Placental Site Plaque of the Uterine Cervix Misinterpreted as Low-Grade Squamous Intraepithelial Lesion in Liquid-Based Cervicovaginal Cytology: Usefulness of Inhibin-α Immunocytochemistry

Cytological features of placental site plaques in liquid-based cervicovaginal preparations have been seldom documented in the literature. We present a rare case of endocervical placental site plaque misinterpreted as a low-grade squamous intraepithelial lesion in a liquid-based cytological preparation. A 32-year-old woman with polycystic ovarian syndrome gave birth 7 months previously. After delivery, she was diagnosed with cervical low-grade squamous intraepithelial lesion during routine cytological examination. Cytologically, many atypical cells showed large hyperchromatic nuclei with irregular membranes. The perinuclear cytoplasmic clearing closely resembled koilocytosis. Histologically, the endocervix showed typical histological features of a placental site plaque. Immunohistochemically, the trophoblasts were positive for p63, CD10, and inhibin-alpha but negative for p16. Based on genotyping, both the cytological and biopsied specimens tested negative for human papillomavirus. We re-examined the liquid-based preparation cytology slides thoroughly and concluded that the atypical cells initially misinterpreted as low-grade squamous intraepithelial lesion were actually trophoblasts. Immunocytochemical staining revealed uniform cytoplasmic inhibin-alpha expression in the trophoblasts. In summary, we demonstrated that endocervical placental site plaques can mimic low-grade squamous intraepithelial lesions in liquid-based cytological preparations. Immunocytochemical staining results and negative results on human papillomavirus genotyping further support that atypical cells resembling koilocytes are trophoblasts obtained from the placental site plaque.ope

Atypical Mesonephric Hyperplasia of the Uterus Harbors Pathogenic Mutation of Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ( KRAS) and Gain of Chromosome 1q

Background/Aim: Mesonephric carcinoma (MNC) is a rare but notable entity of the female genital tract. While many researchers have acknowledged and studied MNC, much remains unknown on the characteristics of mesonephric remnant (MNR) or hyperplasia (MNH). There has not been any study examining the molecular features of MNR and MNH so far. The aim of this study was to investigate the clinicopathological and molecular characteristics of ten uterine mesonephric lesions, including two MNRs without atypia, four MNHs without atypia, and three MNHs with atypia. Materials and Methods: We reviewed the electronic medical records and all available slides of ten cases from multiple institutions. Targeted sequencing and array comparative genomic hybridization were performed. Results: Three atypical MNHs displayed nuclear enlargement, mild-tomoderate nuclear pleomorphism, and nuclear membrane irregularity, and harbored pathogenic Kirsten rat sarcoma 2 viral oncogene homolograt sarcoma 2 viral oncogene homolog (KRAS) mutation. Two of those that co-existed with MNC harbored the same sequence alterations as each of their adjacent MNC. One of the three atypical MNHs harbored chromosome 1q gain. Conclusion: Atypical MNH is a potential premalignant lesion in which KRAS mutation and chromosome 1q gain play an important role in the early stage of mesonephric carcinogenesis.ope

Clinicopathological characteristics of cervical chondrocutaneous branchial remnant: a single-institutional experience

Cervical chondrocutaneous branchial remnant (CCBR) is an uncommon developmental anomaly typically seen on the lateral neck. We recently experienced four cases of CCBR and initiated a comprehensive review of previously published cases. During a 10-year period, four (0.4%) of the 1,096 patients who underwent excision of branchial cleft anomalies were diagnosed as having CCBR at our institution. Patient age ranged from 2-6 years and patients presented with asymptomatic cutaneous masses present since birth measuring approximately 1 cm on the lateral neck. Three patients had congenital thyroid hemiagenesis, subependymal cyst, and tongue tie, respectively. We identified 76 previously published cases of CCBR. The median age of these patients was 18 months. CCBR developed more often in males (48/80; 60.0%). Most of the masses were located on the left (34/80; 42.5%) or right (18/80; 22.5%) lateral neck, whereas 23 (28.75%) involved bilateral lesions. Lesion size ranged from 0.3-3.5 cm. Grossly, the overlying skin of the masses was similar to the surrounding skin of the neck. Histologically, the lesions were covered by keratinizing squamous epithelium and had skin appendages and cartilage. Thirty-nine (48.75%) and 12 (15.0%) patients were found to have elastic and hyaline cartilage, respectively. Twenty-eight patients had single (13/28; 46.4%) or multiple (15/28; 53.6%) congenital anomalies. Forty-four different types of anomalies were reported. The most frequent anomalies were problems with cardiovascular and auditory systems. Our observations suggest that CCBR is a visible marker for more serious associated congenital anomalies. We recommend that clinicians and pediatricians further evaluate patients with CCBR through complete physical examination, abdominal and cardiac ultrasound, karyotyping, and biochemical marker analysis.ope

