Mixed Carcinoma Research Articles

Expression of c-kit in common benign and malignant breast lesions.

c-kit (CD117) is a transmembrane tyrosine kinase that acts as a type III receptor for mast cell growth factor. In recent years, the role of c-kit in the development of preinvasive and invasive breast carcinomas has been investigated. The aim of our study was to detect c-kit expression in the entire spectrum of common benign and malignant breast lesions in correlation with a well-studied myoepithelial or stem-cell like marker (p63). We evaluated 270 cases of benign and malignant breast lesions including fibrocystic disease, fibroadenoma, sclerosing adenosis, atypical ductal hyperplasia, ductal/lobular carcinoma in situ, and ductal/lobular/mixed type carcinoma. C-kit staining was evaluated in the cytoplasm/cell membrane in epithelial and myoepithelial cells and p63 in the nuclei of myoepithelial cells. c-kit was highly expressed (85.3%) in benign lesions (fibrocystic disease, sclerosing adenosis, fibroadenoma), and p63 expression was 95.5% in the aforementioned lesions. c-kit distribution in preinvasive and invasive lesions was as follows: ductal/lobular carcinoma in-situ, 43%/35%; ductal/lobular carcinoma, 36%/39%; and mixed type carcinoma, 20%. c-kit was highly expressed in myofibroblast/fibroblast cells only in grade III ductal/lobular carcinomas. c-kit was totally absent in stromal cells in benign lesions and in situ carcinomas whereas expression was weak in grade I and II carcinomas. Combined overexpression of c-kit and p63 is indicative of benign breast lesions. In contrast, there is reduced expression of c-kit in in situ and invasive breast carcinomas, with simultaneous overexpression in the stromal cells. This suggests that c-kit may play a role in breast cancer progression.

Randomized phase III study of gemcitabine and cisplatin (GC) versus dose dense methotrexate, vinblastine, doxorubicin and cisplatin (DD-MVAC) in the perioperative setting for patients with locally advanced transitional cell cancer of the bladder: The French GETUG/AFU V05 VESPER trial.

TPS530 Background: Radical cystectomy remains the gold standard treatment for invasive non metastatic transitional cell cancer of the bladder. Perioperative chemotherapy (adjuvant ou neoadjuvant) has been developed to increase overall survival. However, the chemotherapy administration time and optimal chemotherapy regimen are not yet determined. As DD-MVAC has been shown to be associated with higher response rates in bladder metastatic disease, also a better efficacy can be suspected in the perioperative setting. Methods: We designed a randomized phase III study to compare the efficacy of GC and DD-MVAC in term of progression-free survival in patients for whom chemotherapy has been decided, before or after radical cystectomy (disease defined by a T2, T3 or T4a N0 M0 stadification for patients receiving neoadjuvant chemotherapy or pT3 or pT4 or pN+ and M0 for patients receiving adjuvant chemotherapy). Secondary endpoints include overall survival, side effects, response rate in the neoadjuvant setting. Main exclusion criteria were histological variants (pure adenocarcinoma or pure epidermoid carcinoma or pure or mixed small-cell neuro-endocrine carcinoma) and ventricular ejection fraction under 50%. The total number of patients projected was 500 based on the median progression-free survival rate of 50% at 3 years observed in patients treated with GC (standard arm A) in the perioperative setting. An absolute improvement of 10% (HR = 0.74) was expected with DD-MVAC (experimental arm B) with a = 0.05 and b = 0.20. In October 2017, 460 patients have been included. An interim analysis is planned after the occurrence of 174 events. With an estimated uniform accrual rate of 140 patients per year for 3.5 years and exponential survival, the final analysis is expected to occur 8 years after the start of the trial. Concomitant ancillary study has also started, focusing on the identification of subgroups for muscle invasive bladder tumors sensitivity to neoadjuvant chemotherapy, as suggested by the recent MDA classification. Clinical trial information: NCT 018 12369.

