Research advances and treatment perspectives of pancreatic adenosquamous carcinoma.

BACKGROUND: As a malignant tumor, pancreatic cancer has an extremely low overall 5-year survival rate. Pancreatic adenosquamous carcinoma (PASC), a rare pancreatic malignancy, owns clinical presentation similar to pancreatic ductal adenocarcinoma (PDAC), which is the most prevalent pancreatic cancer subtype. PASC is generally defined as a pancreatic tumor consisting mainly of adenocarcinoma tissue and squamous carcinoma tissue. Compared with PDAC, PASC has a higher metastatic potential and worse prognosis, and lacks of effective treatment options to date. However, the pathogenesis and treatment of PASC are not yet clear and are accompanied with difficulties. CONCLUSION: The present paper systematically summarizes the possible pathogenesis, diagnosis methods, and further suggests potential new treatment directions through reviewing research results of PASC, including the clinical manifestations, pathological manifestation, the original hypothesis of squamous carcinoma and the potential regulatory mechanism. In short, the present paper provides a systematic review of the research progress and new ideas for the development mechanism and treatment of PASC.

Cost-effectiveness analysis of pembrolizumab for treatment of US patients with persistent, recurrent, or metastatic cervical cancer.

OBJECTIVE: The effectiveness of pembrolizumab for persistent, recurrent, or metastatic cervical cancer has been demonstrated. We aimed to evaluate its cost-effectiveness from the United States (US) healthcare payers perspective. METHODS: A partitioned survival model over a 30-year lifetime horizon was developed to compare the cost and effectiveness of pembrolizumab versus placebo based on clinical data from the KEYNOTE-826 phase 3 randomized trial. Costs and health state utilities were obtained from literature and publicly available databases. The incremental cost-effectiveness ratio (ICER) was measured. One-way and probabilistic sensitivity analyses were conducted. RESULTS: For the Intention-to-Treat patients, pembrolizumab was associated with an additional 0.74 quality-adjusted life-year (QALY) at an additional cost of $182,271 when compared with placebo. The ICER was $247,663/QALY. For patients with a programmed death-ligand 1 combined positive score ≥ 1 and 10, the ICER was $253,322/QALY and $214,212/QALY, respectively. One-way sensitivity analyses showed that pembrolizumab had the greatest impact on the ICER. Probabilistic sensitivity analyses showed that the probability of pembrolizumab being cost-effective was zero at the current willingness-to-pay threshold of $150,000/QALY. The price of pembrolizumab had to reduce at least to $28.336 (55.8% of the current price) for it to be cost-effective in a 50% of chance. CONCLUSION: The addition of pembrolizumab to chemotherapy is costly and might not be cost-effective for persistent, recurrent, or metastatic cervical cancer at the current price in the US.

Contralateral lymph node metastases in patients with vulvar cancer and unilateral sentinel lymph node metastases.

INTRODUCTION: The risk of contralateral lymph node metastases following unilateral sentinel lymph node (SLN) metastases in patients with vulvar cancer(s) remains to be systematically assessed. MATERIAL AND METHODS: We performed a multicenter, retrospective registry-based study of 476 patients with vulvar cancer. The primary outcome measure was the rate of contralateral non-SLN metastases in the case of positive unilateral SLN. RESULTS: Out of 476 patients with primary vulvar cancer, 202 received SLN biopsy: 58 unilateral and 144 bilateral. Out of 66 patients with unilateral metastatic SLN, 62 (93.9%) received contralateral lymphadenectomy-18 after unilateral and 44 after bilateral SLN biopsy. In the study group, 132 SLN were assessed with a median number of 2 (range 1-4) per patient and 76 of these were positive. Lymph node-positivity was associated with advanced tumor stage, as well as lymph and vascular space invasion. In the group of patients with bilateral inguino-femoral lymphadenectomy, 1004 lymph nodes were resected with a median number of 15 (range 10-29) per patient. After full dissection of the inguino-femoral lymph nodes, no contralateral non-SLN metastases were found. CONCLUSIONS: The risk of contralateral non-SLN metastases in patients with unilateral SLN metastases was low. Therefore, the impact of contralateral lymphadenectomy on patient survival should be investigated in further studies.