Characterization of Novel Genetic Alterations in Salivary Gland Secretory Carcinoma

Secretory carcinoma is a salivary gland tumor with a characteristic chromosomal translocation that results in an ETV6-NTRK3 fusion gene. Secretory carcinoma shows relatively frequent rates of lymph-node metastasis and tumor recurrence and has a characteristic histology. Except for the ETV6 translocation, genomic alterations in secretory carcinoma have not been reported. In the present study, we characterized the novel recurrent genetic mutations of secretory carcinoma. On the basis of histology, immunohistochemistry, and ETV6 gene break-apart fluorescence in situ hybridization assays, 22 tumors were classified as secretory carcinomas (19 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) and their clinicopathologic characteristics were reviewed. Targeted deep sequencing analyses were performed on 20 secretory carcinomas (17 ETV6 translocation-positive and 3 ETV6 translocation-negative secretory carcinomas) to investigate their genetic alterations. The A16V (C→T) mutation in PRSS1, which encodes a cationic trypsinogen and has a mutation associated with hereditary pancreatitis and pancreatic adenocarcinoma, was observed in 40% (8/20) (7/17 of ETV6 translocation-positive and 1/3 of ETV6 translocation-negative secretory carcinomas). Pathogenic variants of MLH1, MUTYH, and STK11 were also identified. Variants of uncertain significance included mutations in KMT5A. These novel characteristic genetic alterations may advance current understandings of secretory carcinoma tumorigenesis and progression, leading to improved diagnoses and treatment strategies.ope

Anticancer effect of nucleoline-aptamer-conjugated gemcitabine loaded atellocollagen (IO401) in pancreatic cancer patient-derived orthotropic xenograft model

Introduction: We investigated the anticancer effect and systemic effect of the atelocollagen (AC) patch coated nucleoline-aptamer-conjugated Gemcitabine (IO401 patch) by directly implanting to the tumor cell in pancreatic cancer patient-derived xenograft (PDX) model to purpose a future potential adjuvant surgical strategy during curative pancreatic resection for pancreatic cancer. Methods: Pancreatic cancer PDX model was established. Animals were grouped randomly (7 mice per group) into three types of patch transplantation groups: G1 = Null AC patch, G2 = Gemcitabine AC patch, G3 = IO401 patch. Tumor volume (length × width2, mm3), Tumor weight (mg), and Tumor inhibition rate [1-(Ti-To)/(average tumor volume of group) × 100, Ti = endpoint tumor volume, To = start tumor volume] were calculated. Anticancer therapy-related toxicity was evaluated by hematologic and histological findings. Results: G3 (IO401 patch) showed the most significant reduction of tumor growth and tumor weight comparing with G1 (Null AC patch) and G2 (Gemcitabine AC patch) (p = 0.014, p = 0.018). G3 also showed the most significant tumor inhibition rate comparing with G1 and G2 (p = 0.011). G2 and G3 has the low necrosis proportion in histological finding comparing with G1 (p = 0.005, p < 0.05). Moreover, no leukopenia, no anemia, and no neutropenia were observed in G3. Conclusions: We demonstrated the anticancer effect of the IO401 patch by directly implanting to tumor cell in pancreatic cancer PDX model. This directaly implantable aptaber-drug conjugate system on tumor cell is expected to be a new surgical strategy to further increase the oncological importance of margin negative resection in pancreatic cancer surgery. Further research will be needed.ope

Clinicopathological features of 70 desmoid-type fibromatoses confirmed by β-catenin immunohistochemical staining and CTNNB1 mutation analysis

Desmoid-type fibromatosis (DF) is a locally aggressive neoplasm characterized by mutations in the CTNNB1 gene, which encodes the β-catenin protein. We reviewed 85 cases of DF and performed Sanger sequencing for detecting mutations in CTNNB1 and immunostaining for detecting β-catenin localization. We included 70 DF samples, of which 56 cases demonstrated nuclear β-catenin localization and 43 cases harboured CTNNB1 mutations. CTNNB1-mutant DF samples consistently displayed nuclear β-catenin expression and were derived from larger-sized tumours compared to samples with wild-type CTNNB1. When we further classified DF cases into 2 subgroups based on the type of specimen, excised specimens with nuclear β-catenin expression frequently displayed CTNNB1 mutation and no statistical correlation between nuclear β-catenin expression and CTNNB1 mutation was observed in biopsies. When we classified CTNNB1 mutation cases into 2 subgroups (DF with T41A or T41I, and DF with S45F or S45P), T41A or T41I mutations were observed more frequently in males than in females. Additionally, DF tumours harbouring S45F or S45P mutations were located more frequently in the abdominal wall than tumours with T41A or T41I mutations. In conclusion, CTNNB1 mutation correlates with nuclear β-catenin expression in larger or excised DF tumours, and DF harbouring CTNNB1 mutations manifest variable clinical presentations.ope

Metastatic Osteosarcoma to the Breast Presenting as a Densely Calcified Mass on Mammography.

