Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization.

The analysis of gene expression quantification data is a powerful and widely used approach in cancer research. This work provides new insights into the transcriptomic changes that occur in healthy uterine tissue compared to those in cancerous tissues and explores the differences associated with uterine cancer localizations and histological subtypes. To achieve this, RNA-Seq data from the TCGA database were preprocessed and analyzed using the KnowSeq package. Firstly, a kNN model was applied to classify uterine cervix cancer, uterine corpus cancer, and healthy uterine samples. Through variable selection, a three-gene signature was identified (VWCE, CLDN15, ADCYAP1R1), achieving consistent 100% test accuracy across 20 repetitions of a 5-fold cross-validation. A supplementary similar analysis using miRNA-Seq data from the same samples identified an optimal two-gene miRNA-coding signature potentially regulating the three-gene signature previously mentioned, which attained optimal classification performance with an 82% F1-macro score. Subsequently, a kNN model was implemented for the classification of cervical cancer samples into their two main histological subtypes (adenocarcinoma and squamous cell carcinoma). A uni-gene signature (ICA1L) was identified, achieving 100% test accuracy through 20 repetitions of a 5-fold cross-validation and externally validated through the CGCI program. Finally, an examination of six cervical adenosquamous carcinoma (mixed) samples revealed a pattern where the gene expression value in the mixed class aligned closer to the histological subtype with lower expression, prompting a reconsideration of the diagnosis for these mixed samples. In summary, this study provides valuable insights into the molecular mechanisms of uterine cervix and corpus cancers. The newly identified gene signatures demonstrate robust predictive capabilities, guiding future research in cancer diagnosis and treatment methodologies.

Clinicopathological and molecular characteristics of colorectal adenosquamous carcinoma in an Asian population.

BACKGROUND: Adenosquamous carcinoma is a rare sub-type of colorectal cancer with a poor prognosis. Little is known about its clinicopathological and molecular characteristics in Asian populations. This study aimed to investigate these features in a cohort of patients with adenosquamous carcinoma in the colorectum. METHODS: Tumor cases pathologically diagnosed with colorectal adenosquamous carcinoma were retrieved from the Sixth Affiliated Hospital, Sun Yat-sen University tissue archive between December 2012 and June 2020. Clinicopathological features, molecular characteristics, and oncology outcomes were analyzed. RESULTS: Among 18,139 cases of colorectal cancer, 11 were diagnosed with adenosquamous carcinoma, providing an incidence rate of 0.061%. The median overall survival (OS) was 14 months, and the expected 3-year OS rate was 29.6%. As of October 14, 2022, four cases had local recurrence and five had distant metastasis. KRAS gene mutations were found in four of seven patients (57.1%), and three out of eleven (27.3%) patients had mismatch repair-deficient (dMMR) tumors. CONCLUSIONS: Adenosquamous carcinoma is associated with a poor prognosis. Compared to other sub-types of colorectal cancer, a higher proportion of patients with dMMR and KRAS mutations were observed. These findings suggested that more patients with adenosquamous carcinoma could benefit from targeted therapies, such as immunotherapy.

Adenosquamous carcinoma of the vulva: Rare tumor with unusual clinical presentation.

A 52-year-old female presented with labial ulcer of 4-month duration. Examination showed 1 cm × 1 cm single superficial ulcer in the right labium majus. Excision was done, and histopathologic examination revealed surface ulceration and dermal invasion by epithelial neoplasm formed of biphasic proliferation of squamoid and gland-forming cells. Immunohistochemical staining with p63 showed nuclear staining of the squamoid nests and was negative in areas with glandular differentiation, while epithelial membrane antigen and carcinoembryonic antigen highlighted the glandular elements. The case was diagnosed as primary cutaneous adenosquamous carcinoma (ASC). ASC is an uncommon malignant cutaneous neoplasm that is more aggressive than conventional squamous cell carcinoma. There are a few reports of ASC that presented as an erythematous papule or plaque with a preference for the head, neck, or upper extremities. We report a novel case of vulval ASC presented as a superficial ulcer, which is considered a unique site, and its clinical presentation.

Complete pathologic response to neoadjuvant icotinib in stage IIIA EGFR-mutant lung adenosquamous carcinoma: A case report.

