Aggressive Histologic Variant Research Articles

In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

<h3>Objectives:</h3> Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2-amplified USC tumors at a distinct epitope from that bound by trastuzumab, pertuzumab, and T-DM1 (trastuzumab emtansine) after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A as a single agent against primary USC cell lines and xenografts. <h3>Methods:</h3> Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for <i>C-erbB2</i> gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability in USC primary cell lines after exposure to DHES0815A, the non-targeted ADC, the unconjugated antibody MHES0488A, and T-DM1 were evaluated using flow cytometry-based-assays. <i>in vivo</i> activity of these respective agents was tested against HER2/neu overexpressing USC (ARK2) xenografts. <h3>Results:</h3> High HER2/neu protein expression by IHC and <i>C-erbB2</i> gene amplification by FISH was seen in 25% (3/12) of the primary USC cell lines. Primary tumor cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (<i>p<0.05</i>). DHES0815A caused growth-inhibition and increased survival in HER2/neu overexpressing xenografts when compared to controls (<i>p<0.05</i>). The animals also tolerated DHES0815A treatment with no significant change in their body weight [Figure 1]. <h3>Conclusions:</h3> DHES0815A as a single agent is both highly selective and toxic to USC tumors overexpressing HER2/neu both <i>in vitro</i> and <i>in vivo.</i> HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel and less toxic treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

Survival comparison of primary cytoreductive surgery versus interval cytoreductive surgery for the treatment of advanced-stage uterine serous carcinoma

Objectives: Uterine serous carcinoma (USC) is a rare but aggressive histologic variant of endometrial cancer that accounts for less than 10% of cases but 80% of endometrial cancer deaths. Initial treatment strategies have remained largely unchanged over the years, with the mainstay of treatment being primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy with or without tailored radiotherapy. More recent strategies have incorporated the use of neoadjuvant chemotherapy (NAC) in certain cases with bulky nodal disease or stage IV disease. This study compares survival outcomes between PCS and neoadjuvant chemotherapy followed by an interval cytoreductive surgery (ICS). Methods: Retrospective data spanning 7 years was collected for patients with stage III or IV USC in a large academic institution. PCS was categorized as initial surgical treatment for stage III or IV disease. This was further stratified into microscopic and bulky disease at the time of surgery. ICS was defined as initial treatment with NAC with interval cytoreductive surgery. Overall survival (OS) and progression free survival (PFS) were calculated for each group with Kaplan-Meier estimation and analyzed using the Chi-Square test. Results: Forty-seven patients were identified to have stage III or IV disease at the time of diagnosis. 35 patients underwent PCS and 12 underwent ICS. The PCS and ICS groups were matched for race, age and BMI. Among the PCS patients, 52% had bulky disease. OS was 82.1 months compared to 40.1 months for PCS and ICS respectively (p=0.23). PFS of PCS patients was 42.9 months compared to 18.1 months of ICS patients (p=0.03). PCS of non-bulky disease, PCS of bulky disease and ICS had OS of 82.1, 40.9, and 31.8 months respectively (p=0.47) while PFS was 42.9, 19.6 and 13.8 months for PCS of non-bulky disease, PCS of bulky disease and ICS respectively (p=0.02). For patients with non-bulky disease and bulky disease, OS was 82.1 vs 40.1 months respectively (p=0.23) while PFS was 42.9 and 18.1 months respectively (p=0.32). Patients with bulky disease who had PCS had an OS of 40.9 months compared to 31.8 months for ICS (p=0.86) and PFS of 19.7 months vs 13.9 months (p=0.13). Conclusions: While no statistical difference in OS was observed between the groups, there was a significant improvement in PFS in the PCS patients compared to ICS patients. PFS was significantly longer after PCS regardless of bulky disease. PFS appears to favor PCS over ICS. This study is limited by the small sample size. Additional studies are needed to better determine optimal treatment strategies for patients with advance stage USC.

Pre-Therapeutic Measurements of Iodine Avidity in Papillary and Poorly Differentiated Thyroid Cancer Reveal Associations with Thyroglobulin Expression, Histological Variants and Ki-67 Index.

Simple SummaryIn the treatment of thyroid cancer, tumour uptake of iodine is important because it enables the use of radioactive iodine to kill cancer tissue. How radioactive iodine treatments are performed is usually determined by the size of the tumour. This study attempted to find new ways of predicting iodine uptake in advance of treatment. Several factors were found to predict uptake better than tumour size, all relatively simple to investigate in routine healthcare. This information can potentially be used to treat thyroid cancer patients more in accordance with how their tumours behave.Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy.

