The prevalence and prognostic impact of tumor-infiltrating lymphocytes in uterine carcinosarcoma.

OBJECTIVE: To examine the prevalence and prognostic role of tumor microenvironment (TME) markers in uterine carcinosarcoma (UCS) through immunohistochemical characterization. METHODS: The internal database of our institution was queried out for women with UCS who underwent surgery and thereafter postoperative chemotherapy with carboplatin and paclitaxel between January 2012 and December 2017. Tissue microarrays containing surgical samples of UCS from 57 women were assessed by immunohistochemistry for CD3, CD4, CD8, FOXP3, PD-1, PD-L1, and PD-L2. RESULTS: The mean age was 65.3 years (range, 49 to 79 years). For the epithelial component (E), CD3_E and CD4_E were highly expressed in 38 (66.7%) and in 40 (70.1%) patients, respectively, and were significantly associated with more advanced stages (p = 0.038 and p = 0.025, respectively). CD8_E was highly expressed in 42 (73.7%) patients, FOXP3_E 16 (28.1%), PD-1_E 35 (61.4%), PD-L1_E 27 (47.4%) and PD-L2_E 39 (68.4%). For the sarcomatous component (S), the prevalence of high expression was: CD3_S 6 (10.5%), CD4_S 20 (35.1%), CD8_S 44 (77.2%), FOXP3_S 8 (14%), PD-1_S 14 (24.6%), PD-L1_S 14 (24.6%) and PD-L2_S 8 (14%). By multivariate analysis, the CD8/FOXP3_S ratio (p = 0.026), CD4_E (p = 0.010), PD-L1_E (p = 0.013) and PD-L1_S (p = 0.008) markers significantly influenced progression-free survival. CD4/FOXP3_S ratio (p = 0.043), PD-1_E (p = 0.011), PD-L1_E (p = 0.036) and PD-L1_S (p = 0.028) had a significant association with overall survival. CONCLUSION: Some differences in UCS clinical outcomes may be due to the subtype of TILs and PD-1/PD-L1 axis immune checkpoint signaling.

Detection of PIK3CA E545A mutation in circulating tumor DNA of a patient affected by uterine carcinosarcoma.

Uterine carcinosarcomas are biphasic neoplasms consisting of mixed epithelial and mesenchymal elements, representing less than 5% of all uterine malignancies. Carcinosarcomas are rare, although the most common cause of uterine cancer-specific death. Few information is available on the pathogenesis, and molecular characterization is poorly investigated. Consequently, the treatment has not changed over the last years and is far too being tailored, consisting of surgery and traditional chemotherapy and radiotherapy. Molecular characterization of liquid biopsy by circulating tumor DNA (ctDNA)/circulating cell-free DNA (ccfDNA) evaluation in a patient with uterine carcinosarcoma. Here, we describe a case report of an 83-year-old woman with carcinosarcomas, stage T3aN0M0. Cancer cells did not express estrogen nor progesterone receptors, while p53 and p16 were positive. Molecular characterization of ccfDNA and of ctDNA was performed by quantitative PCR, amplification-refractory mutation system technology. The presence of phosphatidylInositol-4,5-bisphosphate 3-Kinase catalytic subunit alpha p.E545A mutation was detected in plasma. This approach may suggest the use of liquid biopsy and the development of specific targeted therapy for precision personalized medicine even in rare carcinosarcomas.

Neutrophilia and mortality in women with uterine carcinosarcoma.

