New clinicopathological concept of endometrial carcinoma with integration of histological features and molecular profiles.

The dual-stratified pathway of endometrial carcinomas (ECs) has long been dominant. However, in 2013, The Cancer Genome Atlas (TCGA) defined four EC subgroups with distinctive prognoses. Inspired by TCGA, in 2018, the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) provided four pragmatic molecular classifiers to apply surrogate immunohistochemical markers to TCGA subgroup categorization. These trends prompted the revision of 2020 WHO Classification of Female Genital Tumors, 5th edition (2020 WHO classification), in which four molecular subtypes are recognized: POLE-ultramutated; mismatch repair-deficient; p53-mutant; and no specific molecular profile. In the 2020 WHO classification, the diagnostic algorithm is characterized by prioritizing POLEmut over other molecular abnormalities. Following the 2020 WHO classification, Federation of International Gynecology and Obstetrics (FIGO) proposed a new staging system in 2023. The updated system focuses on diagnostic parameters, such as histological type and grade, lymphovascular space invasion, and molecular alterations. These new histomolecular diagnostic concepts of ECs are being accordingly introduced into the routine pathology practice. For the first time, the 2020 WHO classification includes mesonephric-like adenocarcinoma (MLA) as a novel histological entity, mimicking the conventional mesonephric adenocarcinoma, but is considered of Müllerian ductal origin.

Therapeutic indications for antibody-drug conjugates estimated from HER2 and p53 expressions in endometrial carcinoma.

OBJECTIVE: While human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma-especially in the p53 aberrant type- conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression. METHODS: Immunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive. RESULTS: Of the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p<0.001) and OS (p<0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183-5.971, p=0.008) as an independent prognostic factor. CONCLUSIONS: This study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.

Aggressive variant prostate cancer with multiple subcutaneous metastases: a case report.

A 71-year-old man with bone metastasis of hormone-sensitive prostate cancer was treated with androgen deprivation therapy and apalutamide. Radium-223 and radiation therapy were administered after it become castration resistant. Although prostate-specific antigen levels remained low, multiple subcutaneous metastases of neuroendocrine prostate cancer were observed. A review of the pre-treatment prostate needle biopsy revealed a small component with features suggestive of neuroendocrine differentiation. Phosphatase and tensine homolog loss and tumor protein p53 overexpression were observed, confirming the diagnosis of aggressive variant prostate cancer. Platinum-based chemotherapy was administered; however, the patient died 28 months after diagnosis. In this case, if the diagnosis of aggressive variant prostate cancer had been made at an earlier time by biopsy specimens, there might have been a possibility to improve the prognosis by the earlier introduction of the platinum-based regimen. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-024-00673-7.

Robot-Assisted Partial Cystectomy Using the "Double Bipolar Method".

The "double bipolar method" (DBM) in robotic surgery has been widely used in Japanese general surgery and gynecology; however, it is not commonly used in the field of urology. A 55-year-old female was diagnosed with stage IA endometrial cancer. A 2-cm cystic lesion was incidentally observed at the dome of the bladder on magnetic resonance imaging. A simultaneous robot-assisted total hysterectomy and partial cystectomy using the da Vinci Xi system was planned. The gynecological procedure was first performed with the DBM, and the DBM was also used in the partial cystectomy without additional instruments to reduce surgical costs. Maryland bipolar forceps was used to excise the peritoneum, fat, and bladder wall without bleeding, enabling delicate and precise resection using the forceps' tips. Robot-assisted partial cystectomy using the DBM was feasible. When performing combined surgeries with other departments, if the DBM is already being utilized, it is worthwhile to attempt to decrease surgical cost.

HER2-negative or low expression as an unfavorable prognostic factor in patients with stage I/II uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. METHODS: We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. RESULTS: HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status. HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. CONCLUSION: Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Choroidal Metastasis From Papillary Renal Cell Carcinomas: A Case Report and a Review of the Literature.