Characteristics of benign neuroblastic tumors: Is surgery always necessary?

PurposeGanglioneuroma (GN) and ganglioneuroblastoma-intermixed (GNB-I) represent benign variants of neuroblastic tumors in children; however, differentiating from more aggressive histological variants of GNB including the nodular subtype (GNB-N) prior to resection can be challenging, even with biopsy. Currently, no standard treatment guidelines exist. The purpose of this study was to identify pre-operative characteristics of benign neuroblastic tumors and evaluate outcomes for patients who underwent surgical resection or observation. MethodsRetrospective chart review of children treated at a single institution between 2009 and 2019 for non-metastatic tumor with a tissue diagnosis of GN, GNB-N or GNB-I. Demographics, imaging, labs, operative details and outcomes were recorded and analyzed. ResultsOf 53 patients, 45% were male. The most common tumor location was abdomen (49%), followed by thorax (34%). Forty-five percent had at least one image defined risk factor. Biopsy was performed in 32% (17/53) and upfront surgery in 68% (36/53). Three patients (3/53, 5.6%) with biopsy demonstrating GN tumors were observed due to high surgical risk. Pathology of resected specimens demonstrated GN in 52% (26/50) and GNB-I or GNB-N in 48% (24/50). The majority of GNB tumors (75% (18/24) were GNB-I and 25% (6/24) were GNB-N. Therefore, 88% of the resected tumors were benign spectrum neuroblastic tumors (GN & GNB-I). Seven (7/50, 14%) patients experienced perioperative complication (temporary paralysis, Horner's syndrome, chylothorax, vocal cord paralysis). Recurrence was noted in 1 patient with GN (1/50, 2%) and 3 with GNB-N (3/50, 6%). There were no tumor-related deaths. Patients with GN were older than those with GNB (8.8 years (IQR 6–11.25) vs 5.6 years for GN (IQR 3–7); p = 0.01). GNB tumors were also more likely to have calcifications on imaging (63% vs. 38%, p = .01) and more commonly had MIBG avidity (88% vs 66%, p = .04). There were no significant differences in tumor size or symptoms at presentation. ConclusionsIn children with neuroblastic tumors, older age, CT without tumor calcifications, lack of MIBG avidity, and/or normal urine catecholamines may indicate benign GN. Close observation could be considered for asymptomatic patients meeting these criteria with biopsy-proven GN, with resection reserved for progressive growth or symptom development. However, larger, multicenter studies are needed for further validation. Level of evidenceIV.

The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features

BackgroundRenal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy. MethodsExpression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay. ResultsExpression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro. ConclusionInactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.

Abstract 911: In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma

Abstract Objective: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. Methods: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. Results: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p&amp;lt;0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p&amp;lt;0.01). Conclusions: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy. Citation Format: Joan Tymon R. Tymon-Rosario, Elena Bonazzoli, Stefania Bellone, Arancha Manzano, Paola Manara, Luca Zammataro, Silvia Pelligra, Adele Guglielmi, Barbara Gnutti, Burak Zeybek, Justin Harold, Dennis Mauricio, Elena Ratner, Peter Schwartz, Alessandro D. Santin. In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in uterine serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 911.

Implications of a background of Hashimoto's thyroiditis on the current conservative surgical trend towards papillary thyroid carcinoma.

The purpose is to delineate the clinico-pathologic features of papillary thyroid carcinoma (PTC) occurring in a background of Hashimoto's thyroiditis (HT). A retrospective analysis of consecutive PTC patients who underwent surgery at an academic center between Jan. 2010 and Jan. 2020 was performed. The primary end point was to assess whether a background of HT implied a higher likelihood for postoperatively determined high-risk histopathologic features. Accordingly, its implication on initial surgical planning. Tumor high-risk features included aggressive histologic variants, lymphovascular invasion, extrathyroidal extension, multifocality, and positive nodal metastasis. To achieve the primary outcome of interest, a two group-designation was followed: group A (none-HT-group) and group B (HT-group). The two groups were also compared regarding postoperative complications as a secondary outcome of interest. In the specified period, 331 patients were found to have a histologically proven diagnosis of PTC. Group A accounted for 80% (265/331) of the study cohort, while group B accounted for the remainder 20%. PTC was significantly more prevalent in the absence of HT (p < 0.0001). Both groups were comparable in mean-patient-age. However, Group B demonstrated a considerably higher male:female ratio (1:10 vs. 1:3; p = 0.01). All postoperatively determined high-risk histopathologic features were comparable in both groups (p > 0.05). Nevertheless, transient hypoparathyroidism was considerably higher in group B (12% vs. 23%; p = 0.02). A background of HT does not seem to reflect a more aggressive cancerous biologic behavior. Therefore, it should not preclude the conservative surgical strategy adopted by the most recent clinical practice guidelines.