Association between definitive chemoradiotherapy wait-time and survival in locally-advanced cervical cancer: Implications during the coronavirus pandemic.

OBJECTIVE: The current coronavirus pandemic caused a significant decrease in cancer-related encounters resulting in a delay in treatment of cancer patients. The objective of this study was to examine the survival effect of delay in starting concurrent chemo-radiotherapy (CCRT) in women with locally-advanced cervical cancer. METHODS: This is a retrospective observational study querying the National Cancer Database from 2004 to 2016. Women with stage IB2-IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix who received definitive CCRT with known wait-time for CCRT initiation after cancer diagnosis were eligible (N=13,617). Cox proportional hazard regression model with restricted cubic spline transformation was fitted to assess the association between CCRT wait-time and all-cause mortality in multivariable analysis. RESULTS: The median wait-time to start CCRT was 6 (IQR 4-8) weeks. In a multivariable analysis, older age, non-Hispanic black and Hispanic ethnicity, recent year of diagnosis, Medicaid and uninsured status, medical comorbidities, and absence of nodal metastasis were associated with longer CCRT wait-time (P<.05). Women with aggressive tumor factors (poorer differentiation, large tumor size, nodal metastasis, and higher cancer stage) were more likely to have a short CCRT wait-time (P<.05). After controlling for the measured covariates, CCRT wait-time of 6.1-9.8 weeks was not associated with increased risk of all-cause mortality compared to a wait-time of 6 weeks. Similar association was observed when the cohort was stratified by histology, cancer stage, tumor size, or brachytherapy use. CONCLUSION: An implication of this study for the current coronavirus pandemic is that in the absence of aggressive tumor factors, a short period of wait-time to start definitive CCRT may not be associated with increased risk of mortality in women with locally-advanced cervical cancer.

Clinical Efficacy and Safety of Apatinib for the Treatment of Patients with Metastatic, Recurrent Cervical Cancer after Failure of Radiotherapy and First-Line Chemotherapy: A Prospective Study.

PURPOSE: As a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), apatinib has shown a survival benefit in multiple solid tumors. This study aims to evaluate the efficacy and safety of apatinib in patients with metastatic, recurrent cervical cancer after failure of radiotherapy and first-line chemotherapy. METHODS: A total of 42 patients between June 2018 and March 2019 were involved in this study. All patients orally received apatinib once daily in a 4-week cycle until disease progression or adverse events that prohibit further therapy. The primary endpoint was progression-free survival (PFS), the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), health-related quality of life (HRQoL) and adverse events. RESULTS: During a median follow-up of 13 months, 8 patients achieved a partial response and 24 cases achieved stable disease. None of them reported a complete response. The ORR and DCR were 19.0 and 76.2%, respectively. The median PFS was 6.0 months (95% CI 4.9-7.1), and the median OS was 12.0 months (95% CI 10.1-13.9). The global health score/HRQoL improved significantly following 3-cycle treatment (50.4 ± 12.5 vs. 60.1 ± 11.8; p < 0.01). The most frequent grade 3-4 adverse events were hand-foot syndrome, hypertension and fatigue. CONCLUSION: Apatinib should be an effective and tolerable treatment option for patients with metastatic, recurrent cervical cancer after failure of radiotherapy and first-line chemotherapy.

A case report on expanding horizon of endobronchial ultrasound through esophagus.

Endobronchial ultrasound has revolutionized the field of bronchoscopy and has become one of the most important tools for the diagnosis of intrathoracic lymphadenopathy and para-bronchial structures. The reach of this technique has not been limited to these structures and pleural lesions have been at times accessible. To our knowledge, pleural fluid collections have not been accessed with endobronchial ultrasound (EBUS) through oesophageal approach and rationale behind using this approach. We report a case of 70 years old man who has been referred from physician for the EBUS in view of hilar mass with mediastinal lymphadenopathy with pleural effusion. The endobronchial ultrasound through oesophagus (EUS-B) was done for thoracocentesis and lymph node cytology evaluation and ultimately endobronchial biopsy of hilar mass was done as rapid on-site (ROSE) analysis of lymph node was suggestive of necrotic tissue. The cytology report of lymph node and pleural effusion was positive for malignant cells. The final diagnosis was metastatic poorly differentiating adeno-squamous carcinoma.

