Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

Metastatic cutaneous squamous cell carcinoma (cSCC) is associated with a high risk of recurrence and poor prognosis. There is limited published data exploring whole genome sequencing (WGS). The aim of this project was to provide the first comprehensive genomic understanding of the state of metastatic cSCC. In this study, we used WGS on matched tumor and blood DNA to detect somatic genetic alterations from 25 patients with regional metastases of head and neck cSCC. Our computational analyses interrogate clinical impacts of these genetic alterations on metastatic cSCC across the cohort for both the coding and non-coding genome. In the non-coding genome, 3UTR regions of EVC (48%), PPP1R1A (48%) and LUM (16%) were significantly functionally altered (Q-value < 0.05). Further, significant functional alterations are observed in the tumor suppressing lncRNA LINC01003 ( 68% of specimens, Q-value: 0.0158). In addition, significant recurrent copy number loss in tumor suppressor genes KANSL1 and PTPRD and gain in CALR, CCND1 and FGF3 was observed for coding regions. SNVs driver analyses predicted TP53, CDKN2A, as potential drivers of the metastasis cSCC (using 3 different tools). Indel signature analysis highlight dominance of ID signature 13 followed by ID8 & ID9. Interestingly, ID 9 has previously been shown to have no association with skin melanoma, unlike ID 13 and 8, suggesting some point of difference between these two skin-based diseases. The overall landscape of variation in metastatic cSCC is dominated by cell cycle and DNA repair disruption.

Multiple Free Flap Reconstruction of a Complex Intraoral Defect after Squamous Cell Carcinoma Excision: A Case Report

Background: Squamous cell carcinoma is the most frequent malignant cancer of the oral cavity. Metastasis involvement is one of the most relevant prognostic factors in terms of survival probability. Patients with oral cancers often undergo extensive en bloc resective surgery of the mandible and maxilla, with or without cervical nodal dissection, based on the presence or occult risk of regional metastases. Several factors affect the choice of flap, to recover aesthetics and function. Case Presentation: The case of a 60-year-old man who underwent maxillectomy with neck dissection as well as a reconstruction with a combination of multiple vascularized free flaps is presented. Conclusions: The excellent integration of the free flaps and the total absence of complications led to a high-quality aesthetic and functional performance of the reconstruction obtained through two different flaps. More specifically, the fibular free flap for bone reconstruction allows a two-team approach and maintains an excellent vascularization, even in case of several osteotomies for the maxillary reconstruction as reported. In addition, the use of free radial forearm flap for soft tissue reconstruction permits to obtain long caliber vessels, thus facilitating surgery without repositioning of the patient during surgery and therefore, consequently reducing surgery times.

CD44 Variant Exon 6 Isoform Expression as a Potential Predictor of Lymph Node Metastasis in Invasive Breast Carcinoma of No Special Type

Background. Invasive breast carcinoma of no special type (IBC-NST) is the most widespread invasive carcinoma subtype causing primarily regional metastases of the lymphatic node (LNM). The capacity of CD44 variant exon 6 (CD44v6) expression as an LNM predictor biomarker in IBC-NST was explored. Methods. We conducted a cross-sectional research with 48 paraffin blocks containing IBC-NST primary tumors that were divided into two groups by LNM. The assessment has been carried out in terms of age, tumor size, tumor grade, lymphovascular invasion (LVI), and CD44v6 expression. The expression of CD44v6 was analyzed on the grounds of immunohistochemical (IHC) staining, while other data were taken from archives. Statistical analysis is carried out by univariate, multivariate, and AUROC. Results. CD44v6 exhibits a dominant expression in IBC-NST tumor cells. Univariate analysis revealed a significant association between CD44v6 and LNM status ( p = 0.001 ). Multiple logistic regression results showed that CD44v6 expression and LVI were significantly associated with LNM with OR 10.7 (95% CI: 2.43 to 47.08) and 6.22 (95% CI: 1.4 to 27.88), respectively. CD44v6 expression was able to discriminate against LNM with AUROC 0.863 ± 0.053 (95% CI: 0.759 to 0.967) at the H-score cut-off 133.889 (75% sensitivity and 83.3% specificity). Conclusion. CD44v6 expression and LVI are potential predictors of LNM in IBC-NST. The H-score cut-off of the CD44v6 expression can also be used as a threshold for classification in further investigation.