Choroidal metastasis originating from renal cell carcinomas (RCCs) is rare. To the best of our knowledge, 31 cases of choroidal metastasis from RCC have been reported in the English literature as of January 31, 2024. Nevertheless, physicians need to be vigilant in recognizing this condition, as its progression impacts the quality of life (QOL) of affected patients. In Case 1, a 60-year-old male with a medical history of papillary RCC experienced a deterioration in visual acuity (VA) and was diagnosed with solitary choroidal metastasis. Subsequently, multiple metastases were identified, prompting the initiation of a combination therapy regimen consisting of pembrolizumab plus axitinib. Despite treatment, progression of choroidal metastasis and a further decline in VA were observed. The patient underwent stereotactic radiotherapy and experienced complete resolution of the choroidal metastasis, accompanied by a slight improvement in VA. In Case 2, a 76-year-old man presented with a renal tumor accompanied by lung metastases. He underwent nephrectomy, and the histological diagnosis was papillary RCC. We initiated combination therapy consisting of nivolumab plus cabozantinib. The patient experienced a decrease in VA during treatment. We identified extensive fine metastases scattered throughout the bilateral choroid. We administered axitinib, but the patient experienced bilateral blindness. Given the absence of established therapy for choroidal metastasis, it is crucial to maintain flexibility in treatment selection. Local or systemic approaches should be used as deemed appropriate for each individual case.

Premature Classification of Early-stage Endometrioid Ovarian Carcinoma With Mesonephric-like Differentiation as Mesonephric-like Adenocarcinoma.

Ovarian mesonephric-like adenocarcinoma (MLA) is a rare tumor with potential origins in endometriosis and Müllerian-type epithelial tumors. The morphologic patterns of MLA overlap with those of endometrioid ovarian carcinoma (EnOC). We speculated that a subset of MLAs would be classified as EnOCs. In this study, we attempted to identify MLAs from malignant endometrioid tumors. Given that the study patients with MLAs had both endometrioid-like and mesonephric-like morphologies, we defined mesonephric-like differentiation (MLD) as an endometrioid tumor with focal or diffuse MLA morphology and immunophenotype. Twelve patients exhibited mesonephric-like morphologic patterns. Immunohistochemistry analysis for CD10, TTF-1, estrogen receptor (ER), GATA3, calretinin, and PAX8 expression was done using whole-section slides. Two patients without the MLA immunophenotype were excluded. Ten patients with EnOCs with MLD (8.3%) were identified from a cohort of 121 patients with malignant endometrioid tumors. All 10 patients were positive for TTF-1 and/or GATA3. Most patients were ER-negative. Morphologically, MLD was associated with papillary thyroid carcinoma-like nuclei, flattened cells, tubular, nested, reticular, or glomeruloid architecture, and infiltrative growth. All 10 patients had pre-existing endometriosis and/or adenofibromas. Among the EnOCs with MLD, 5 had coexisting components such as EnOC grade 1 [(G1), cases 4, 7, and 9], mucinous borderline tumor (case 1), and dedifferentiated carcinoma (case 10), with distinct borders between EnOC with MLD and the other components. Nine of the 10 MLA patients (90%) harbored KRAS hotspot mutations. In addition, 4 patients harboring other components shared common KRAS hotspot mutations. No significant prognostic differences were observed between patients with and without MLD. Based on our findings, we suggest that EnOC with MLD, especially in the early stages and without high-grade components, should be considered a subtype of EnOC. Overtreatment should be avoided in such patients, particularly in the early stages. In this study, as the characteristics between EnOC with MLD and MLA were not distinguishable, we considered both conditions to be on the same spectrum. EnOCs with MLD exhibit the MLA phenotype during disease progression and are prematurely classified as MLA. Nevertheless, more patients with EnOC who have MLD/MLA are required for a more robust comparison between conventional EnOC according to staging and grading.

A Rare Case of Adenocarcinoma With Micropapillary Structure and Apocrine Differentiation Arising in a Sebaceous Tumor.

ABSTRACT: A 77-year-old Japanese man presented to our hospital with subcutaneous tumors of the right upper arm and axilla. A biopsy revealed a cutaneous adnexal tumor, showing apocrine differentiation, and axillary lymph node metastasis. After chemoradiotherapy to shrink the tumors, both lesions were resected. A resected specimen of the arm tumor showed a variegated histology: (1) a classic sebaceoma with an organoid pattern and sebocytes; (2) a sebaceous tumor with cellular atypia; (3) a papillotubular tumor showing a biphasic pattern of pale eosinophilic cells with apocrine differentiation and basaloid cells; and (4) an invasive adenocarcinoma with a micropapillary structure, reminiscent of an invasive micropapillary carcinoma of the breast. The axillary tumor was regressed. To our knowledge, this is the first reported case of an adnexal tumor of the skin with an invasive micropapillary structure arising in a sebaceous tumor.