RATIONALE: Radical surgery offers the best chance of cure, it is critical to expand surgery opportunities for patients with early-stage lung cancer to prolong overall survival. However, evidence is still limited regarding the application of neoadjuvant therapy with EGFR-tyrosine kinase. PATIENT: The patient reported here was a 53-year-old woman with right lower lung adenosquamous carcinoma. DIAGNOSES: The lung cancer was staged as T3N1M0. Tumor genotype disclosed EGFR Exon19 c.2235-2249de p.E746-A750del. INTERVENTION: After neoadjuvant treatment with icotinib, she underwent thoracotomy and achieved pathological complete response. OUTCOMES: She is currently receiving adjuvant icotinib therapy without recurrence or metastasis during 18-month follow-up. LESSONS: Our case indicated that the feasibility of neoadjuvant icotinib in EGFR-mutant lung adenosquamous carcinoma.

Deep Learning Nomogram for the Identification of Deep Stromal Invasion in Patients With Early-Stage Cervical Adenocarcinoma and Adenosquamous Carcinoma: A Multicenter Study.

BACKGROUND: Deep stromal invasion (DSI) is one of the predominant risk factors that determined the types of radical hysterectomy (RH). Thus, the accurate assessment of DSI in cervical adenocarcinoma (AC)/adenosquamous carcinoma (ASC) can facilitate optimal therapy decision. PURPOSE: To develop a nomogram to identify DSI in cervical AC/ASC. STUDY TYPE: Retrospective. POPULATION: Six hundred and fifty patients (mean age of 48.2 years) were collected from center 1 (primary cohort, 536), centers 2 and 3 (external validation cohorts 1 and 2, 62 and 52). FIELD STRENGTH/SEQUENCE: 5-T, T2-weighted imaging (T2WI, SE/FSE), diffusion-weighted imaging (DWI, EPI), and contrast-enhanced T1-weighted imaging (CE-T1WI, VIBE/LAVA). ASSESSMENT: The DSI was defined as the outer 1/3 stromal invasion on pathology. The region of interest (ROI) contained the tumor and 3 mm peritumoral area. The ROIs of T2WI, DWI, and CE-T1WI were separately imported into Resnet18 to calculate the DL scores (TDS, DDS, and CDS). The clinical characteristics were retrieved from medical records or MRI data assessment. The clinical model and nomogram were constructed by integrating clinical independent risk factors only and further combining DL scores based on primary cohort and were validated in two external validation cohorts. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, or Chi-squared test were used to compare differences in continuous or categorical variables between DSI-positive and DSI-negative groups. DeLong test was used to compare AU-ROC values of DL scores, clinical model, and nomogram. RESULTS: The nomogram integrating menopause, disruption of cervical stromal ring (DCSRMR), DDS, and TDS achieved AU-ROCs of 0.933, 0.807, and 0.817 in evaluating DSI in primary and external validation cohorts. The nomogram had superior diagnostic ability to clinical model and DL scores in primary cohort (all P < 0.0125 [0.05/4]) and CDS (P = 0.009) in external validation cohort 2. DATA CONCLUSION: The nomogram achieved good performance for evaluating DSI in cervical AC/ASC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Intratumoral and peritumoral MRI radiomics nomogram for predicting parametrial invasion in patients with early-stage cervical adenocarcinoma and adenosquamous carcinoma.

OBJECTIVE: To develop a comprehensive nomogram based on MRI intra- and peritumoral radiomics signatures and independent risk factors for predicting parametrial invasion (PMI) in patients with early-stage cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC). METHODS: A total of 460 patients with IB to IIB cervical AC and ASC who underwent preoperative MRI examination and radical trachelectomy/hysterectomy were retrospectively enrolled and divided into primary, internal validation, and external validation cohorts. The original (Ori) and wavelet (Wav)-transform features were extracted from the volumetric region of interest of the tumour (ROI-T) and 3mm- and 5mm-peritumoral rings (ROI-3 and ROI-5), respectively. Then the Ori and Ori-Wav feature-based radiomics signatures from the tumour (RST) and 3 mm- and 5 mm-peritumoral regions (RS3 and RS5) were independently built and their diagnostic performances were compared to select the optimal ones. Finally, the nomogram was developed by integrating optimal intra- and peritumoral signatures and clinical independent risk factors based on multivariable logistic regression analysis. RESULTS: FIGO stage, disruption of the cervical stromal ring on MRI (DCSRMR), parametrial invasion on MRI (PMIMR), and serum CA-125 were identified as independent risk factors. The nomogram constructed by integrating independent risk factors, Ori-Wav feature-based RST, and RS5 yielded AUCs of 0.874 (0.810-0.922), 0.885 (0.834-0.924), and 0.966 (0.887-0.995) for predicting PMI in the primary, internal and external validation cohorts, respectively. Furthermore, the nomogram was superior to radiomics signatures and clinical model for predicting PMI in three cohorts. CONCLUSION: The nomogram can preoperatively, accurately, and noninvasively predict PMI in patients with early-stage cervical AC and ASC. CLINICAL RELEVANCE STATEMENT: The nomogram can preoperatively, accurately, and noninvasively predict PMI and facilitate precise treatment decisions regarding chemoradiotherapy or radical hysterectomy in patients with early-stage cervical AC and ASC. KEY POINTS: The accurate preoperative prediction of PMI in early-stage cervical AC and ASC can facilitate precise treatment decisions regarding chemoradiotherapy or radical hysterectomy. The nomogram integrating independent risk factors, Ori-Wav feature-based RST, and RS5 can preoperatively, accurately, and noninvasively predict PMI in early-stage cervical AC and ASC. The nomogram was superior to radiomics signatures and clinical model for predicting PMI in early-stage cervical AC and ASC.