OBJECTIVE: The objective of this study was to investigate the relationship between pre-treatment absolute neutrophil count and clinical outcomes in patients with uterine carcinosarcoma. METHODS: In an Institutional Review Board approved, retrospective cohort study of 103 patients with uterine carcinosarcoma, the pre-treatment absolute neutrophil count data were obtained from the medical records, along with clinical, pathologic, treatment, and outcome data. Kaplan-Meier survival estimates were calculated and compared by the log rank test. Univariable and multivariable Cox proportional hazard regression models were used to examine the relationship of pre-treatment absolute neutrophil count with progression-free survival and overall survival. RESULTS: Uterine carcinosarcoma patients in the highest quartile of pre-treatment absolute neutrophil count had significantly reduced progression-free survival (p<0.001, log rank test), and overall survival (p<0.001, log rank test), compared with patients in the lower absolute neutrophil count quartiles. On multivariable analysis, high absolute neutrophil count was an independent poor prognostic factor for disease recurrence, HR 2.97 (95% CI 1.35 to 6.53, p=0.007) for highest versus lowest quartile absolute neutrophil count, and for mortality, HR 4.43 (95% CI 1.64 to 12.00, p= 0.003). CONCLUSIONS: High pre-treatment absolute neutrophil count is an independent poor prognostic factor in patients with uterine carcinosarcoma and may be useful as a potential biomarker in clinical trials. The mechanistic relationship of neutrophilia and uterine carcinosarcoma progression merits further investigation.

Intrahepatic Carcinosarcoma With Cholangiocarcinoma Elements and Prominent Bile Duct Spread.

Carcinosarcomas with elements of cholangiocarcinoma and sarcoma are rare and have a poor prognosis. The spreading pattern and radiological findings of these lesions remain unclear. A 74-year-old man presented with a high γ-glutamyl transferase level. Magnetic resonance imaging revealed dilation of the right intrahepatic and common bile ducts, consistent with an intraductal papillary neoplasm of the bile duct (IPNB), and diffusion-weighted imaging (DWI) indicated an area of high signal intensity in the intrahepatic bile duct. Bile duct biopsy yielded a small amount of atypical spindle cells, and the patient underwent a right hepatectomy. Microscopically, the tumor contained cholangiocarcinoma and sarcomatous components, including osteosarcoma and leiomyosarcoma, leading to a diagnosis of intrahepatic carcinosarcoma. The tumor spread primarily through the intrahepatic bile duct. An accurate radiological diagnosis of carcinosarcoma was challenging, given the apparent similarities with IPNB. The findings from DWI and pathology of a bile duct biopsy may assist with preoperative diagnosis.

Esophageal carcinosarcoma that disappeared pathologically by palliative radiotherapy alone.

Only a few cases of esophageal granulocyte-colony-stimulating-factor (G-CSF)-producing esophageal carcinosarcoma are reported, and patients with G-CSF-producing tumors are typically considered to have poor prognosis. An 89-year-old man was examined for low-grade fever and dysphagia. Chest computed tomography revealed a huge 80-mm tumor on the thoracic esophagus without direct invasion to surrounding organs. Esophagogastroduodenoscopy (EGD) showed a huge mass occupying the esophageal lumen with a superficial flat lesion. Histopathological examination revealed that the tumor was composed of bizarre giant cells and pleomorphic spindle cells with hyperchromatic nuclei. Laboratory data showed aberrant elevation of leukocyte and neutrophil counts and G-CSF levels. The tumor was finally diagnosed as a G-CSF-producing esophageal carcinosarcoma, stage II (T2N0M0, Union for International Cancer Control-TNM Classification of Malignant Tumors, 8th edition). Considering his general condition, we performed palliative radiotherapy (45 Gy/15 fr) alone after consultation with surgeons and radiation oncologists. Follow-up EGD demonstrated the disappearance of the tumor, and the histological assessment of biopsy specimens confirmed no evidence of malignancy. The leukocyte count and G-CSF levels decreased within normal range. This is a very rare case of G-CSF-producing esophageal carcinosarcoma in which a pathologically complete response was achieved using palliative radiotherapy alone.

Association of Serum HE4 with Primary Tumor Diameter and Depth of Myometrial Invasion in Endometrial Cancer Patients at Rajavithi Hospital.

