective autophagy inhibition and its overactivation are showing efficacy in chemosensitization. Autophagy requires a tightly regulated intracellular pH. Vacuolar ATPases (V-ATPases) are proton extruding nanomotors present on cellular/vesicular membranes where they act as primary pH regulators. V-ATPase ‘a2’ isoform (V0a2), the major pH sensing unit, is markedly overexpressed on the plasma membrane and the early endosomes of OVCA cells. Previously, V0a2 inhibition sensitized cis-R cells to platinum drugs by acidifying cytosolic pH that elevated DNA damage. Here, we examined how V0a2 inhibition affected endosomal function and the autophagy process as a possible factor for cisplatin sensitization. Clinically, V0a2 expression was significantly higher in tissues from drug nonresponder OVCA patients compared to treatment responders. In vitro V0a2 knockdown in cis-R cells (sh-V0a2-cisR) significantly reduced the tumor sphere-forming ability and caused complete disintegration of the spheres upon cisplatin treatment. The apoptotic capacity of sh-V0a2-cisR improved substantially with potentiation of both intrinsic and extrinsic apoptotic pathway when treated with cisplatin. Unlike the chemical V-ATPase inhibitors that acutely induce autophagy, here, the stable V0a2 inhibition dampened the protective autophagy process in sh-V0a2-cisR cells with downregulated expression of proteins beclin-1, ATG-7, and LC3B and low autophagosome numbers compared to control cis-R cells. These cells showed downregulated ERK/MEK pathway that is known to repress autophagy. Interestingly, upon cisplatin treatment of sh-V0a2-cisR, the autophagy initiation proteins (LC3B, ATG7, and Beclin 1) were found upregulated as a stress response compared to the untreated cells. However, there was a concomitant downstream autophagosome accumulation and an enhanced P62 protein levels indicating the overall block in autophagy flux. Mechanistically, V0a2 knockdown caused defects in early endosome function as the transferrin internalization was impaired. Taken together, this study provides a novel insight into the mechanism by which V-ATPase-isoform regulates autophagy that assists in chemoresistance in ovarian cancer. We conclude that V-ATPase-V0a2 is a potent target for developing an effective treatment to enhance patient survival rates in ovarian cancer.
Objectives
To study the effects of adjuvant therapy in patients with sarcomatoid renal cell carcinoma (sRCC) enrolled in the randomised phase III clinical trial E2805.
Patients and Methods
The ...original trial (E2805) was a randomised, double‐blinded phase III clinical trial comparing outcomes in 1943 patients with RCC accrued between 2006 and 2010 and treated with up to 1 year of adjuvant placebo, sunitinib, or sorafenib. The present study analyses the cohort of patients with sRCC that participated in E2805.
Results
A total of 171 patients (8.8%) had sarcomatoid features. Of these, 52 patients received sunitinib, 58 received sorafenib, and 61 received placebo. Most patients were pT3–4 (71.1%, 63.7%, and 70.5%, respectively); 17.3%, 19.0%, and 27.9% had pathologically positive lymph nodes; and 59.6%, 62.1%, and 62.3% of the patients were University of California Los Angeles (UCLA) Integrated Staging System (UISS) very‐high risk. In 49% of patients with subsequent development of metastatic disease, recurrence occurred in the lung, followed by 30% in the lymph nodes, and 13% in the liver. There was a high local recurrence rate in the renal bed (16%, 29%, and 18%, respectively). The 5‐year disease‐free survival (DFS) rates were 33.6%, 36.0%, and 27.8%, for sunitinib, sorafenib and placebo, respectively (hazard ratio HR 0.74, 95% confidence interval CI 0.45–1.20 for sunitinib vs placebo, and HR 0.82, 95% CI 0.53–1.28 for sorafenib vs placebo).
Conclusions
Adjuvant therapy with sunitinib or sorafenib did not show an improvement in DFS or OS in patients with sRCC.