Two Head and Neck Carcinomas With Squamous and Mucinous Components and Human Papillomavirus Associations: Maxillary Mucoepidermoid Carcinoma ex Sinonasal Schneiderian Papilloma and Tonsillar Invasive Stratified Mucin Producing Carcinoma (ISMC).

Carcinomas of the head-and-neck region with squamous and glandular/mucinous features constitute a heterogeneous group, with a significant minority of tumors showing an human papillomavirus (HPV) association. The differential diagnosis is usually between mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma. We present here two tumors that exemplify both the challenges of diagnostic classification, as well as the complex relationship to HPV: (a) a low risk HPV positive/p16 negative carcinoma that is most consistent with a relatively typical intermediate grade mucoepidermoid type carcinoma with complete MEC phenotype (three cell types), originating from intranasal sinonasal papillomas with exophytic and inverted patterns, and invading surrounding maxillary compartments, and (b) a p16 and keratin 7 (KRT7) positive carcinoma of the right tonsil, characterized by stratified squamous and mucinous cell (mucocyte) features. Whereas the first tumor represents a typical MEC ex-Schneiderian papilloma, the second is morphologically most consistent with the, novel for this anatomic location, diagnosis of "invasive stratified mucin producing carcinoma" (ISMC), pointing to an analogy to similar, high-risk HPV-driven malignancies recently described in the gynecologic (GYN) and genitourinary (GU) areas. Both tumors, despite their mucoepidermoid-like features had no connection to salivary glands and lacked the MAML2 translocation typical of salivary gland MEC, pointing to a mucosal/non-salivary gland origin. Using these two carcinomas as examples, we attempt to address questions related to: (a) the histological distinction between MEC, adenosquamous carcinoma, and ISMC, (b) similarities and differences between these histological entities in mucosal sites versus morphologically similar salivary gland tumors, and (c) the role of HPV in these tumors.

Primary Adenosquamous Carcinoma of the Prostate With Multiple Heterogenic Metastases Demonstrated on 68 Ga-PSMA and 18 F-FDG PET/CT Imaging.

ABSTRACT: A 54-year-old man presented with a 2-month history of urination disturbances. Serum prostate-specific antigen level was 4.96 ng/mL, and a possibility of benign prostate hyperplasia was raised by outside medical CT. Histopathology revealed adenosquamous carcinoma. Staging workup showed large areas of high PSMA uptake and focal intense hypermetabolism in the prostate, multiple lymphatics, bone, and pulmonary heterogenic metastases on 68 Ga-PSMA and 18 F-FDG PET/CT imaging.

Unusual Case of Splenic Metastasis in Adenosquamous Carcinoma of the Cervix Uteri: Diagnosis and Treatment Considerations.

BACKGROUND Due to several factors such as its specific cellular and biochemical microenvironment, the spleen is not a predestined organ of frequent metastatic colonization in the case of primary solid carcinoma. Hence, the mode of diagnosis and the preferred treatment of a lesion highly suspicious of splenic metastasis must be decided on a case-by-case basis, considering not only the biological tumor entity but also the stage of the primary disease. CASE REPORT In the present case, we demonstrate the clinical course of a 37-year-old female patient who initially presented to our clinic with irregular vaginal bleeding. A consecutive gynecological examination revealed a 3×3-cm large mass of the cervix uteri, and the subsequent histomorphological workup led to the diagnosis of an adenosquamous carcinoma of the cervix uteri. Therapeutically, the patient received multimodal treatment, namely radical hysterectomy with adjuvant radio-chemotherapy. After 1.5 years, the patient presented to our Emergency Department with intermittent left-sided abdominal pain. Subsequent abdominal imaging (computed tomography scan, magnetic resonance imaging, positron emission tomography) determined a metabolically active splenic lesion with a central necrosis - signs of malignancy in line with a splenic metastasis. Presentation and discussion of the case within our interdisciplinary tumor board led to the decision of splenectomy followed by chemotherapy, a procedure that could be considered as therapeutic treatment in such exceptional cases. CONCLUSIONS The collection and reporting of atypical clinical courses remains a key factor in precision medicine to enable the most evidence-based decision making in such cases.