BACKGROUND: Although there are no biomarkers that are routinely used in endometrial cancer (EC) management, many studies have found that serum human epididymis protein 4 (HE4) is superior to cancer antigen 125 (CA125) in the detection of EC. The correlation of HE4 with two prognostic factors for EC, primary tumor diameter (PTD) and depth of myometrial invasion (DMI) may be useful in identifying EC patients at high risk of lymphatic dissemination. OBJECTIVE: To evaluate the correlation of serum HE4 with PTD and DMI in patients with EC. MATERIALS AND METHODS: A cross-sectional study was conducted on 70 EC patients who were scheduled for elective surgery at Rajavithi Hospital between 1st September 2013 and 30th May 2014. Preoperative serum levels of HE4 and CA125 were investigated, and then gross measurement of PTD was taken and postoperative pathologic slides were reviewed for DMI including histologic types, grading and staging. RESULTS: Preoperative serum HE4 levels were strongly correlated with PTD (r=0.65, p<0.001) and moderately correlated with DMI (r=0.46, p<0.001). Moreover, serum HE4 levels were significantly elevated in EC patients with PTD >2 cm (p<0.001) and DMI > 50% (p=0.004). The performance of serum HE4 in identifying EC patients at low risk and high risk of lymph node metastasis was significantly better than that of CA125 (AUC 0.88 vs. 0.65, p=0.003). At an optimal cut-off value of 70 pM/L, serum HE4 had a sensitivity of 83.3% and a specificity of 80.0%. CONCLUSIONS: In EC patients, preoperative serum HE4 is significantly correlated with PTD and DMI. Serum HE4 levels could be useful in identifying endometrial cancer patients at high risk of lymphatic spread who would benefit from systemic lymphadenectomy at the cut-off value of 70 pM/L.

Prognostic factors in patients with uterine carcinosarcoma: a multi-institutional retrospective study from the Japanese Gynecologic Oncology Group.

BACKGROUND: Uterine carcinosarcomas (UCSs) are rare and aggressive tumors. The prognostic factors are not sufficiently known. METHODS: We performed a multi-institutional, retrospective study of women with stage I-IV UCS, diagnosed between 2007 and 2012. Data obtained from medical records included demographic, clinicopathological, treatment, and outcome information. RESULTS: A total of 486 patients (median age 65 years) were identified-224 (46 %) were stage I, 32 (7 %) were stage II, 139 (28 %) were stage III, and 91 (19 %) were stage IV. Among them, 277 (57 %) had disease recurrence. Median disease-free survival (DFS) was 16.4 months [95 % confidence interval (CI) 15.7-27.2], and median overall survival (OS) was 72.0 months (95 % CI 43.0-not reached). In total, 454 (94 %) patients received adjuvant treatment, and 440 (91 %) received adjuvant chemotherapy. In multivariate analysis, stage III-IV disease, CA-125 level, and lymphovascular space invasion (LVSI) were significantly associated with shorter median DFS. Stage III-IV disease, performance status 2-4, ≥50 % myometrial invasion depth, and postsurgical residual tumor size >1 cm were significantly associated with shorter median OS. Conversely, pelvic lymph node lymphadenectomy was associated with improved DFS and OS. CONCLUSIONS: Stage, performance status, CA-125 level, LVSI, and myometrial invasion were associated with poor prognoses. Pelvic lymphadenectomy was associated with improved survival, and may be necessary for the surgical management of UCS.

Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin.

AIM: To study indices of energy metabolism, content of K(+) and Mg(++) both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. METHODS: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains - by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. RESULTS: It has been determined that development of drug resistance causes the decrease of K(+), Mg(++), glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor's loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. CONCLUSION: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.

Anti-Müllerian hormone is associated with extrauterine involvement and stage of disease in patients with endometrial cancer.