MicroRNA Profile for Diagnostic and Prognostic Biomarkers in Thyroid Cancer.

Simple SummaryThyroid nodules are frequently detected, but the majority of these nodules are benign. Molecular markers have become useful for diagnosing the minority of thyroid cancer. We performed high-throughput small RNA sequencing in a discovery cohort and identified three miRNAs (miR-136, miR-21, and miR-127) as potential biomarkers for thyroid cancer. We validated the diagnostic and prognostic utilities of three miRNAs in patients with thyroid cancer in an independent cohort. High expression of the three miRNAs could be used to differentiate thyroid cancers from benign tumors and tumors with extremely low malignant potential. In patients with thyroid cancers, a high expression of three miRNAs was associated with poor clinicopathological features and recurrent or persistent disease following surgery. Therefore, testing for high expression levels of these three miRNAs in thyroid nodules may be useful for diagnosing and assessing the recurrence of the thyroid cancer’s risk stratification.The challenge in managing thyroid nodules is to accurately diagnose the minority of those with malignancy. We aimed to identify diagnostic and prognostic miRNA markers for thyroid nodules. In a discovery cohort, we identified 20 candidate miRNAs to differentiate between noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and papillary thyroid carcinomas (PTC) by using the high-throughput small RNA sequencing method. We then selected three miRNAs (miR-136, miR-21, and miR-127) that were differentially expressed between the PTC follicular variant and other variants in The Cancer Genome Atlas data. High expression of three miRNAs differentiated thyroid cancer from nonmalignant tumors, with an area under curve (AUC) of 0.76–0.81 in an independent cohort. In patients with differentiated thyroid cancer, the high-level expression of the three miRNAs was an independent indicator for both distant metastases and recurrent or persistent disease. In patients with PTC, a high expression of miRNAs was associated with an aggressive histologic variant, extrathyroidal extension, distant metastasis, or recurrent or persistent disease. Three miRNAs may be used as diagnostic markers for differentiating thyroid cancers from benign tumors and tumors with extremely low malignant potential (NIFTP), as well as prognostic markers for predicting the risk of recurrent/persistent disease for differentiated thyroid cancer.

Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma

BackgroundPlasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC.MethodsCases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified.ResultsWe identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively.ConclusionsPUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.

CD73 Overexpression Promotes Progression and Recurrence of Papillary Thyroid Carcinoma.

Simple SummaryThis study aimed to evaluate the clinicopathologic significance of CD73 expression in patients with papillary thyroid carcinoma (PTC) and the potential for CD73 to serve as a therapeutic target of PTC. CD73 was highly expressed in PTC, but not in the normal thyroid tissue. Overexpression of CD73 was associated with unfavorable clinicopathologic characteristics and a shorter recurrence-free survival. The expression level of CD73 mRNA was associated with the abundance of Tregs and dendritic cells, depletion of natural killer (NK) cells, and high expression of immune checkpoint genes and epithelial-to-mesenchymal transition-related genes. CD73 inhibitor attenuated PTC cell proliferation, migration, and invasion in vitro, and suppressed PTC xenograft tumor growth in nude mice. These results suggest that CD73 expression is an unfavorable prognostic marker for patients with PTC. CD73 blockade would be an attractive candidate for therapeutic strategies in patients with advanced PTC.CD73 is involved in tumor immune escape and promotes the growth and progression of cancer cells. The functional role of CD73 expression in papillary thyroid carcinoma (PTC) has not yet been established. In 511 patients with PTC, immunohistochemistry for CD73 on tissue microarrays showed that the high expression of CD73 was associated with an aggressive histologic variant (p = 0.002), extrathyroidal extension (p < 0.001), lymph node metastasis (p < 0.001), and BRAFV600E mutation (p = 0.015). Survival analysis results showed that patients with high CD73 expression had worse recurrence-free survival (p = 0.023). CD73 inhibitors induced G1 cell cycle arrest and apoptosis, inhibited the migration and invasion of PTC cells, and suppressed tumor growth in PTC xenograft nude mice. High expression of CD73 (NT5E) mRNA was associated with unfavorable clinicopathologic characteristics, the abundance of Tregs and dendritic cells, depletion of natural killer (NK) cells, and high expression of immune checkpoint genes and epithelial-to-mesenchymal transition-related genes in The Cancer Genome Atlas (TCGA) dataset. Taken together, CD73 expression promotes tumor progression and predicts low recurrence-free survival. Targeting the CD73–adenosine axis in the tumor microenvironment offers an attractive pathway for therapeutic strategies aimed at advanced PTC.