Quality of care measurement for patients with ovarian cancer in Japan.

AIM: Quality of care is important to reduce disease progression, and improve both survival and quality of life. The Japan Society of Gynecologic Oncology has published treatment guidelines to promote standardized high-quality care for ovarian cancer in Japan. We developed quality indicators based on the guideline recommendations and used them on large datasets of health service use to examine the quality of ovarian cancer care. METHODS: A panel of experts developed the indicators using a modified Delphi method. Adherence to each indicator was evaluated using data from a hospital-based cancer registry of patients diagnosed in 2018. All patients receiving first-line treatment at participating facilities were included. The adherence rates were returned to participating hospitals, and reasons for nonadherence were collected. A total of 580 hospitals participated, and the study examined the care received by 6611 patients with ovarian cancer and 1879 with borderline tumors using 11 measurable quality indicators. RESULTS: The adherence rate ranged from 22.6% for "Estrogen replacement within 6 months of operation" to 93.5% for "Bleomycin, etoposide, and cisplatin for germ cell tumor more than Stage II." Of 580 hospitals, 184 submitted the reasons for nonadherence. CONCLUSIONS: The quality of ovarian cancer care should be continuously assessed to encourage the use of best practices. These indicators may be a useful tool for this purpose.

Evaluation of Uterine Carcinosarcoma and Uterine Endometrial Carcinoma Using Magnetic Resonance Imaging Findings and Texture Features.

Aim  This study aimed to evaluate the diagnostic feasibility of magnetic resonance imaging (MRI) findings and texture features (TFs) for differentiating uterine endometrial carcinoma from uterine carcinosarcoma. Methods This retrospective study included 102 patients who were histopathologically diagnosed after surgery with uterine endometrial carcinoma (n=68) or uterine carcinosarcoma (n=34) between January 2008 and December 2021. We assessed conventional MRI findings and measurements (cMRFMs) and TFs on T2-weighted images (T2WI) and apparent diffusion coefficient (ADC) map, as well as their combinations, in differentiating between uterine endometrial carcinoma and uterine carcinosarcoma. The least absolute shrinkage and selection operator (LASSO) was used to select three features with the highest absolute value of the LASSO regression coefficient for each model and construct a discriminative model. Binary logistic regression analysis was used to analyze the disease models and conduct receiver operating characteristic analyses on the cMRFMs, T2WI-TFs, ADC-TFs, and their combined model to compare the two diseases. Results A total of four models were constructed from each of the three selected features. The area under the curve (AUC) of the discriminative model using these features was 0.772, 0.878, 0.748, and 0.915 for the cMRFMs, T2WI-TFs, ADC-TFs, and a combined model of cMRFMs and TFs, respectively. The combined model showed a higher AUC than the other models, with a high diagnostic performance (AUC=0.915). Conclusion A combined model using cMRFMs and TFs might be helpful for the differential diagnosis of uterine endometrial carcinoma and uterine carcinosarcoma.

A case of ovarian endometrioid carcinoma: Atypical MR imaging.

Endometrioid carcinoma is the second most common ovarian tumor, classified as an epithelial-stromal ovarian tumor, and is usually characterized by a cystic tumor with partial solid components on magnetic resonance (MR) images. In this case report, we discuss an 81-year-old female who presented with atypical genital bleeding and distended abdomen, for which she underwent abdominal computed tomography and MR imaging. Solid endometrioid carcinoma of the ovary is very rare but was confirmed in our patient during the histological examination after surgery.

Carcinoma showing thymus-like elements (CASTLE) with amyloid deposition in the parotid gland.