Pancreatic cystic lesions include inflammatory pseudocysts, benign serous tumors, and mucinous neoplasms, some of which are malignant. Clinical and radiologic indices are often inadequate to ...discriminate reliably among these possibilities. In an attempt to develop new preoperative diagnostic criteria to assist in decisions regarding therapy, the authors have performed cyst fluid analysis for tumor markers (carcinoembryonic antigen: CEA, CA 125, and CA 19.9), amylase content, amylase isoenzymes, relative viscosity, and cytology on 26 pancreatic cysts. The cases included nine pseudocysts, five serous cystadenomas, 4 mucinous cystic neoplasms, 7 mucinous cystadenocarcinomas, and one mucinous ductal adenocarcinoma with cystic degeneration. Carcinoembryonic antigen levels were high (> 367) in all benign and malignant mucinous cysts, but were low (< 23) in the pseudocysts and benign serous cystadenomas, an indication that CEA discriminates between mucinous and nonmucinous cysts (p < 0.0001). Values for CA 125 were high in all malignant cysts, low in pseudocysts, and variable in mucinous cystic neoplasms and serous cystadenomas. Levels of Ca 19.9 were nondiscriminatory. Cyst fluid amylase and lipase content were variable but were generally high in pseudocysts and low in cystic tumors. Amylase isoenzyme analysis was useful to differentiate pseudocysts from cystic tumors. Measurement of the relative viscosity in cyst fluid showed high (> serum viscosity) values in 89% of mucinous tumors and low values (< serum) in all pseudocysts and serous cystadenomas (p < 0.01). Cytologic analysis of cyst fluids was of limited value in differentiating pseudocysts from serous cystadenoma, but in seven of eight mucinous tumors provided useful diagnostic information and correctly classified three of five malignant tumors. The authors conclude that cyst fluid analysis can provide a preoperative classification of these diagnostically difficult lesions. The combination of viscosity, CEA, CA 125, and cytology can reliably distinguish malignant cystic tumors and potentially premalignant mucinous cystic neoplasms from pseudocysts and serous cystadenomas. Amylase content with isoenzyme analysis is useful to identify pseudocysts.
The past several years have seen unprecedented advances in the application of various therapeutic strategies for the treatment of patients with renal cancer. The availability of active immunotherapy, ...antiangiogenic therapy, and targeted therapy for this disease has brought front and center issues related to choosing the appropriate treatment for particular patient populations. It is increasingly evident that the most promising treatment selection strategies will incorporate identifying specific features of the tumor itself. To facilitate this move toward personalized medicine, it is critically important to establish some standard principles for renal cancer tissue collection, preparation, and analysis for translational research studies. In this article, we identify and discuss some critical issues related to tissue-based kidney cancer research. We focus on five major areas as follows: (a) surgical and image-guided techniques for tissue collection; (b) quality control of specimen collection, processing, storage, and review; (c) issues related to analysis of paraffin embedded tissues; (d) genomic studies; and (e) assessment of reproducibility of assays across institutions. In addition, some practical implementation strategies are proposed. Although many of the topics discussed are specific for renal cancer, several are also relevant to tissue based biomarker investigations in a broad array of malignancies.
Papillary renal cell carcinomas (RCCs) traditionally have been defined histologically as tumors with at least 50% true papillae. However, these tumors also have characteristic immunohistochemical and ...genetic features that separate them from other RCCs. We identified six tumors composed of solid sheets of cells without true papillae but that otherwise resembled papillary RCCs, which we feel represent solid variants of papillary RCCs. All six tumors were primary lesions of the kidney, all were strongly reactive for epithelial membrane antigen, cytokeratin 7, and callus keratin, and all were negative for the high molecular weight keratin antibody 34BE12. Four of four tumors tested showed trisomies for chromosome 7, chromosome 17, or both by either cytogenetic analysis or fluorescence in situ hybridization. Four cases were composed of solid sheets of cells containing distinct micronodules that in some cases resembled abortive papillae. The cells composing the micronodules had abundant eosinophilic cytoplasm, open chromatin, and in some cases prominent nucleoli. The intervening cells had similar nuclei, but the amount of cytoplasm was variable. In three of these micronodular cases, multiple tumors diffusely replaced the kidney; in the fourth case two typical clear cell RCCs and a typical papillary RCC were also present in the same kidney, but the micronodular tumor was unifocal. The two remaining cases were solitary tumors consisting of solid sheets of cells forming ill-defined tubules. These cells had scant clear cytoplasm and small round to elongate nuclei with occasional nuclear grooves but only rare small nucleoli. Limited follow-up has shown no evidence of disease in any patient thus far. The differential diagnosis includes "renal adenoma," renal adenomatosis, metanephric adenoma, and clear/granular cell RCC. We conclude that solid variants of papillary RCCs lack true papillae but have characteristic histologic, immunohistochemical, and genetic features.
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