Tailored radical hysterectomy for locally advanced cervical cancer.

OBJECTIVE: The survival and prognostic factors for locally advanced cervical cancer treated with nerve-sparing Okabayashi-Kobayashi radical hysterectomy have not been elucidated. We aimed to evaluate the oncological outcomes of those patients after radical hysterectomy with adjuvant chemotherapy. METHODS: This retrospective cohort study was conducted from January 2002 to December 2011. Treatment was conducted at a single tertiary center in northern Japan. We used the Okabayashi-Kobayashi radical hysterectomy with lymphadenectomy. We applied unilateral nerve preservation for stage IIA/IIB cancer if there was a one-sided extension of the disease outside the cervix. Indication for adjuvant therapy was based on Sedlis criteria. High-risk was defined as evidence of lymph node metastasis, pathological parametrial invasion, and a positive/close surgical margin. The choice of adjuvant therapy was chemotherapy which consisted of paclitaxel and cisplatin. RESULTS: The study included 76 early-stage IB1 (≤4 cm) and IIA1 cervical cancer and 45 locally advanced stage IB2 (>4 cm), IIA2, and IIB disease treated consecutively. The median follow-up was 106 (range: 6-203) months. There were 18 (15%) patients with recurrence, with five of 76 in the early-stage (7%) and 13 of 45 in the locally advanced disease (29%) (P<0.001). For locally advanced cervical cancer, pT classification (P<0.001), lymph node metastasis (P=0.007), and histology (P=0.05) were associated with locoregional recurrence. The five-year locoregional recurrence rate in the locally advanced disease was 20% and 5% in the early-stage disease (P=0.01). The five-year disease-free survival in the locally advanced cervical cancer was 71% and 93% in the early-stage disease (P<0.001). The overall survival in locally advanced disease depended on the adeno-type histology and lymph node metastasis. CONCLUSION: The tailored use of nerve-sparing Okabayashi-Kobayashi radical hysterectomy with adjuvant chemotherapy based on tumor histology and lymph node metastasis may be a possible option as a treatment of locally advanced cervical cancer in selected patients.

Metastatic pancreatic adenosquamous carcinoma to the scalp: A case report and review of the literature.

Metastatic carcinoma to the skin occurs in only a minority of patients with a visceral or internal malignancy, with breast, lung, and colorectum accounting for the majority of cases. We present the case of a 66-year-old man with a recent violaceous nodule of the left scalp (1.2 × 1.0 × 0.2 cm) that was a metastatic pancreatic adenosquamous carcinoma, representing a seemingly rare event. Two months prior, after complaining of right hip pain, an image revealed a right femoral lesion. A biopsy of that lesion showed moderately differentiated adenocarcinoma. Subsequent imaging showed a mass in the pancreatic tail and also markedly elevated serum tumor markers, CA 19-9 and carcinoembryonic antigen (5325 and 111.5 U/mL, respectively). Before the appearance of the scalp nodule, the patient received radiotherapy and was started on chemotherapy, which was continued after diagnosis and resection of the nodule. Subsequent metastases developed in the liver, lung and additional cutaneous lesions. He died 11 months after initial presentation with right hip pain. As this case shows, cutaneous metastases confer a poor prognosis, often with less than a year survival following their appearance.

Intestinal adenosquamous carcinoma with a synchronous skin metastasis: a immunohistochemical and molecular analysis.