Defining diagnostic criteria for ductal prostate cancer on prostatic MRI.

e17532 Background: Ductal prostate adenocarcinoma (DAC) is an aggressive histologic variant of prostate cancer (PCa) which often be missed due to their low PSA secretion. Further, a large proportion of DACs have extra-prostatic extension and nodal disease at presentation warranting accurate diagnosis and treatment planning. However studies have yet to differentiate DACs from high grade acinar PCas (PAC) on MRI. Therefore we aimed to develop MRI criteria to identify DACs and assess its diagnostic accuracy. Methods: Patients with histologically proven DAC who had MRIs prior to RP were identified from January 2011 to November 2018. Histology-based MRI diagnostic criteria were developed using RP specimens from nine patients with a pure dominant DAC focus and corresponding MRIs. Sixty-eight DAC patients were compared to a matched cohort of 70 patients with Gleason Score 8 or 9 PAC using the pre-defined MRI criteria. Chi-Squared, T tests, Mann Whitney U tests and sensitivity analyses were performed. Results: The following features of DAC were defined on MRI after correlation with histology: 1) intermediate T2 signal 2)well-circumscribed 3) lobulated tumor and 4) a dark peripheral rim. Majority of DACs were lobulated (79.4% vs 5.7%), with a dark peripheral rim on T2 weighted imaging (55.9% vs 4.3%) and had ≥3 MRI features compared to PAC (73.6% vs 7.2%) (all p &lt; 0.001). Moreover, a higher proportion of pure DACs were lobulated (100% vs 5.7%), had a dark peripheral rim (94.7% vs 4.3%) and ≥3 MRI features (100% vs 7.2%) compared to PAC (all P &lt; 0.001). There were no differences in median T2 contrast enhancement, ADC values or ADC ratios between the groups. Using our criteria MRI demonstrated sensitivity of 73.5%, specificity of 92.9 %, PPV of 90.9%, and NPV of 78.3% in diagnosing DACs if ≥3 features were present. In the diagnosis of pure DACs, MRI demonstrated sensitivity of 100%, specificity of 92.9%, PPV of 95.2%, and NPV of 100%. The area under the curve (AUC) for the diagnosis of all DACs was 0.81 and 0.98 for pure DACs. Conclusions: The presence of ≥3 features (well-circumscribed, lobulations and a dark peripheral rim and intermediate signal on the T2 phase) on prostatic MRI can help differentiate DAC from PAC. While this is the largest cohort of DACs to be analyzed, further studies are needed to validate these findings.

Adenosquamous Carcinoma of the Prostate: A Unique Presentation of a Rare Entity and Review of the Literature

Abstract Adenosquamous carcinoma of the prostate is an exceedingly rare and aggressive histologic variant of prostate cancer, which is composed of glandular and squamous components. Up to two-thirds of these cases are identified in patients with a history of adenocarcinoma after treatment with androgen deprivation therapy or radiation therapy; however, multiple cases have been reported arising de novo. Patients frequently present with obstructive urinary complaints and bony osteolytic metastases. Serum prostate-specific antigen is usually normal or slightly elevated. We describe a rare case of de novo metastatic adenosquamous carcinoma in a patient presenting with a markedly elevated serum prostate-specific antigen and multiple osteoblastic lesions. The prognosis for patients with adenosquamous carcinoma of the prostate has historically been dismal, with death occurring within 12 to 24 months of diagnosis.

Clinical and Oncological Outcome of Chondroblastic Osteosarcoma: A Single Institutional Experience.