Abstract PD2-11: Contrast-enhanced spectral mammography is comparable to MRI in the assessment of residual breast cancer following neoadjuvant systemic therapy

Abstract OBJECTIVE: Currently, no study has assessed the performance of contrast-enhanced spectral mammography (CESM) in evaluating tumor response in breast cancer patients undergoing neoadjuvant systemic therapy (NST). This study aims to evaluate whether the accuracy of CESM is comparable to MRI in detection of residual breast cancer following NST. MATERIALS AND METHODS: Retrospective review of CESM cases at our institution between September 2014 and June 2016 identified patients who had both CESM and MRI pre- and post-NST with pathologic assessment after surgical management. Size of residual malignancy (if any) on post-neoadjuvant CESM and MRI was compared to surgical pathology (reference standard). Pathologic complete response (pCR) was documented and compared to Residual Cancer Burden (RCB) score for confirmation. Bland-Altman plots were used to visualize the differences between CESM/MRI and pathologic tumor size. RESULTS: Forty female patients met inclusion criteria. Mean age was 52.3 years (range 35-73). Type of NST included: 34 (85%) chemotherapy and 6 (15%) endocrine therapy. Histological analysis showed invasive ductal carcinoma in 38 (95%), the remaining cases consisted of one invasive lobular carcinoma, and one mixed invasive carcinoma. Mean tumor size after NST was 10.3 mm (range 0-75 mm) for CESM and 9.7 mm (range 0-60 mm) for MRI compared to 15.7 mm (range 0-100 mm) on final surgical pathology. Equivalence tests demonstrated that the mean tumor size measured by CESM or by MRI is equivalent to the mean tumor size measured by pathology within -1 and 1 cm range (p=0.0132 for CESM and p=0.0194 for MRI). Difference in Measurement Post-NST Compared to Pathology Path Tumor Size (mm)CESM Tumor Size (mm)MRI Tumor Size (mm)Mean (SD)15.7 (24.5)10.3 (18.9)9.7 (16.3)Difference Compared with Path (SD); P value -5.4 (12.6); 0.0132-6.0 (11.7); 0.0194 A complete radiologic response was seen in 25 CESM and 22 MRI cases which was confirmed by pathology in 17 and 14, respectively. Alternatively, CESM and MRI demonstrated residual disease in 15 patients and 18 patients respectively and this was confirmed on pathology in 15 and 15, respectively. Accuracy of CESM vs. MRIModalityResidual Disease by Pathology (N=23)Complete Response by Pathology (N=17)SensitivitySpecificityPPVNPVResidual Disease by CESM (N=15)150Complete Response by CESM (N=25)81765.2%100%100%68%Residual Disease by MRI (N=18)153Complete Response by MRI (N=22)81465.2%82.4%83.3%63.6% All patients who achieved a pCR had an RCB score of 0 indicating no residual cancer in lymph nodes. Among patients with residual disease, their mean RCB score was 2.6 (range 0.8-4.18). CONCLUSION: In this study, CESM was comparable to MRI in assessing residual malignancy after completion of NST, thereby offering a potentially faster and less expensive alternative to MRI for monitoring treatment response in the neoadjuvant setting. Citation Format: Hilal T, Covington M, Sugi M, Zhang N, Pockaj B, Northfelt D, Ocal IT, Patel BK. Contrast-enhanced spectral mammography is comparable to MRI in the assessment of residual breast cancer following neoadjuvant systemic therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD2-11.

Abstract P4-08-04: The clinical utility of oncotype Dx for patients with recurrence scores of 10 or less: A value based pathology study of tumor histopathology and outcomes analysis in an integrated delivery and finance health system