Carcinoma showing thymus-like elements (CASTLE) is a rare tumor that commonly occurs in the thyroid gland. Extrathyroidal CASTLE is rarer, and only 11 cases of CASTLE of major salivary glands have been reported to date. We report the first case of amyloid deposition in parotid CASTLE. A 63-year-old man presented with a slowly growing mass in the left parotid region. Computed tomography revealed an approximately 28 × 23 mm mass lesion in the left parotid gland, and squamous cell carcinoma was suspected on biopsy. The patient underwent a parotidectomy with neck dissection. Morphologically, the tumor cells were squamoid and formed nests with lymphoid infiltration. Immunohistochemically, the tumor cells exhibited immunoreactivity for CD5, CD117/c-kit and Bcl-2, p40, and CK5 but not for p16. We diagnosed the tumor as parotid CASTLE. Amyloid deposition was also observed in the primary tumor and metastatic lymph node lesions, which were immunoreactive for cytokeratin 5. Tumor cytokeratin-derived amyloid deposition may be one of characteristics of parotid CASTLE.

Concordance Between Biopsy and Resection Diagnoses of Uterine Cervical Adenocarcinoma According to the Updated World Health Organization 2020 Classification: A Multi-Institutional Study Elucidating Real-World Practice in Japan.

CONTEXT.­: Endocervical adenocarcinoma is divided into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) in the 5h edition of the World Health Organization (WHO) tumor classification launched in 2020. However, the validity of the morphological criteria used for biopsy specimens in real-world practice remains undetermined. OBJECTIVE.­: To validate the utility of the 5th edition of the WHO classification for biopsy samples, focusing on its diagnostic criteria with the aid of ancillary studies. DESIGN.­: We retrieved 217 cases of endocervical adenocarcinoma from 6 institutions, in which glass slides of both biopsy and resection specimens were available for review. Concordance between the biopsy and resection specimen diagnoses was evaluated. For discordant diagnoses, an algorithmic approach with ancillary studies proposed by the international group was applied to confirm their utility to improve the accuracy of biopsy diagnosis. RESULTS.­: The biopsy diagnosis matched the resection specimen diagnosis in 197 cases (concordance rate, 91%; κ = 0.75). The concordance rate was significantly higher for HPVA than HPVI (95% versus 81%, P = .001). There were no significant differences in the proportions of HPVA and HPVI or the accuracy of biopsy diagnosis between the participating institutions. All 19 discordant cases with unstained glass slides available were accurately recategorized as HPVA or HPVI using HPV in situ hybridization; p16 immunohistochemistry was positive in 3 of 9 cases of gastric-type HPVI that were negative by in situ hybridization. CONCLUSIONS.­: The 5th edition of the WHO criteria for biopsy diagnosis of endocervical adenocarcinoma distinguishes HPVA from HPVI well when ancillary studies are adequately applied.

High-grade Solid Pseudopapillary Neoplasms of the Pancreas: Distinct Clinicopathological Malignant Features With Intriguing Gene Alterations through a Comparison With the Conventional Type.

Pancreatic solid pseudopapillary neoplasm (SPN) is a low-grade malignant neoplasm with a good prognosis. Clinically aggressive SPNs have rarely been reported but have not been analyzed in detail. In this study, we referred to this highly malignant type of SPN as high-grade SPN (HG-SPN) and compared its clinicopathological and genetic characteristics with conventional SPN (C-SPN) using immunohistochemistry and gene panel analyses. Five HG-SPNs and 15 C-SPNs were evaluated in this study. HG-SPNs share many pathologic characteristics: macroscopically, solid/cystic appearances, microscopically, pseudopapillary/pseudorosette pattern (100%), tumor cell loose cohesiveness (100%), thin/delicate vasculature (100%), tumor cell cytoplasmic vacuolization (100%), immunohistochemical positivity for ß-catenin (nuclear expression) (100%), CD10 (80%), CD56 (80%), and vimentin (100%). Conversely, HG-SPNs showed distinct malignant features compared with C-SPNs: mean tumor size (11.7 vs. 2.9 cm, P <0.001); true necrosis (100% vs. 0%, P <0.001); high-grade nuclear atypia (100% vs. 0%, P <0.001); lymphatic and/or venous invasion (100% vs. 20%, P =0.004); mean mitotic count (4.38 vs. 0.05/high-power field, P <0.001); and mean Ki-67 labeling index (33.9% vs. 3.4%, P <0.001). All HG-SPN patients died of primary disease 3 to 36 months after surgery, while all C-SPN patients were alive without disease. Genetic studies have shown that all analyzed HG-SPNs have CTNNB1 mutations. Two HG-SPN cases showed RB1 mutations with altered immunohistochemical findings for RB1 and p16. Two HG-SPN cases had TP53 mutation and/or p53 overexpression. In conclusion, HG-SPNs show distinct malignant features and some genetic alterations that differ from C-SPNs, indicating the importance of differentiating between these 2 subtypes.