INTRODUCTION: Intestinal adenosquamous carcinoma (ASC) is a rare colorectal neoplasm frequently occurring at onset as a locally advanced disease with distant metastases. The liver is the most common site of metastasis, followed by the peritoneum and the lung. Cutaneous metastases from usual colorectal adenocarcinoma occur in about 3% of cases, both at the time of diagnosis in advanced disease and during the follow-up. To the best of our knowledge, skin metastasis from ASC has never been described, and no biological landscape of ASC has ever been investigated. METHODS: We report a case of synchronous intestinal ASC and cutaneous single facial metastasis in a 70-year-old man with morphological, immunohistochemical, and molecular analysis of primary and metastatic lesions. RESULTS: Primary and metastatic ASC showed the same morphological and immunohistochemical features. Target sequencing analysis revealed, both in primary tumor and metastasis, a pathogenic KRAS gene missense mutation c.38G > A p.(Gly13Asp) and a likely pathogenic CTNNB1 gene missense mutation c.94G > A p.(Asp32Asn). A nuclear localization of ß-catenin protein in adenocarcinomatous component of primary and metastatic lesions was observed on immunohistochemistry. CONCLUSION: We describe a case of single synchronous facial cutaneous metastasis from intestinal ASC showing KRAS and CTNN1B mutations both on primary and metastatic lesions.

Targeted sequencing identifies the mutational signature of double primary and metastatic malignancies: a case report.

BACKGROUND: The accurate identification of the tissue of origin is critical for optimal management of cancer patients particularly those who develop multiple malignancies; however, conventional diagnostic methods at times may fail to provide conclusive diagnosis of the origin of the malignancy. Herein, we describe the use of targeted sequencing in distinguishing the primary and metastatic tumors in a patient with metachronous malignancies in the lung, colon and kidney. CASE PRESENTATION: In December 2016, a 55-year-old Chinese male was diagnosed with stage IB lung adenosquamous carcinoma and treated with left lower lobectomy and 4 cycles of platinum-based chemotherapy. After being disease-free for 3.5 months, three colonic polyps were discovered and were diagnosed as invasive adenocarcinoma after polypectomy. Within 5.4 months from the polypectomy, squamous cell renal carcinoma was identified and was managed by radical nephrectomy. Immunohistochemistry results were inconclusive on the origin of the kidney tumor. Hence, the three archived surgical tissue samples were sequenced using a targeted panel with 520 cancer-related genes. Analysis revealed similar mutational signature between the lung and kidney tumors and a distinct mutational profile for the colon tumor, suggesting that the lung and colon malignancies were primary tumors, while the kidney tumor originated from the lung, revealing a diagnosis of metastatic double primary cancer - lung carcinoma with renal cell metastasis and second primary colon carcinoma. CONCLUSION: Mutational profiling using targeted sequencing is valuable not only for the detection of actionable mutations, but also in the identification of the origin of tumors. This diagnostic approach should be considered in similar scenarios.

Extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy for cervical cancer with para-aortic lymph nodes metastasis.

OBJECTIVE: This study was conducted to evaluate the efficacy and toxicity of extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy in patients with cervical cancer with positive para-aortic lymph nodes (PALN). METHODS: From September 2007 to December 2014, a total of 59 patients who had cervical cancer with para-aortic lymph node metastasis were treated with concurrent chemoradiotherapy at our institution. A dose of 45-50.4 Gy in 25-28 fractions with extended-field intensity-modulated radiation therapy was prescribed to planning target volume, and a dose of 30-36 Gy in 5-6 fractions was prescribed to Point A with high-dose-rate brachytherapy. A concurrent first-line cisplatin-based chemotherapy regimen was used. RESULTS: The median duration of follow-up was 32.1 months (range, 3.2-103.7 months). The 2- and 3-year overall survival, disease-free survival and local control rates were 69.0 and 52.8%, 45.0 and 41.3% and 83.4 and 81.0%, respectively. Distant metastasis was the major pattern of treatment failure, which occurred in 26 patients (44.1%). The incidence of Grade 3 or greater acute hematologic, gastrointestinal and genitourinary toxicity was 50.9, 1.7 and 3.4%, respectively. Only one patient had both Grade 3 late gastrointestinal and genitourinary toxicity. CONCLUSIONS: The study found that extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy was safe and effective in patients who had cervical cancer with positive PALN.

DDR2 and IFITM1 Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas.