Abstract Introduction The majority of publications regarding breast cancer GEPTs rarely supply detailed breast tumor histopathology in their outcome studies. As a result, the cost effective role of clinical risk assessment with histopathology of breast carcinomas tends to be minimized. The aims of this study are to characterize the details of breast tumor histopathology of patients with Oncotype Dx Recurrence Scores (RS) of 10 or less, and determine if Oncotype Dx offers value and clinical utility for patients with these low grade tumors Methods A total of 459 patients (18%) with Oncotype Dx RS of 10 or less were retrieved from a registry of 2558 patients with Oncotype Dx results. Patients had five years of follow-up with tumor registry and were treated with endocrine therapy alone. Tissue slides were available to review on 441/459 patients. Recorded details included (1) histopathologic type of carcinoma (2) mitotic score (MS), tubule formation, nuclear pleomorphism and Notttingham histologc (NG) grade. (3) Estrogen (ER) and progesterone (PgR) semiquantitated by Allred Score and Histologic Score (H Score: strong 200-300, moderate 100-199, weak <100). (4) Lymph node status. (5) overall survival and breast cancer specific survival. Results Patient ages were 33-92, with mean/median age of 60, and all had endocrine therapy alone. 148 of 441(34%) patients had carcinomas of “special types”, notable for low grade/good prognosis including tubular 22(15%), cribriform 15 (10.1%), papillary 17 (11.5%), and mucinous 28 (21%), along with 63 (42.5%) low grade classic lobular carcinomas and 3 (2%) low grade mixed ductal and lobular carcinomas. All 148 tumors had a MS of 1, were NG1 and had high ER HScores (280 median/263 mean) (Allred Scores 7-8) and high PR HScores (210 median/201 mean) (Allred Scores 6-8). The remaining 293 tumors were ductal carcinomas of no special type (NST), and 261/293 (89%) of these had a MS of 1/NG2. Of the remaining cases, 10 (3%) had a MS of 2/NG2, 18 (6%) had MS of 2/NG3 and four (1%) were MS3/NG3. Estrogen receptor H Score/Allred Score was strong (Allred Score 7-8) in 395/441 (89.6%), moderate in 45 (10.2%) and weak in 1 patient (0.2%). Progesterone HScores were strong in (Allred Score 6-8) 269/441 (76%) and moderate in the remainder. Strong and moderate ER comprised 99.8% of tumors. Thus, tumors with MS1, and NG1, all with ER HScore >200 (Allred Score of 7-8) were enriched in the RS <10, and these features distinguished this group from other tumors with a MS1. At 5 years, 433 patients (98%) were alive, 8 were dead, 1 from breast cancer due to distant recurrence. The 5-year breast cancer specific survival for this group was 99.7%. [95%CI 98.5-99.9.] 87 cases were accrued in the ongoing prospective study to date. There were 15/87 (17%) cases, 95% of which were correctly identified by pathologists as having an RS <10 using the criteria defined, with sensitivity 95%, specificity 86%, PPV 63% 95% CI(49.76-75.08), NPV 99% 95% CI(90.7-99.78). No patient had a recurrence score >22. Conclusions Pathologists can identify these low risk tumors with high accuracy. Oncotype Dx lacks clinical value and utility in this setting. Citation Format: Dabbs DJ, Serdy K, Onisko A, Clark BZ, Bhargava R, Smalley S, Perkins S, Brufsky AM. The clinical utility of oncotype Dx for patients with recurrence scores of 10 or less: A value based pathology study of tumor histopathology and outcomes analysis in an integrated delivery and finance health system [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-08-04.

Combination of Kras activation and PTEN deletion contributes to murine hepatopancreatic ductal malignancy

Kras mutations are among the most common genetic abnormalities in human neoplasms, including cholangiocarcinomas, pancreatic cancer and colon cancer. PTEN has previously been associated with cholangiocarcinoma development in murine models. Here, we have established novel mouse models of neoplasms by liver-specific and biliary-pancreatic Kras activation and PTEN deletion. By liver-specific disruption of PTEN and activation of Kras in mice caused rapid development of intrahepatic biliary epithelial proliferative lesions (Intrahepatic cholangiocarcinoma, ICC), which progress through dysplasia to invasive carcinoma. In contrast, Kras activation in combination with heterozygous PTEN deletion induced mixed carcinomas of liver (both ICC and hepatocellular carcinoma, HCC), whereas Kras activation alone did not induce biliary tract neoplasm. Use of Sox9-Cre-LoxP-based approach to coordinately delete PTEN and activate Kras in the adult mouse resulted in not only development of low-grade biliary lesions (ICC and extrahepatic bile duct carcinoma, ECC) but also pancreatic carcinomas. Our data provide a functional link between PTEN gene status, hepatobiliary cell fate, and HCC, biliary carcinoma, pancreatic cancer pathogenesis, and present novel genetically engineered mouse models of PTEN loss-driven malignancy.

Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs).

214 Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.