Our aim was to evaluate serum levels of anti-Müllerian hormone (AMH) and also immunohistochemical (IHC) staining properties of AMH receptor type II (AMHRII) in patients with endometrial cancer (EC) and a control group. Preoperatively, serum levels of AMH were assessed and AMHRII expression was evaluated by immunohistochemistry in a benign and malignant group. AMH serum levels of the control group and EC patients were comparable. For EC patients, there was no difference with respect to the AMH levels and tumour stage; grade; histological type; deep myometrial invasion; lymphovascular space invasion or lymph node involvement. However, AMH levels in patients with extrauterine involvement were higher than patients with disease confined to the uterus. EC samples were more likely to be stained positive for AMHRII than benign lesions. Also, as the stage of the lesion worsens, the rate of IHC staining of AMHRII decreases. In conclusion, AMHRII is expressed in normal endometrial cells as well as endometrial cancer cells. AMH levels increase in EC, with extrauterine involvement at least in locally advanced disease. Also AMH expression decreases as the disease is staged-up.

Esophageal sarcomatoid carcinoma presenting as a Fever with elevated serum leukocytes.

The study presented a case of esophageal cancer presenting as intermittent fever with markedly elevated serum leukocyte and C-reactive protein. The patient's symptoms had not improved with antibiotic treatment. However, after thoracic esophagectomy, the fever faded and leukocyte serum levels rapidly normalized.

Prostate cancer collaborative stage data items--their definitions, quality, usage, and clinical implications: a review of SEER data for 2004-2010.

BACKGROUND: Version 2 of the Collaborative Stage Data Collection System (CSv2) became effective with cases diagnosed in 2010. This report focuses on the CSv2 components required to derive the American Joint Committee on Cancer (AJCC) stage for prostate cancer and on the site-specific factors for prostate cancer captured in CSv2. The report also highlights differences between the AJCC 6th and 7th editions for classifying prostate cancer stage. METHODS: Data from 18 Surveillance, Epidemiology, and End Results (SEER) Program population-based registries (SEER-18) were analyzed for the years 2004-2010, which included 400,591 prostate cancer cases. RESULTS: CSv2 provides specificity with regard to the Gleason grading system by distinguishing between clinical and pathologic patterns and scores. The AJCC 7th edition incorporates prostate-specific antigen values into staging, subdivides stage II into IIA and IIB, and reclassifies extraprostatic invasion with microscopic bladder neck invasion from T4 in the 6th edition to T3a; this latter change affected the AJCC stage of 283 cases in 2010. Of the 44,578 prostate cancer cases diagnosed in 2010 that would have been classified as stage II in the AJCC 6th edition, 32.7%, 27.5%, and 39.8% are classified as stages I, IIA, and IIB, respectively, in the 7th edition. CONCLUSIONS: CSv2 provides more information than was previously available to researchers using SEER prostate data. The absence of a clearly defined clinical stage for each prostate case is the overriding limitation that researchers face in relying on Collaborative Stage information to analyze prostate cancer data.

Carcinosarcoma of the uterine corpus on 18F-FDG PET/CT in a postmenopausal woman with elevated AFP.

Uterine carcinosarcoma (termed malignant mixed müllerian tumor) is a rare neoplasm of the uterus with a poor prognosis. There have been very few cases in the literature describing the PET/CT findings of uterine carcinosarcoma. We report a case of tissue-proven carcinosarcoma of the uterine corpus in a 65-year-old woman with elevated serum alpha-fetoprotein (AFP), whose 18F-FDG PET/CT showed a 10.3-cm mass in the uterus with uneven high FDG uptake. The SUVmax was 12.8. After surgery, the patient received 6 courses of chemotherapy, and the serum levels of AFP decreased to reference range.

Unusual early-stage pancreatic sarcomatoid carcinoma.