Chondroblastic osteosarcoma is an aggressive bone tumor characterized by chondroid matrix production with variable cellularity. This retrospective study is aimed to assess the demographic distribution, clinical behavior and oncological outcome of chondroblastic osteosarcoma. 27 patients (14 males, 13 females) with chondroblastic osteosarcoma were included. The site of involvement included: proximal tibia (41%), distal femur (26%) and distal tibia (15%).The mean age of patients was 17years (S.D: 6.9years) (range 6-45years). Painful swelling was the main complaint in all cases. Two patients were classified as Enneking III (lung) stage and the remaining patients had Enneking IIB stage. Post-neoadjuvant chemotherapy limb sparing surgery was performed in 70% of cases while in 30% of cases limb amputation was done. On histopathological examination of specimens mean necrosis was 64% (20-95%). Disease free survival (DFS) at 2years was 46.4% and at 4years was 27.9%. Median disease free survival was 24 ± 10.30months. Overall survival (OS) at 2years was 53.3% and at 4years was 16.6%. Median overall survival is 28 ± 5.93months. Chondroblastic osteosarcoma is associated with poor prognosis, high recurrence rate and metastatic potential with dismal long-term survival. Chondroblastic osteosarcoma is an aggressive histological variant of conventional osteosarcoma with frequent location around the knee joint, affecting young population. Chemotherapy with Methotrexate, Adriamycin, Cisplatin (MAP) regimen is a well-tolerated regimen, resulting in limb salvage surgery in majority of the cases.

The evolving concept of aggressive histological variants of differentiated thyroid cancer.

It is recommended by current clinical guidelines that pathologists identify and report aggressive histological variants of differentiated thyroid cancer (e.g., tall cell, columnar cell, and hobnail variants of papillary thyroid carcinoma; widely invasive follicular thyroid carcinoma). This review analyzes the historical evolution of these entities and highlights unresolved issues with respect to the diagnostic criteria for these tumors.

LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. Patients with the most aggressive histological variant have an unfavorable prognosis due to a high metastasis incidence. Lysyl oxidase-like 2 (LOXL2) is a lysyl oxidase, member of a family of extracellular matrix (ECM) crosslinking enzymes that recently have emerged as important regulators of tumor progression and metastasis. We report that LOXL2 is overexpressed in RMS, suggesting a potential role for LOXL2 in RMS oncogenic progression. Consistently, transient and stable LOXL2 knockdown decreased cell migratory and invasive capabilities in two ARMS cell lines. Furthermore, introduction of LOXL2 in RMS non-expressing cells using wild type or mutated (catalytically inactive) constructs resulted in increased cell migration, cell invasion and number and incidence of spontaneous lung metastasis in vivo, independently of its catalytic activity. To further study the molecular mechanism associated with LOXL2 expression, a pull-down assay on LOXL2-transfected cells was performed and analyzed by mass spectrometry. The intermediated filament protein vimentin was validated as a LOXL2-interactor. Thus, our results suggest an oncogenic role of LOXL2 in RMS by regulating cytoskeleton dynamics and cell motility capabilities.

Neuroendocrine Carcinoma of the Cervix with Sister Mary Joseph's Nodule: About a Case and Literature Review

Neuroendocrine tumors are a rare and aggressive histological variant of the cervix, and they have several differences compared to other types of cervical cancer, in prognosis, diagnosis and treatment. In this paper we report the case of a 39-year-old patient that was taken care of in the medical oncology department at the Hassan II University Hospital Center, for an advanced neuroendocrine carcinoma of the cervix with a Sister Mary Joseph’s nodule. The aim of this work is to highlight this rare location of neuroendocrine tumors and their very aggressive character; by describing the different clinical, radiological and anatomopathological aspects of the primary tumor as well as umbilical metastasis.

Newer Concepts in the Classification of Pituitary Adenomas.

The classification of tumors of the pituitary gland has seen several changes in recent years. The 4th edition of the World Health Organization Classification of Tumours of Endocrine Organs, published in 2017, saw the introduction of a classification based on cell lineage using immunohistochemistry for both pituitary specific hormones as well as pituitary specific transcription factors. The term "hormone-producing" was thus replaced by "-troph." The other major change was that the entity of "atypical adenoma," which was introduced in the 2004 classification, to identify tumors with a poor prognosis, was removed as it failed to identify aggressive tumors. Instead, assessment of markers of proliferation, clinical parameters, such as invasive status and histological subtypes were recommended to identify tumors with aggressive potential. The diagnostic criteria for pituitary carcinoma, however, remained unchanged and continued to be defined as a tumor of adenohypophyseal cells that metastasize craniospinally or systemically. Null cell adenomas were more clearly defined as tumors that did not show any cell-type differentiation, lacking immunoexpression of hormones as well as transcription factors. Since 2017, the classification has continued to evolve with the identification of aggressive histological variants. There is more recently a proposal to change the terminology from pituitary adenoma to pituitary neuroendocrine tumor (PitNET). This review summarizes the recent advances in the classification of pituitary adenomas.