Are the uterine serous carcinomas underdiagnosed? Histomorphologic and immunohistochemical correlates and clinical follow up in high-grade endometrial carcinomas initially diagnosed as high-grade endometrioid carcinoma

Histologic subclassification of high-grade endometrial carcinomas can sometimes be a diagnostic challenge when based on histomorphology alone. Here we utilized immunohistochemical markers to determine the immunophenotype in histologically ambiguous high-grade endometrial carcinomas that were initially diagnosed as pure or mixed high-grade endometrioid carcinoma, aiming to determine the utility of selected immunohistochemical panel in accurate classification of these distinct tumor types, while correlating these findings with the clinical outcome. A total of 43 high-grade endometrial carcinoma cases initially classified as pure high-grade endometrioid carcinoma (n=32), mixed high-grade endometrioid carcinoma/serous carcinoma (n=9) and mixed high-grade endometrioid carcinoma/clear cell carcinoma (n=2) were retrospectively stained with a panel of immunostains, including antibodies for p53, p16, estrogen receptor, and mammaglobin. Clinical follow-up data were obtained, and stage-to-stage disease outcomes were compared for different tumor types. Based on aberrant staining for p53 and p16, 17/43 (40%) of the high-grade endometrial carcinoma cases initially diagnosed as high-grade endometrioid carcinoma were re-classified as serous carcinoma. All 17 cases showed negative staining for mammaglobin, while estrogen receptor was positive in only 6 (35%) cases. The remaining 26 cases of high-grade endometrioid carcinoma showed wild-type staining for p53 in 25 (96%) cases, patchy staining for p16 in 20 (77%) cases, and were positive for mammaglobin and estrogen receptor in 8 (31%) and 19 (73%) cases, respectively, thus the initial diagnosis of high-grade endometrioid carcinoma was confirmed in these cases. In addition, the patients with re-classified serous carcinoma had advanced clinical stages at diagnosis and poorer overall survival on clinical follow-up compared to that of the remaining 26 high-grade endometrioid carcinoma cases. These results indicate that selected immunohistochemical panel, including p53, p16, and mammaglobin can be helpful in reaching accurate diagnosis in cases of histomorphologically ambiguous endometrial carcinomas, and can assist in providing guidance for appropriate therapeutic options for the patients.

The Clinicopathological Features and Survival Outcomes of Different Histological Subtypes in Triple-negative Breast Cancer.

Purpose: To determine the clinicopathological features and survival outcomes of triple-negative breast cancer (TNBC) according to different histological subtypes.Methods: Using the Surveillance, Epidemiology, and End Results database, we included TNBC cases in 2010-2013. The effect of histological subtype on breast cancer-specific survival (BCSS) and overall survival (OS) were analyzed using univariate and multivariate analyses.Results: A total of 19,900 patients were identified. Infiltrating ductal carcinoma not otherwise specified accounted for 91.6% of patients, followed by metaplastic carcinoma (2.7%), medullary carcinoma (1.4%), mixed lobular-ductal carcinoma (1.4%), lobular carcinoma (1.3%), apocrine carcinoma (1.0%), and adenoid cystic carcinoma (0.6%). Medullary carcinoma was more frequently poorly/undifferentiated. Significantly more lobular carcinoma, mixed lobular-ductal carcinoma, and metaplastic carcinoma patients had larger tumors. Adenoid cystic carcinoma, metaplastic carcinoma, medullary carcinoma, and apocrine carcinoma were more frequently node-negative. Lobular carcinoma (16.0%) and mixed lobular-ductal carcinoma (10.4%) more frequently had distant stage at initial diagnosis. Histologic subtype was an independent prognostic factor of BCSS and OS. Compared with infiltrating ductal carcinoma, medullary carcinoma and apocrine carcinoma had better BCSS and OS, while mixed lobular-ductal carcinoma and metaplastic carcinoma had worse survival. Adenoid cystic carcinoma survival was not significantly different from that of infiltrating ductal carcinoma.Conclusions: TNBC histological subtypes have different clinicopathological characteristics and survival outcomes. Medullary carcinoma and apocrine adenocarcinoma have excellent prognosis; mixed lobular-ductal carcinoma and metaplastic carcinoma are the most aggressive subtypes.