Sarcomatoid carcinoma of the pancreas (SCP) is a very rare pathological type of carcinoma that usually has a poor prognosis. Its pathogenesis has not been elucidated. We herein report a case of an early-stage SCP involving successful treatment and a good prognosis. The patient was a 48-year-old Chinese man with a 5-mo history of vague abdominal pain. Ultrasonography revealed a 93 mm × 94 mm × 75 mm mass of mixed echogenicity in the tail of the pancreas. Laboratory test results were within the normal range, with the exception of an obviously increased pretreatment neuron-specific enolase level. The plasma transforming growth factor (TGF)ß1 and interleukin-11 levels were obviously increased according to enzyme-linked immunosorbent assay. Microscopically, the excised tumor tissue comprised cancer cells and mesenchymal cells. Immunohistochemical analysis was positive for α-1-antichymotrypsin, pan-cytokeratin, cytokeratin 19, cytokeratin 8/18, and vimentin and negative for CD68 and lysozyme. The pathogenetic mechanism of this case shows that TGFß1 may regulate the epithelial-to-mesenchymal transition in SCP. With early eradication of the tumor and systemic therapy, this patient has been alive for more than 3 years without tumor recurrence or distant metastasis. This case is also the first to show that TGFß1 may regulate the epithelial-to-mesenchymal transition in early-stage SCP.

Hepatic carcinosarcoma: clinicopathologic features and a review of the literature.

Hepatic carcinosarcoma (HCS) is defined as a malignant tumor containing an intimate mixture of carcinomatous and sarcomatous elements. Here, we report the case of a 72-year-old man who developed HCS from an otherwise normal liver. The patient had no history of alcohol abuse or hepatitis B or C infection. An enhanced abdominal CT scan revealed a 9-cm heterogeneous tumor, with enhancement during the arterial phase and delayed wash-out in the latter phases. Also, a marked elevation in alpha-fetoprotein level (15,164 ng/mL; normal range, < 10 ng/mL) was noted. He underwent resection of liver segments V and VI under a pre-operative diagnosis of atypical hepatocellular carcinoma (HCC). The diagnosis of HCS was made based on thorough pathologic examination with a panel of immunohistochemical staining. Following surgery, the patient made an uneventful recovery, and at present, 16 months post-surgery, he remains well with no evidence of tumor recurrence. In conclusion, pre-operative diagnosis of HCS is difficult and radical resection in the early stage is encouraged to improve the prognosis of these patients.

Parathyroid carcinosarcoma: a rare form of parathyroid carcinoma with normal parathyroid hormone levels.

Parathyroid carcinosarcoma was first described by Nacamuli et al in 2002. We present the second case of this rare disease. This rare carcinosarmoca presented as a parathyroid carcinoma with uncharacteristically normal parathyroid hormone levels. The patient is a 57-year-old woman with long-standing right-sided vocal cord paralysis presented with a progressive 3 × 2 × 3 cm mass in the right neck. She had previously undergone a total thyroidectomy revealing benign pathology. Parathyroid hormone and calcium blood levels were within normal limits. The mass was removed with negative surgical margins. Histopathology and immunohistochemical analysis showed a biphasic pattern, with positive for chromogranin and vimentin, consistent with carcinoma and sarcoma. The disease in our patient, as in the previously reported case, has shown systemic progression despite aggressive surgical resection and adjuvant therapy.

Serum CA 125, CA 15-3, CEA, and CA 19-9: a prognostic factor for uterine carcinosarcomas?

PURPOSE: There is a controversy in the literature regarding the role and the prognostic significance of serum markers in uterine carcinosarcomas (CSs). We attempted to determine the utility of serum CA 125, CA 15-3, CA 19-9, and CEA as prognostic factors and disease follow-up in patients with CS of the uterus. METHODS: Thirty-seven patients with CS of the uterus were included in this study. Information regarding demographic, clinical, pathologic, tumor marker data (CA 125, CA 19-9, CA 15-3, and CEA both pre- and postoperatively) treatment and outcome information was obtained, followed by Statistical analysis. RESULTS: The mean follow-up period was 3.5 years. None of the study serum markers showed significant association with the outcome. Greater hazard was found for cases that staged from IIIA to IV compared to those staged from IA to IIB (HR = 4.75, 95 % CI: 1.99-11.3). Also, greater hazard was found for adenosquamous histological type compared to the other histological types. When multiple Cox regression analysis with stepwise approach was implied, it indicated stage as the only significant factor for the outcome. Elevated CA19-9 was more frequent in cases with heterologous sarcoma (p = 0.036). CONCLUSION: In this retrospective study, none of the preoperative serum tumor markers, neither epithelial component, histological type, nor grade showed a significant association with prognosis. This null finding may have significant implications in the common clinical practice; given that there is a controversy in the literature regarding the role and the significance of the prognostic significance of serum CEA, CA 125, CA 19-9, and CA 15-3.