This study was conducted to investigate the expressions of DDR2 and IFITM1 and their clinical and pathological significances in the rare type squamous cell/adenosquamous carcinomas (SC/ASC) and ordinary adenocarcinomas (AC) of gallbladder cancers. DDR2 and IFITM1 expression was examined in 69 SC/ASCs and 146 ACs using EnVision immunohistochemistry. Results showed that the percentage of positive DDR2 and IFITM1 expression was significantly higher in SC/ASC patients with high TNM stage, lymph node metastasis, invasion, and no resection surgery compared to patients with low TNM stages, no lymph node metastasis, no invasion, and resection surgery (P < 0.05 or P < 0.01). The positive rate of DDR2 was significantly higher in SC/ASC patients with large tumor sizes than patients with small tumor sizes (p < 0.05). The percentage of positive DDR2 and IFITM1 expressions was significantly higher in AC patients with high TNM stages that didn't receive resection surgery compared to patients with low TNM stages that did receive resection surgery (P < 0.05 or P < 0.01). The positive rate of IFITM1 was significantly higher in AC patients with lymph node metastasis and invasion than in patients without metastasis and invasion (p < 0.05). Positive DDR2 and IFITM1 expression was closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). AUC analysis showed that DDR2 and IFITM1 was sensitive and specific for the diagnosis of SC/ASC (AUC = 0.740 and AUC =0.733, respectively) and AC (AUC = 0.710 and AUC =0.741, respectively). In conclusion, positive DDR2 and IFITM1 expression is a marker for the clinical severity, poor prognosis, and diagnosis of gallbladder SC/ASC and AC.

[A Case of Locally Advanced Adenosquamous Carcinoma of the Pancreas Accompanied by Hepatic Metastasis Treated by Resection of the Primary Lesion as Palliative Care].

A 61-year-old man presented to our hospital with appetite loss. Gastroscopy revealed a tumor on the upper body of the stomach. Persistent bleeding was observed from the tumor; therefore, the patient was immediately hospitalized. An abdominal CT scan revealed that the tumor arose from the pancreas and invaded the spleen, stomach, and transverse colon. Furthermore, a hepatic tumor was observed at the posterior segment and blood tests showed increased CA19-9 level. Therefore, the tumor was diagnosed as pancreatic cancer with invasion of the adjacent organs and hepatic metastasis. Although the tumor was classified as unresectable for the distant metastasis, resection of the primary lesion was performed to control the bleeding and obstruction at the invasion sites. The pathological diagnosis of the tumor was adenosquamous carcinoma. The patient subsequently underwent chemotherapy and was discharged from the hospital on postoperative day 34. The patient was able to spend time at home and was treated at an outpatient clinic until postoperative day 110, when his generalcondition deteriorated. In this case, resection of the primary lesion was ineffectual for a life prognosis but was beneficial for palliative care.

Isolated pulmonary metastases in patients with cervical cancer and the factors affecting survival after recurrence.

OBJECTIVES: The aim of this study was to assess the treatment options and survival of uterine cervical cancer (UCC) patients who develop isolated pulmonary metastases (IPM) and to establish risk factors for IPM. MATERIAL AND METHODS: Data from patients diagnosed with UCC between June 1991 and January 2017 at the Gynecological Oncology Department, Tepecik Training and Research Hospital, were investigated. In total, 43 cases with IPM were evaluated retrospectively. Additionally, 172 control patients diagnosed with UCC without recurrence were matched according to the International Federation of Gynecology and Obstetrics (FIGO) 2009 stage when the tumor was diagnosed. They wereselected using a dependent random sampling method. RESULTS: Of the 890 patients with UCC, 43 (4.8%) had IPM. The presence of lymphovascular space invasion (LVSI) and a mid-corpuscular volume (MCV) < 80 fL were statistically significant prognostic factors for IPM development in UCC patientsaccording to univariate regression analyses, and the presence of LVSI, a hemoglobin level < 12 g/dL, and an MCV < 80 fLwere statistically significant according to the multivariate regression analyses. We were unable to assess the role of lymph node status (involvement or reactive) as a prognostic factor in the development of IPM, because only seven patients (16.2%) in the case group underwent lymph node dissection. CONCLUSIONS: IPM typically develops within the first 3 years after the diagnosis of UCC, and survival is generally poor. An MCV < 80 fL and the presence of LVSI are significant risk factors for IPM development.

Solitary thin-walled cystic lung cancer with extensive extrapulmonary metastasis: A case report and review of the literature.