Mixed Mucinous Male Breast Carcinoma: A Rare Histological Variant of a Rare Disease

Male breast carcinoma is rare neoplasm, accounting for <1% of all diagnosed breast malignancy. Histologically, most often it is infiltrating ductal carcinoma and rarely mucinous carcinoma. A 73-year-old male presented with lump in right breast since six months. On examination a 5x5 cm hard, non tender lump fixed to overlying skin, with no right axillary lymphadenopathy. Incisional biopsy showed mixed mucinous carcinoma of breast. After investigations he underwent right modified radical mastectomy. Histopathology confirmed mixed mucinous carcinoma and infiltrating ductal carcinoma. Patient received adjuvant radiotherapy, chemotherapy and hormonal therapy. Mixed mucinous and infiltrating ductal carcinoma is extremely rare. Clinical stage and axillary lymph node status are of prognostic value.

Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers.

The aim of this study was to comparatively evaluate the efficacy of strontium-89 chloride (89 SrCl2) in treating bone metastasis-associated pain in patients with lung, breast, or prostate cancer. The 126 patients with lung cancer included 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, nonsmall cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, and the control group consisted of patients with breast (71 patients) or prostate cancer (49 patients) who underwent 89 SrCl2 treatment during the same period. The treatment dose of 89 SrCl2 was 2.22 MBq/kg. The efficacy rate of treatment in the lung cancer group was 75.4%, compared to 95.0% in the control group. Approximately 67% of patients with lung cancer and bone metastases and 47% of control patients exhibited mild-to-moderate reductions of leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment. 89 SrCl2 can safely and effectively relieve bone pain caused by bone metastasis from lung cancer. However, its efficacy was lower in patients with lung cancer with bone metastasis than in those with breast or prostate cancer with bone metastasis, and its effects on the peripheral hemogram were also significantly stronger in the lung cancer group.

A FISH assay efficiently screens for BRAF gene rearrangements in pancreatic acinar-type neoplasms

Approximately 1–2% of pancreatic neoplasms are acinar cell carcinomas. Recently, BRAF gene rearrangements were identified in over 20% of acinar-type neoplasms, which included both pure acinar cell carcinomas and mixed carcinomas with acinar differentiation, using next-generation sequencing-based platforms, providing a potential therapeutic target for patients with these neoplasms. Thus, it is clinically important to develop a rapid, cost- and material-efficient assay to screen for BRAF gene fusions in pancreatic acinar-type neoplasms. We developed a dual color, break-apart FISH assay to detect BRAF gene rearrangements in these neoplasms and evaluated its performance in comparison to next-generation sequencing-based studies. A blinded BRAF rearrangement FISH investigation was performed on 31 acinar-type neoplasms that had been studied previously by next-generation sequencing-based analysis as well as on 18 additional acinar-type neoplasms that were accrued over the past 2 years. In total, BRAF fusions were identified in 12/49 (24%) acinar-type neoplasms by FISH. BRAF fusion partners were uncovered by using targeted next-generation sequencing studies in 11 FISH-positive cases that had sufficient material for next-generation sequencing studies. SND1 was the most frequent fusion partner involved in BRAF-fusion acinar-type neoplasms (50%), followed by HERPUD1 (18%). No BRAF fusions were identified by next-generation sequencing in any of the FISH-negative cases investigated. FISH analysis showed that BRAF rearrangements were diffusely present across tumor-rich areas in BRAF-fusion acinar-type neoplasms, which is consistent with an oncogenic driver alteration pattern. Thus, we demonstrated that, in comparison to targeted next-generation sequencing-based technologies, the FISH assay is highly sensitive and specific as well as time- and cost-efficient in the detection of BRAF fusions in acinar-type neoplasms. The FISH assay can be easily implemented in diagnostic settings to identify acinar-type neoplasms patients potentially suitable for targeted therapy to inhibit MAPK pathway activity.