Cervical lymphoepithelioma-like carcinoma with deficient mismatch repair and loss of SMARCA4/BRG1: a case report and five related cases.

BACKGROUND: We encountered a cervical lymphoepithelial carcinoma (LEC) possessing a predominantly solid architecture with deficient mismatch repair (dMMR) and loss of expression of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex subunit. This is the first case report of LEC with dMMR and loss of SWI/SNF complex subunit. CASE PRESENTATION: A 34-year-old woman presented at our hospital with menstrual irregularities and abnormal vaginal bleeding. Magnetic resonance imaging revealed an exophytic mass in the posterior uterine cervix. Biopsy specimens confirmed squamous cell carcinoma with a 2018 International Federation of Gynecology and Obstetrics (FIGO) uterine cervical cancer stage of IB2. In a subsequent conization specimen, the tumor appeared exophytic. Microscopically, the tumor cells formed a predominant solid architecture. Abundant lymphocytic infiltration was observed. The pathological diagnosis indicated human papillomavirus (HPV)-associated squamous cell carcinoma with LEC pattern and pT1b2. Immunohistochemically, high programmed death-ligand 1 (PD-L1) expression, dMMR, and loss of the switch/sucrose non-fermentable family-related, matrix-associated, actin-dependent regulator of chromatin subfamily member 4 (SMARCA4)/BRG1, an SWI/SNF complex subunit, were observed. The patient underwent a radical hysterectomy and is alive without disease one year and five months later. Our analysis of five additional LEC cases revealed a consistent association with high-risk HPV and elevated PD-L1 expression. In addition to the present case, another patient exhibited dMMR. The SWI/SNF complex was retained except in the present case. The prognosis was favorable in all cases. CONCLUSIONS: This unique case of LEC with dMMR suggests a distinct clinical entity with potential immunotherapy implications. Analysis of the other five LEC cases revealed that LEC was immune hot, and immune checkpoint inhibitors may be effective. The two dMMR cases showed loss of MLH1 and PMS2 expressions, and prominently high tumor PD-L1 expression. In those cases, dMMR might have contributed to the morphological characteristics of LEC.

Coincidence of de novo T-lymphoblastic lymphoma and cutaneous gamma/delta peripheral T-cell lymphoma.

The coincidence of acute T-lymphoblastic leukemia/lymphoma, NOS (T-ALL/LBL), and peripheral T-cell lymphoma (PTCL) is unusual, and there have only been a few cases of their metachronous occurrence. In these cases, PTCLs emerged as recurrence after primary therapy for primary T-ALL, were the rare gamma/delta type, and uncommonly involved skin for T-ALL/LBL. We herein report the first case of de novo T-LBL that coincided with cutaneous gamma/delta PTCL before primary therapy. A 70-year-old man presented with systemic lymphadenopathy. Lymph node biopsy revealed a massive proliferation of lymphoblastoid cells; immunohistochemically, they were positive for TdT/CD1a/CD99, and cytoplasmic CD3ε, CD4, and CD8 and were negative for T-cell receptor (TCR) ßf-1. A few TCRδ-positive cells were intermingled. Atypically, TIA was focally positive, whereas granzyme/perforin was negative. Multiple papules and plaques emerged on the trunk before the initiation of treatment for T-LBL. Skin biopsy revealed a massive proliferation of medium-to-large atypical lymphoid cells that were TdT/CD1a-negative mature T-cells; they were negative for TCRßf1 and CD4, and positive for TCRδ, CD5, CD8, CD56, TIA, granzyme B, and perforin. A conventional PCR analysis of TCRG showed no identical clonal band between the two tumors. The skin lesion was diagnosed as cutaneous gamma/delta T-cell lymphoma. Whether the lesion was primary or a transformation of T-LBL was unclear. After treating with reduced hyper-CVAD/MA targeting T-LBL, molecular complete remission was achieved. When an uncommon cutaneous lesion emerges in the course of T-ALL/LBL, both need to be evaluated pathologically and genetically, whether de novo or recurrent, assuming the possibility of coincident gamma/delta PTCL.