RATIONALE: Asymptomatic, isolated, and thin-walled cystic lung cancer with extensive extrapulmonary metastasis is rare, and the risk of pulmonary cyst developing into lung cancer is poorly understood. The efficacy of apatinib for end-stage pulmonary adenosquamous carcinoma has not been clarified yet. PATIENT CONCERNS: We herein report a rare case of primary lung cancer that appeared as an isolated thin-walled cystic lesion on computed tomography (CT) image, who was initially misdiagnosed as having pulmonary cyst empirically. DIAGNOSES: Fluorine-18-fluorodeoxyglucose-positron emission tomography and CT-guided liver biopsy of the patient revealed extra-pulmonary metastasis of lung cancer. INTERVENTIONS: Eight cycles of cisplatin-based chemotherapy were administered, followed by oral apatinib for 6 months. Thereafter, best supportive care was given for this patient. OUTCOMES: The pulmonary cystic lesion indicated stable disease through the therapy, but the hepatic tumors were progressed gradually after anticancer treatment. The patient died 16 months after the correct diagnosis. LESSONS: Solitary thin-walled cystic lung cancer should be kept in mind during the differential diagnosis of pulmonary cavitary lesions. Chest CT alone is insufficient for surveillance of these cystic diseases. Timely biopsy and resection are essential to avoid delayed management. Besides, apatinib may play a role in the treatment of end-stage pulmonary adenosquamous carcinoma.

[The efficacy and influence factors analysis of EGFR TKIs on patients with lung adenosquamous carcinoma].

Objective: To investigate the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) on patients with lung adenosquamous carcinoma, and to analyze relative factors. Methods: From August 2007 to July 2017, 40 patients who were pathologically diagnosed as lung adenosquamous carcinoma in our hospital and received EGFR TKIs treatment were retrospectively analyzed. All patients underwent EGFR mutation detection, resulted in 11 wild type, 13 19Del, 13 21L858R mutations, and 3 uncommon EGFR mutations in 20 exon and 19/21 complex mutation. A higher frequency of EGFR mutation was found in non-smokers and patients with adenocarcinoma components over 50.0%. Results: Twenty-six (65.0%) patients had disease progression after EGFR TKIs treatment, with a median progression-free survival (PFS) of 5.5 months (95% CI 0.52-10.49 months). A total of 20 (50.0%) patients died with an median overall survival (OS) of 15 months (95% CI 11.03-18.97 months). Multivariate analysis showed that gender, age, smoking, histopathological subtypes, EGFR mutations, and brain metastasis had no influence on PFS (all P>0.05). Gender, age, smoking, histopathological subtypes, and the presence of brain metastasis during TKI treatment had no influence on OS (P>0.05), while EGFR mutation is the only influencing factor of OS (P<0.05) in the current study. Conclusions: EGFR TKIs had modest efficacy in lung adenosquamous carcinoma, especially in patients with EGFR mutation. Based on the pathological features, EGFR mutation and EGFR TKIs treatment should be introduced into the routine clinical practice to improve the survival of patients with lung adenosquamous carcinoma.

[Lung Adenosquamous Cell Carcinoma in which the Administration of Nivolumab Became Untenable due to Bleeding from Small Intestine Metastasis].

A 59-year-old man who had postoperative recurrence of lung adenosquamous cell carcinoma was administered nivolumab as 3rd-line chemotherapy. Although nivolumab was considered effective, bleeding from a metastatic lesion at the jejunum was recognized by double-balloon enteroscopy, and partial resection was performed. Although the re-administration of nivolumab was planned, the patient died of acute respiratory failure 6 days postoperatively.

Keloidal-like local recurrence after infiltrating adenosquamous breast carcinoma with stromal-overgrowth mimicking a benign skin lesion.

We present a very rare case of an adenosquamous infiltrating breast carcinoma with sarcomatous stromal overgrowth of hypocellular collagenised type, which subsequently developed local recurrence, mistaken for a benign skin lesion due to bland keloid-like morphological appearance. All the histological, immunohistochemical, and clinical features must be taken into consideration when distinguishing between a benign skin lesion and a local recurrence of a rare subtype of breast carcinoma.