Histopathological classification and immunohistochemical characterization of canine mammary tumours

The present study was carried out to investigate breed wise and age wise prevalence of canine mammary tumours (CMTs) along with histopathological and immunohistochemical characterization. A total of 97 CMTs samples were collected from different parts of Gujarat, India over period of three years (April 2014-March 2017). The mean age of the dogs, involvement of breeds and mammary glands were recorded. The mean±SD age of all affected dogs was 7.5±2.8 years. Among 12 breeds affected, most cases (n=77) of CMTs were recorded in four breeds viz., Pomeranian, Mongrel, Germen Shepard and Labrador. Caudal abdominal and inguinal mammary glands were frequently showed neoplastic growth. Among histological characterization of 97 CMTs, 16(16.49%) were non neoplastic proliferative/dysplastic lesions, 11 (11.34%) were benign neoplasms and 70 (72.16%) were malignant tumours. Out of 70 malignant neoplasms, epithelial neoplasms, special type epithelial neoplasms, mesenchymal neoplasms and carcinosarcomas were 53(54.64%), 6(6.19%), 8(8.25%), and 3(3.09%), respectively. Further, mixed carcinoma, tubulopapillary carcinoma, solid carcinoma, carcinoma and malignant myoepithelioma, tubular carcinoma and ductal carcinoma were frequently noted. Immunohistochemistry was found to be a powerful tool to classify the CMTs. In the present study, smooth muscle actin (SMA) helped in diagnosing complex adenoma, complex carcinoma, malignant myoepithelioma and fibrosarcoma. In complex adenoma, complex carcinoma and malignant myoepithelioma, myoepithelial cells showed strong SMA immunoreactivity, although stromal myofibroblasts and vascular smooth muscle cells also immunostained.

Papillary Carcinoma Arising in Thyroglossal Duct Cyst: A Retrospective Analysis (Cancer of the Thyroid or Primary Cancer of the Thyroglossal Cyst)

Thyroglossal duct cysts are one of the most common congenital abnormalities of the cervical region. Complications of these swellings are rare, and among these, appearance of a carcinoma has also been noted. Thyroglossal duct cyst carcinoma (TGDC) is a rare entity and its management is controversial. The incidence of thyroid papillary carcinoma in thyroglossal duct cyst is less than 1%, in most cases, the diagnosis is made postoperatively. We report the case of an adult female patient with a papillary carcinoma arising in a thyroglossal duct cyst. Our aim is defining a clinical protocol to diagnose the thyreoglossal duct carcinoma through clinical features, radiological investigations, cytological and histopathological examinations and, through this diagnostic protocol, to choose the best surgical approach. The literature contains 300 cases of this pathology; papillary histotype constitutes about 80%, then squamocellular carcinoma, mixed folliculo-papillary carcinoma and adenocarcinoma follow. The literature suggests two different hypotheses: neoplasia originating from ectopic thyroid tissue and plurifocal theory. The adopted diagnostic investigations are: ultrasonography, Fine Needle Aspiration Biopsy (FNAB), Magnetic Resonance Imaging (MRI). Our patient was treated using a modified Sistrunk’s procedure operation, in which thyroidectomy proved crucial for the correct diagnosis and continuation of appropriate treatment. Our case confirms the difficulty in distinguishing a primitive thyroglossal duct carcinoma from a synchronous metastatic papillary carcinoma of the thyroid. This dilemma often remains unresolved. The two different surgical approaches reported in the literature, one more conservative and the other more aggressive, apparently alternatives are instead complementary and adequate when strict diagnostic criteria and adequate follow-up, are observed. The first year follow-up includes the thyroglobulin level determination and a neck ecografic scan every 3 months. The patient has been following for two years without any metastasis.

Mucinous Breast Carcinoma: Anatomo-Clinical Radiological and Therapeutic Features