Initial treatment for FIGO 2018 stage IIIC cervical cancer based on histological type: A 14-year multicenter study.

BACKGROUND: To compare the oncological outcomes of radical chemotherapy (R-CT), abdominal radical hysterectomy (ARH), and neoadjuvant chemotherapy and radical surgery (NACT) for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIIC cervical cancer, according to histological types: squamous cell carcinoma (SCC) and adenocarcinoma (AC)/adenosquamous cell carcinoma (ASC). METHODS: A comparison of 5-year overall survival (OS) and disease-free survival (DFS) was performed for the SCC and AC/ASC subgroups for the three initial treatments, assessed using Kaplan-Meier and Cox proportional hazards regression analysis and validated using propensity score matching (PSM). RESULTS: The study included 4086 patients: R-CT, n = 1913; ARH, n = 1529; and NACT, n = 644. AC/ASC had a lower survival rate (63.7%) than SCC (73.6%) and a higher recurrence and mortality rate (36.3% and 26.4%, respectively). The 5-year OS and DFS rates were different in the SCC group for R-CT, ARH, and NACT (OS: 69.8% vs. 80.8% vs. 73.0%, p < 0.001; DFS: 66.7% vs. 70.7% vs. 56.4%, p < 0.001), also in the AC/ASC group (OS: 46.1% vs. 70.6% vs. 55.6%, p < 0.001; DFS: 42.7% vs. 64.6% vs. 40.8%, p < 0.001). As for initial treatment, survival outcomes were worse for AC/ASC treated with R-CT and ARH than for SCC (both p < 0.05), with no group differences between the two treated with NACT. CONCLUSION: Initial treatment influences oncological prognosis for patients with FIGO 2018 stage IIIC cervical cancer. ARH is an alternative treatment for stage IIIC cervical SCC and AC/ASC, and NACT needs to be chosen with caution, moreover, R-CT for AC/ASC requires careful selection.

Clinicopathologic study of stage I adenosquamous carcinoma of the lung.

OBJECTIVE: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components. Adenosquamous carcinoma is reported to have an aggressive clinical course, but its clinicopathological features and prognosis are unclear in the early stage. METHODS: Patients who underwent surgical resection for pathological stage I non-small cell lung cancer between April 2009 and December 2014 were retrospectively reviewed. Preoperative and postoperative data, histologic characteristics and outcomes of patients with adenosquamous carcinoma (n = 40) were compared to adenocarcinoma (n = 598) and squamous cell carcinoma (n = 131) patients. Factors affecting prognosis, particularly on recurrence, were assessed via Cox regression analyses. RESULTS: Patients with adenosquamous carcinoma had a worse prognosis than did patients with adenocarcinoma and squamous cell carcinoma in terms of 5 year overall (66.7%) and recurrence-free survival rates (44.9%), as well as a significantly higher recurrence rate (13/40 patients, 32.5%). Multivariable Cox regression analysis for recurrence-free survival rates revealed that the histology of adenosquamous carcinoma was an independent factor for recurrence (hazard ratio: 2.473, 95% confidence interval: 1.328-3.367; P = 0.0004). High serum carcinoembryonic antigen levels (hazard ratio: 5.962) and vascular invasion (hazard ratio: 4.899) were identified as risk factors for recurrence, and patients with adenosquamous carcinoma tended to have distant relapses, such as in the brain. CONCLUSIONS: Early-stage adenosquamous carcinoma of the lung is a histological type associated with severe prognosis and postoperative recurrence, often in distant sites, in approximately one-third of cases. High serum carcinoembryonic antigen levels and vascular invasion might be risk factors of recurrence.

Adenosquamous proliferation in radial sclerosing lesions: Histologic spectrum and key features in systematic review of 247 lesions.