A phase II trial of thalidomide in patients with refractory uterine carcinosarcoma and correlation with biomarkers of angiogenesis: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate the efficacy and adverse events of thalidomide in previously-treated, measurable, persistent or recurrent carcinosarcoma of the uterus, and to explore associations between angiogenic markers with patient demographics and clinical outcome. METHODS: Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. Endpoints included progression-free survival (PFS)≥6 months (primary), toxicity, response, overall PFS and survival. Pre- and post-treatment plasma were evaluated for a panel of angiogenic biomarkers and assessed against clinical outcomes. RESULTS: Of 55 enrolled patients, 45 were evaluable for toxicity and survival. Two patients (4%; 90% CI 1-13%) experienced a partial response, and 8 (18%; 90% CI 9-30%) had PFS≥6 months. Median PFS was 1.9 months and median survival was 5.9 months. Grade 2-3 sensory neuropathy was noted in 6 patients, and 4, 3, and 3 patients experienced grade 3 sedation, fatigue, and constipation, respectively. Three patients had grade 4 adverse events (2 thromboembolic, 1 anemia). High pre-treatment VEGFA levels were associated with poorer PFS and survival. CONCLUSIONS: Treatment with thalidomide met the protocol specified goal of prolonging PFS at 6 months. However, based on results with newer agents, the activity was insufficient to support further investigation. Association between pre-treatment VEGFA and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine carcinosarcoma.

Primary adrenal gland carcinosarcoma associated with metastatic rectal cancer: a hitherto unreported collision tumor.

In this report we describe the case of a young woman with familial adenomatous polyposis who developed metastatic rectal cancer during pregnancy. At diagnosis, we decided to perform a transabdominal laparoscopic adrenalectomy, because of the high risk of bowel obstruction, and to define the origin of the adrenal gland lesion, suspected to be primary on the basis of imaging results. The histological specimen showed a collision tumor between an adrenal metastasis of a rectal tumor and a primary adrenal gland carcinosarcoma. The peculiarity of the case is due not only to its clinical presentation during pregnancy, but also to the presence of this uncommon adrenal collision tumor. A particular challenge for the clinician is to define the priority between these two tumors: the presence of two distinct and colliding aggressive neoplasms poses a problem in the choice of the best therapeutic approach, also given the impossibility to biopsy all metastatic sites. However, we decided to treat the patient as having a metastatic rectal cancer, because we had a solid histological confirmation of metastases.

Carcinosarcoma of the ovary: analysis of 13 cases and review of the literature.

OBJECTIVES: The aim of this study was to evaluate our experience with patients affected by ovarian carcinosarcoma. PATIENTS AND METHODS: During a 16-year period, data on 13 patients with ovarian carcinosarcoma were collected. They were obtained from hospital charts and follow-up visits. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test. All tests were two-tailed with p values < 0.05 considered significant. RESULTS: Our study was conducted on 13 patients with ovarian carcinosarcoma referred to our unit, during an observation time of about 16 years (March 1994 to October 2010). An improved survival was observed in patients treated with optimal cytoreductive surgery with residual tumors <2 cm (30 vs. 5 months; p = 0.042). All patients underwent adjuvant chemotherapy based on the combination of cisplatin, epirubicin and ifosfamide (PEI) and taxol and carboplatin (TAX-CBDCA) regimen. Overall survival of the patient population was 17 months. CONCLUSIONS: Similarly to data published in the literature, we observed that malignant mixed mullerian ovarian tumors are very aggressive and are usually diagnosed at an advanced age and at an advanced stage of disease. Therefore, due to the rarity of the tumor we would like to add our series to those already published in the literature, although our treatment recommendations are actually based upon retrospective studies with a small patient population.