Introduction: Mucinous carcinoma of the breast constitutes 1% to 4% of all breast cancers. Two different forms of presentation are distinguished: pure mucinous carcinoma and mixed mucinous carcinoma. The purpose of our work was to clarify the anatomo-clinical and radiological particularities of this rare form of breast cancer. Materials and methods: This was a retrospective study of a series of 14 cases of mucinous carcinoma of the breast, including 8 pure mucinous carcinomas and 6 mixed mucinous carcinomas treated at the Maternity and Neonatal Center of Monastir between January 2009 and December 2017. Results: The frequency of mucinous carcinoma of the breast in our study period was 1.9%. The average of the patients was 55 years old. The average tumor size was 40 mm. Mucinous carcinoma of the breast was pure in 8 cases, mixed in 6 cases. The clinical size of pure CM was smaller than that of mixed CM (41 mm vs 45 mm) [p = 0.12]. Axillary adenopathies were found in 28.5% of patients. Mammography detected a total of 19 masses with three cases of multifocality. The average size was 27 mm, there was no significant difference between subtype sizes. Pure CMs had an oval shape in 83% of the cases with microlobulated contours in half of the cases, mixed CM rather had an irregular shape (71%) with indistinct contours (85%) (p = 0.01/p = 0.04). On ultrasound, pure CMs had a homogeneous hypoechogenic oval mass appearance with microlobulated contours enhancing ultrasound. The mixed CMs had an irregular shape of non-geometric contours and heterogeneous hypoechogenic appearance with posterior ultrasound attenuation (p = 0.06). Microcalcifications were present in 37% of pure CM and 60% of mixed CM (p = 0.13). Ganglionic invasion was noted in 28% of cases. The extension assessment was negative in all cases. The tumors were of low histological grade with predominance of SBR I and II grades. They expressed hormone receptors in 85% of cases. Overexpression of the HER2 gene was noted in only one case. Conclusion: It is important to distinguish between the two pure and mixed forms, because the therapeutic attitude and the prognosis depend on it. The pure form remains a favorable prognosis, whereas that of the mixed form matches that of infiltrating ductal carcinomas.

A case of mixed type squamous cell carcinoma of the breast with enlarged squamous component during neoadjuvant chemotherapy

A case of mixed type squamous cell carcinoma of the breast with enlarged squamous component during neoadjuvant chemotherapy

Prognostic Factors in Canine Mammary Carcinomas and HER2 Expression Relationship

Background: The human epidermal growth factor type 2 (HER2) receptor is a membrane glycoprotein tyrosine kinase. In woman, HER2 expression is diagnosed in 30% of breast carcinomas and it is associated with a worse prognosis, higher rate of recurrence and mortality. In the bitch, the HER2 overexpression in canine mammary tumors is still controversial and the prognostic value remains uncertain. Thus, we aimed to verify the HER2 expression in canine mammary carcinomas and relate it to the type and histological grade, lymph node metastasis and clinical staging.Materials, Methods &amp; Results: Ninety bitches diagnosed with mammary carcinoma were included in this study. The inclusion criteria were bitches with complete clinical examination, thoracic radiographic examination and submitted unilateral or bilateral mastectomy. Ninety-nine samples of mammary carcinoma were used and the fragments of tumor and regional lymph nodes were fixed in 10% neutral formalin for histopathological and immunohistochemistry analysis. The lesions were evaluated by two pathologists and classified according to the type and histological grade. HER2 expression was performed by semi-quantitative analysis of the slides according to the HerceptTestTM (Dako) recommended score. Simple carcinomas were the most frequent (51.51%) followed by complex carcinomas (46.47%) and in situ carcinoma (2.02%). The histological grade of 97 carcinoma samples was attributed, except in situ carcinoma, 37 (38.14%) of the neoplasms were grade I, 50 (51.55%) grade II and only 10 (10.31%) tumors were classified as grade III. Forty bitches were submitted to clinical staging (TNM) and 42.50% of the bitches received staging in grade I and, 25% of the bitches staged in grade IV and V, with metastases. The HER2 expression, 13/99 samples (13.13%) received score +2, 19/99 (19.19%) score +1 and absence of marking (score 0) was identified in 67 samples (67.80 %). Immunostaining in hyperplastic or normal epithelial cells was evidenced, often in association with weak or moderate cytoplasmic labeling. Of the samples expressing +2 score for HER2 (n = 13), eight samples (17.39%) were complex carcinoma and five (9.80%) simple carcinomas. There was no relationship between HER2 immunostaining with age, tumor size, TNM, histological type, histological gradation, lymph node metastasis and distance. Animals with lymph node metastasis, as well as those diagnosed with distant metastasis, did not present HER2 expression in the tumors.Discussion: The simple carcinoma seems to be the most frequent type histological diagnosed in canine mammary carcinomas, followed by carcinoma in mixed tumor and complex carcinoma. Tubulopapillary carcinomas are more invasive in the female dogs as well as in the woman. Carcinomas grade I and II are more frequent and present a better prognosis for the dog. However, bitches with grade III carcinoma survived for a shorter time when compared to dogs with grade I or II tumors. A factor that may have contributed to the lower number of bitches at worst prognostic stage (EC IV and V) is the current owners’ awareness that they have sought veterinary help earlier, as soon as they detect small nodules in mammary gland. Overexpression of HER2 in women breast cancer is diagnosed in 20-30% of cases, whereas in bitches, this expression is variable. Also the different percentages of canine HER2 immunostaining are due to the lack of standardization for the analysis of the immunostaining, the immunohistochemical techniques employed and the non-specificity of the HER2 antibody. In canine mammary carcinomas the HER2 expression in low and this immunostaining is not related to other established prognostic factors. This study reinforces the hypothesis put forward by other authors that in the bitch the expression of HER2 may not be related to malignancy and tumor progression.