Adenosquamous proliferation (ASP) is known to occur in the central nidus of radial sclerosing lesions (RSL) of the breast. However, their significance is debated and remains largely unknown. In addition, there is a histologic overlap between ASP and low-grade adenosquamous carcinomas (LGASC). We conducted a large retrospective review of 247 RSLs to evaluate the prevalence of ASP and quantitatively analyze associated histologic features of RSLs including size, stromal cellularity, and presence of chronic inflammation. The central nidus of RSLs were classified as hyalinized in 121 cases (49%), cellular in 37 cases (15%), and equally mixed hyalinized and cellular in 89 (36%). ASP occurred in 92 of 247 RSLs (37.2%). Cases with ASP were significantly associated with a cellular stroma; 78.4% of RSLS with cellular stroma had ASP versus just 11.6% of hyalinized RSLs. In our large cohort, inflammation is commonly found in RSLs with ASP (p= <0.001). In conclusion, we confirm that ASP is statistically more likely to be found in RSLs with a cellular stroma. In addition, ASP is commonly associated with chronic inflammation. The finding challenges the notion that prominent lymphocytes are a diagnostic clue to LGASC on limited biopsy material.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Adenosquamous carcinoma of the gallbladder simultaneously producing granulocyte-colony-stimulating factor and parathyroid hormone-related protein.

We report a rare case of adenosquamous carcinoma of the gallbladder which simultaneously produces granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP), confirmed serologically and histologically. A 71-year-old man was examined for a gallbladder tumor with multiple lymph nodes and liver metastases. Histopathological evaluation by endoscopic ultrasound fine-needle aspiration revealed adenosquamous carcinoma of the gallbladder. Laboratory data showed markedly elevated white blood cell (WBC) count of 34,700 µL and corrected serum calcium level of 14.9 mg/dL. Serum G-CSF (191 pg/mL) and PTHrP (23.1 pmol/L) levels were high. Zoledronic acid and calcitonin were administered to treat hypercalcemia, which normalized serum calcium levels. Gemcitabine-cisplatin chemotherapy was started for cStage IVB gallbladder cancer. After chemotherapy initiation, WBCs showed a rapid downward trend; however, the patient suddenly developed acute respiratory distress syndrome; thus, chemotherapy was discontinued. Subsequently, WBC count increased again, and the patient's overall condition deteriorated. The patient died on day 27. Immunohistochemistry using autopsy specimens demonstrated patchy staining for G-CSF in the squamous cell carcinoma portion and diffuse and weak positive staining for PTHrP in the squamous cell carcinoma and poorly differentiated adenocarcinoma portions of the tumor, suggesting simultaneous G-CSF and PTHrP production by the tumor. This is the first report of a patient with gallbladder cancer with serological and histological evidence for G-CSF and PTHrP production.

Genetic analysis of low-grade adenosquamous carcinoma of the breast progressing to high-grade metaplastic carcinoma.

PURPOSE: Low-grade adenosquamous carcinoma (LGASC) is a rare type of metaplastic carcinoma of the breast (MBC) with an indolent clinical course. A few LGASC cases with high-grade transformation have been reported; however, the genetics underlying malignant progression of LGASC remain unclear. METHODS: We performed whole-genome sequencing analysis on five MBCs from four patients, including one case with matching primary LGASC and a lymph node metastatic tumor consisting of high-grade MBC with a predominant metaplastic squamous cell carcinoma component (MSC) that progressed from LGASC and three cases of independent de novo MSC. RESULTS: Unlike de novo MSC, LGASC and its associated MSC showed no TP53 mutation and tended to contain fewer structural variants than de novo MSC. Both LGASC and its associated MSC harbored the common GNAS c.C2530T:p.Arg844Cys mutation, which was more frequently detected in the cancer cell fraction of MSC. MSC associated with LGASC showed additional pathogenic deletions of multiple tumor-suppressor genes, such as KMT2D and BTG1. Copy number analysis revealed potential 18q loss of heterozygosity in both LGASC and associated MSC. The frequency of SMAD4::DCC fusion due to deletions increased with progression to MSC; however, chimeric proteins were not detected. SMAD4 protein expression was already decreased at the LGASC stage due to unknown mechanisms. CONCLUSION: Not only LGASC but also its associated high-grade MBC may be genetically different from de novo high-grade MBC. Progression from LGASC to high-grade MBC may involve the concentration of driver mutations caused by clonal selection and inactivation of tumor-suppressor genes.

Adenosquamous carcinoma of the liver: The challenge of diagnosis.

Adenosquamous carcinoma of the liver is extremely rare. We report a case of adenosquamous carcinoma in the intrahepatic bile duct of a 56-year-old woman who complained of persistent abdominal pain, shivering and hyperthermia. Computed tomography demonstrated a solid-cystic neoplasm in segment 5/6/8 of the liver with a gradual enhancement pattern in the solid area. However, postoperative pathological examination showed adenosquamous carcinoma of intrahepatic bile duct.