OS8.2 Risk stratification in chordoid meningioma depends on mutation status and epithelial differentiation

Abstract BACKGROUND Meningiomas are heterogenous tumors and their pathologic classification in the WHO Classification of Tumors of the CNS comprises 13 recognized histologic variants. Chordoid meningioma is a rare and more aggressive histologic variant of meningioma. Due to paucity of cases, the molecular profiling and patient risk stratification were not addressed in this variant. MATERIAL AND METHODS We performed an integrated clinical, NHERF1 immunohistochemical (IHC) and next generation sequencing (NGS) analysis of WHO grade II chordoid meningiomas from 30 patients (35 cases), representing the largest study to date. The NGS was performed by using a custom Agilent-generated 295-gene library containing genes with recurrent mutations in adult and pediatric, primary and metastatic brain cancer. Five of these cases cases were confirmed by performing NGS at Tempus on the xT panel containing 596 genes, and an additional 10 atypical (non-chordoid) meningioma, WHO grade II, cases were sequenced at Tempus, for comparison. RESULTS The patients with chordoid meningioma have demographic characteristics different from the general population: younger age of onset (45 vs 65), skull base (SB) location for the female patients (6:1), and increased recurrence rate (25% at 5 years). NHERF1 microlumen extent directly correlated with skull base location (p=0.0002), and segregated tumors into three cell differentiation categories -fibroblastic (13.3%), epithelial/poorly-differentiated (26.7%) and epithelial/well-differentiated (60%). NGS identified NF2 and TRAF7, as the most common mutated genes, correlating with the location and epithelial differentiation of the tumors. Mutations in AKT1, KLF4 and MN1 were found in isolated well-differentiated skull base tumors. Mutations in genes not previously involved in meningioma pathogenesis were also found. CONCLUSION The integrated tumor analysis stratified the patients into: (1) HIGH RECURRENCE RISK , characterized by tumors harboring NF2 mutations and low epithelial differentiation and (2) LOW RECURRENCE RISK , characterized by tumors exhibiting either epithelial differentiation, skull base location and TRAF7/AKT1/KLF4 mutations, or fibroblastic differentiation, non-skull base location and other mutations. This is the first study of the integrated mutational landscape of chordoid meningioma with important implications for patient risk stratification and management.

Programmed cell death 4 (PDCD4) as a novel prognostic marker for papillary thyroid carcinoma.

BackgroundThe primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease.PurposeThe aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC.Patients and methodsWe investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15–98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset.ResultsWe found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome.ConclusionThese results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.

Papillary Thyroid Cancers with Focal Tall Cell Change are as Aggressive as Tall Cell Variants and Should Not be Considered as Low-Risk Disease.

The tall cell variant of papillary thyroid carcinoma (PTC) is as an aggressive histological variant. The proportion of tall cells needed to influence prognosis is debated. Patients with PTC and tall cells, defined as having a height-to-width ratio of ≥ 3:1, seen at a high-volume center between 2001 and 2015, were reviewed. Specimens were classified as (1) focal tall cell change, containing < 30% of tall cells; (2) tall cell variant, ≥ 30% of tall cells; and (3) control cases selected from infiltrative classical PTCs without adverse cytologic features. Univariate, sensitivity, and multivariate analyses were performed with persistent/recurrent disease as the primary outcome. We identified 96 PTCs with focal tall cell change, 35 with the tall cell variant and 104 control cases. Factors associated with poor clinical prognosis were significantly greater in those with focal tall cell change and tall cell variants. Regarding primary outcome, hazard ratios were 2.3 (95% confidence interval [CI] 1.0-5.7) for focal tall cell change, and 3.4 (95% CI 1.2-8.7) for tall cell variants compared with controls. Five-year disease-free survival was higher for the control group (92.7%, CI 87.4-98.0) compared with focal tall cell change (76.3%, CI 66.1-86.5) and the tall cell variant (62.2%, CI 43.2-81.2). When stratified in groups consisting of tall cell proportions (< 10%, 10-19%, 20-29% and ≥ 30%), identification of ≥ 10% tall cell change was associated with worse outcome (p = 0.002). PTCs with ≥ 10% tall cell change have worse prognosis than those without tall cells. Our data indicate that thyroid cancer management guidelines should consider PTCs with focal tall cell change outside of the low-risk classification.