The image performance of mucinous breast carcinoma on automated breast volume scanner and its pathologic features

Objective To explore the image performance of mucinous breast carcinoma(MBC) on automated breast volume scanner (ABVS) and its pathologic features, for the purpose of improving the recognition of this disease on ABVS, as well as diagnostic ability. Methods Retrospectively analyzed the sonogram and pathological data of 17 patients with 18 MBC lesions that included 9 PMBC(pure mucinous breast carcinoma) and 9 MMBC(mixed mucinous breast carcinoma), all patients were examined by ABVS before operation and confirmed by pathology. Results Luminal A was the main molecular subtype of MBC, as well as rarely lymph node metastases; The image of the MBC on ABVS mainly showed a round like or irregular mass, isoechoic or slightly lower with posterior acoustic enhancement, and clearly edge with microlobulated or angular; While on the coronal plane, it might presented unsmoothed contour, retraction phenomenon and expansive growth pattern like a spherical nodular; The image characteristics of the PMBC and MMBC lesions on ABVS had no statistical difference(P>0.05), but the PMBC often performed isoechoic mass with clearly marge, in contrast, the MMBC usually performed hypoechoic mass with indistinct and angular edge, and the malignant image features on the coronal plane. Conclusions The three vertical sections of ABVS are beneficial to observe the morphological features of MBC completely, which can help to identify it from the benign lesions, reduce misdiagnosis, and provide some guidance for MBC surgical treatment in the early stage. Key words: Ultrasonography; Breast neoplasms; Adenocarcinoma, mucinous; Automated breast volume scanner

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136 patients.

The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI-NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI-NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-γ and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD-1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy.

Morphometric study of adipocytes on breast cancer by means of photonic microscopy and image analysis.

Worldwide, breast cancer (BrCa) is currently the leading cause of deaths associated to malignant lesions in adult women. Given that some studies have mentioned that peritumoral adipocytes may contribute to breast carcinogenesis, present work sought to quantitative evaluate the morphometry of these cells in a group of adult women. Three thousand six hundred sixty four breast adipocytes, that came from biopsies of a group of adult females with different types of breast carcinomas (ductal, lobular, and mixed) and one with normal tissues, were evaluated through an image analysis (IA) process regarding six morphometric descriptors: area (A), perimeter (P), Feret diameter (FD ), aspect ratio (AR), roundness factor (RF), and fractal dimension of cellular contour (FDC ). Data showed that the adipocytes of the normal tissues group were bigger (A: 3398 ± 2331 µm2 , P: 239 ± 83 µm, and FD : 79.9 ± 24.5 µm) than those from BrCa samples (A: 2860 ± 1933 µm2 , P: 214 ± 66 µm, and FD : 73.2 ± 22.5 µm), and presented a more irregular contour (FDC of 1.370 ± 0.037 for normal group and of 1.335 ± 0.049 for the oncologic one). Moreover, it could be accounted that adipocytes of mixed carcinomas were largest (FD : 75.1 ± 22.4 µm) than those of lobular lesions (FD : 61.6 ± 22.6 µm), while the adipocytes of ductal carcinomas were the most oval (AR: 1.421 ± 0.524) and roughest (FDC : 1.324 ± 0.050) cells. IA results suggest that BrCa lesions can be categorized through a quantitative morphometric evaluation of peritumoral adipocytes. These findings could let the development of an analytical tool to help the Pathologist to enhance the accuracy of the oncologic diagnose.