Prognosis of patients operated on for renal cell carcinoma and tumor venous thrombosis: experience of the Urology Clinics, N.N. Blokhin National Medical Research Center of Oncology

Objective: to identify independent risk factors affecting survival of patients with renal cell carcinoma (RCC) and tumor venous thrombosis who have undergone nephrectomy and thrombectomy.Materials and methods. This study included 768 patients with RCC complicated by tumor venous thrombosis who have undergone nephrectomy and thrombectomy. Median age was 58 years (range: 16-82 years); the male to female ratio was 2.3:1. The symptoms of tumor venous thrombosis were identified in 232 patients (30.2 %); laboratory abnormalities at baseline were observed in 456 patients (59.3 %). Grade I and II tumor thrombosis was diagnosed in 456 (59.3 %) and 201 (26.2 %) patients, respectively; grade III and IV thrombosis was found in 171 (22.3 %) and 177 (23.0 %) patients, respectively. One hundred and twenty-nine participants (16.8 %) had infrarenal inferior vena cava thrombosis. Regional metastases were detected in 188 individuals (24.4 %), distant metastases were registered in 274 patients (35.7 %). All patients have undergone surgery: either radical (n = 555; 72.3 %) or cytoreductive (n = 213; 27.7 %). All primary tumors were histologically classified as RCC (G3-4 in 337 cases; 43.9 %). A total of 719 patients (93.6 %) survived the perioperative period; 183 patients with metastasis (23.8 %) received systemic antitumor therapy.Results. The median follow-up was 24 months (range: 1-200 months). The 24-month overall and cancer-specific survival of all patients were 96.9 and 99.7 %, respectively; recurrence-free survival of patients after radical surgery reached 92.9 %. Progression-free survival among those patients who underwent cytoreductive surgery and received first-line therapy/follow-up was 41.7 %. Negative predictive factors of overall survival included hepatomegaly (p = 0.024), ascites (p = 0.033), level IV tumor thrombosis (p <0.0001), infrarenal inferior vena cava thrombosis (p = 0.002), regional metastases (p <0.0001), and cytoreductive surgery (p = 0.012). Depending on the number of risk factors, we have identified 3 prognostic groups: favorable (0 factors), intermediate (1-2 factors), and poor (3-6 factors). Median overall survival differed significantly between the groups and was 128.6 ± 11.8; 40.9 ± 6.7 and 12.3 ± 2.2 months, respectively (p <0.0001 for all).Conclusion. Stratification of patients operated on for RCC and venous tumor thrombosis with their allocation to prognostic groups will ensure the choice of an optimal management strategy.

RADT-08. A VOLUMETRIC ANALYSIS OF STEREOTACTIC RADIOSURGERY LOW DOSE VOLUMES IN PREVENTING FUTURE BRAIN METASTASES

PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions. MATERIALS AND METHODS Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was &lt; 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level. RESULTS The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094). CONCLUSION We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.

Features of tumor heterogeneity in regional metastasis of breast cancer

The review looked at the issues of tumor heterogeneity in breast cancer. Tumor heterogeneity is classified according to the main feature demonstrating regional differences within a tumor (for example, heterogeneity of clinical manifestations, histological heterogeneity, heterogeneity of protein expression, etc.) and by tumor regions (differences between primary tumors and metastases, differences between cell clones within a single tumor node, etc.). Temporal heterogeneity is also distinguished, which manifests itself in the clonal evolution of tumor cells. The review covers the heterogeneity in the expression of four biomarkers from the gold standard for immunohistochemical staining of breast cancer: estrogen receptors, progesterone receptors, Her2/neu and Ki67 in primary tumor tissue and regional metastases. According to various studies, discordance in estrogen receptor status of primary tumor cells and metastases was observed with a frequency of 4 to 62%, progesterone receptors from 12 to 54%, Her2/neu from 0 to 24%, Ki67 from 4 to 39%. The results of studies of changes in the expression levels of individual markers in breast cancer metastases, as well as the heterogeneity of surrogate subtypes of tumor tissue in metastasis, are briefly described. Possible reasons for heterogeneity in the expression of key prognostic and predictive markers by primary tumor and metastatic cells, such as artificial factors at the preanalytic and analytic stages of the study, polyclonality of the primary tumor before metastasis, clonal evolution of tumor cells during metastasis, selection of tumor clones under the therapy are highlighted.

Medullary Thyroid Cancer: Case Series Reports and Literature Review

Background: Medullary thyroid carcinoma (MTC) is a rare neuro-endocrine tumor that arises from the C-cells of the thyroid. About 20- 25 % of MTC cases may be associated with hereditary syndromes like MEN 2A, MEN 2B and Familial MTC. The survival rate is related mainly to the age of the patient, stage of the disease and completion of the surgical resection. Methods: Retrospective review of 11 patients who were diagnosed with medullary thyroid cancer in our general surgery department during the period from 2011 to 2021. All patients had preoperative assessment including history taking, clinical examination, tumor marker (calcitonin and CEA), thyroid function testing, ultrasonography and FNAC. All patients underwent genetic assessment to exclude any underlying genetic mutation. Results: The mean age of diagnosis was 57.73 ± 16.45 years of age. Three patients were males and eight were females. All patients had total thyroidectomy, central and lateral neck dissection except one patient who had prophylactic thyroidectomy due to familial inherited RET mutation. Two patients had recurrence; both of them had high-stage tumor (T3 and T4) with multiple cervical lymph nodes metastasis. The sensitivity of serum calcitonin for the detection of MTC was about 98%. Patients, who had localized disease and underwent complete surgical resection, had good overall survival rates compared with patients with advanced disease. Conclusion: MTC represent a heterogeneous group of thyroid cancers. The overall survival is better than that of undifferentiated thyroid cancers. Complete resection of the thyroid tumor and any local or regional metastases provides the only cure for patients with MTC. Further researches are still needed to improve our understanding and management of MTC.

Medullary thyroid carcinoma and pregnancy

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor of the parafollicular cells of the thyroid gland. The tumor occurs, either sporadically or in a hereditary form, as a component of the type 2 multiple endocrine neoplasia (MEN) syndromes, MEN2A and MEN2B, both with an autosomal dominant transmission. Due to its higher aggressiveness and urgency to treat, it poses a challenge when diagnosed during pregnancy. We performed a literature review searching medical databases as UpToDate and PubMed for relevant information about diagnosis, impact, treatment, and outcome of medullary thyroid carcinoma during pregnancy. Diagnosis of MTC is established by clinical and ultrasound evaluation, followed by a fine needle aspiration biopsy. Further analyses decide whether it is a sporadic or a hereditary disease. Surgery offers the curative solution, but careful postoperative follow-up is needed for the best outcome. The decision for surgery is taken considering the DNA mutation of RET oncogene and pregnancy status. A premature planned delivery is associated with potential complications for the newborn, but it is recommended when maternal status worsens. Conclusions. Complete resection of the thyroid tumor and any local and regional metastases is the only curative solution. Timing of the intervention is extremely important to decrease fetal outcomes. Close follow-up during the postoperative period, by both biochemical and imaging methods, is needed.

A PECULIAR CASE OF ISOLATED METASTATIC INGUINAL LYMPHADENOPATHY IN A YOUNG LADY – A CASE REPORT

Lymphadenopathy refers to the swelling of lymph nodes which can be secondary to bacterial, viral or fungal infections, autoimmune disease and malignancy. Lymphadenopathy can be localized or diffuse. About 75% of most lymphadenopathies are localized, and about 50% of those occur in the head and neck regions . Inguinal lymphadenopathy (3) occurs at the groin region and most common causes include infections of leg or foot, STDs, non Hodgkin's lymphoma, tuberculosis and pelvic malignancies. One of the rare causes includes distant metastasis of nasopharyngeal carcinoma (NPC) which is present in our case. Nasopharyngeal cancer is an uncommon squamous cell carcinoma in the head and neck region, in most parts of the world. It has a high propensity for lymphatic spread and is known for regional metastases with occult primary at presentation . The incidence of distant (1) metastasis at presentation ranges from 4.4 to 6%. The most common sites of metastasis are bone (70%–80%) followed by liver (30%), lungs (18%) and distant lymph nodes (axillary, mediastinal, pelvic and inguinal, in that order) . About 98% of them are discovered within 3 (2) years of treatment. As it is a highly chemo and radio-sensitive tumor, radiotherapy with concurrent chemotherapy is the mainstay in the management of local and advanced diseases. Here we are presenting a peculiar case of previously treated NPC presenting as isolated left inguinal metastatic lymphadenopathy in a young lady

Prognostic significance of CD204 and IDO1 expression in esophageal tumors

Introduction. Cancer of the esophagus ranks sixth in mortality among malignant neoplastic diseases. To understand the molecular mechanisms of its progression, it is necessary to study not only tumor cells directly, but also cells of the microenvironment. In this work, we studied tumor-associated macrophages and their different phenotypes using membrane protein, indoleamine 2,3‑dioxygenase-1 (IDO1) as a marker for type 1 macrophages and macrophage scavenger receptor (CD204) as a marker for type 2 macrophages.The objective of this work was to study the expression of IDO1 and CD204 in tumors of squamous cell carcinoma of the esophagus and to assess its prognostic value.Materials and methods. The study included tumor samples obtained from 48 patients with squamous cell carcinoma of the esophagus. The expression of CD204 and IDO1 was assessed by immunohistochemistry. Survival analysis was carried out by constructing survival curves using the Kaplan–Meier method. Comparison of the significance of differences was performed using the logarithmic rank test. Differences were considered statistically significant at p <0.05.Results. We analyzed the expression of CD204 and IDO1 in esophageal squamous cell carcinoma tumors. Expression of CD204 was detected in stromal macrophages in 100 % of cases and was not detected in tumor cells. We have shown that in esophageal cancer, IDO1 is expressed in both stromal and tumor cells. In tumor cells, the expression of IDO1 was found in 44 % of the samples, in stromal cells, IDO1 was expressed in 92 % of cases. No association with clinical and morphological characteristics was observed for CD204 in stromal cells and IDO1 in tumor cells. For IDO1 expressed in stromal cells, an association with the stage of the disease (p = 0.0450) and the presence of regional metastases (p = 0.0279) was observed. Survival analysis showed that CD204 is a marker of a favorable prognosis for esophageal cancer (hazard ratio 0.455, p = 0.0419).Conclusion. This study has shown that the expression of IDO1 in the tumor stroma is associated with more favorable clinical characteristics. It has also been shown that an increased content of CD204+ macrophages is a marker of a good prognosis for esophageal cancer.