Osteosarcoma most commonly metastasizes to the lung or the skeleton, and metastatic osteosarcoma to the breast is very rare, with only a few cases reported. Due to its rarity, little has been reported about its imaging features. In this report, we represent a 58-year-old woman with metastatic osteosarcoma to the right breast from a tibial osteosarcoma. The imaging features of the metastatic osteosarcoma to the breast by using dedicated breast imaging modalities are described. Although rare, metastatic osteosarcoma to the breast should be considered when dense calcified masses with suspicious features are seen on breast imaging in patients with a history of osteosarcoma.ope

PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma

Background: Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. Methods: Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. Results: Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006). Conclusion: We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.ope

종양 군집을 둘러싸는 혈관형 간세포암: 불량한 예후를 보이는 간세포암 아형

간세포암은 전 세계에서 암 사망의 주요한 원인이다. 최근 간세포암에서 vessels encapsulating tumor cluster (VETC)라는 특이한 혈관 모양이 종양의 급격한 전파와 높은 재발율과 연관됨이 보고된 바 있으며, 이것은 CD34 면역염색에서 종양 군집을 혈관 내피세포가 동그랗게 둘러싸는 형태로 확인할 수 있다. 본 연구에서, 우리는 VETC의 임상 병리학적 특징을 규명하고, 특히 종양 미세 환경적 특징을 알아보고자 하였다. 본 연구는 2006년부터 2012년까지 세브란스 병원에서 수술적으로 절제된 원발성 간암 (코호트 1, 322례)과 간외 전이성 간암 (코호트 2, 130례) 조직을 대상으로 시행하였다. 각 종양에서 임상 및 병리학적 변수들 검색하였으며, 특히 종양의 섬유성 기질과 염증 세포 침윤을 반정량적으로 평가하였다. 면역 염색은 각각의 표지자로서 다음의 항목에 대하여 조직미세배열을 이용하여 시행하였다: CD34 (종양 혈관), αSMA, FAP (종양 섬유모세포), CD163 (제2형 종양 연관 대식세포), Zebl, Snail, Ezrin, S100A4, E-cadherin (상피-간엽 이행), PD-L1 (종양 면역), CAIX(저산소), K19 (종양 줄기세포), p53, glutamine synthetase, β-catenin (분자 아형). VETC 값은 조직 미세 배열과 큰 조직 절편에서 양호한 일치율을 보였으며 (급내 상관계수=0.642), 관찰자간 재현성 또한 우수하였다 (코헨 카파계수=0.879). VETC 값은 불량한 무병 생존율 (HR: 1.04 [1.01-1.08]; p=0.006), 조기 재발율 (HR: 1.04 [1.01-1.08]; p=0.006), 전체 생존율 (HR: 1.06 [1.00-1.11]; p=0.041), 그리고 간외 전이 (HR: 1.06 [1.01-1.11]; p= 0.009)와 연관 있었다. K-adaptive partitioning algorithm을 통해 VETC (%)의 최적의 절사값을 구하여 VETC가 종양 면적의 55% 이상인 것을 VETC 아형으로 정의하였다. VETC 아형은 전체 증례 중 23.0% (74/322)이었으며, 높은 혈중 AFP (> 400 ng/ml)/PIVKA-II (> 300 mAU/mL) 농도, 종양 크기 5 cm 이상, 대혈관 침범, 나쁜 분화, 거대기둥 모양, 소혈관 침범, 다핵 종양세포과 연관이 있었다. 또한 VETC 아형은 조기 재발 (HR 1.91 [1.20-3.02]; p=0.006), 불량한 전체 생존율 (HR 2.84 [1.29-6.26]; p=0.010), 그리고 간외 전이 (HR 2.38 [1.21-4.64]; p=0.011)와 연관 있음이 다변량 분석에서 확인되었다. VETC 아형은 거대기둥형 간세포암과 분자적으로는 β-catenin/Wnt 활성화와 연관 있는 것으로 관찰되었다. 종양미세환경 측면에서, VETC아형은 상피-간엽 이행성이 낮고 섬유성 종양 기질 및 염증세포 침윤이 적고, PD-L1 발현이 낮고, 저산소성을 보였다. 반면 VETC가 아닌 간암 (non-VETC)의 종양미세환경은 다양한 소견을 보였으며, 섬유성 기질이 있는 경우 (117례), 섬유성 기질이 없는 경우 (131례)로 세분하였다. 이중 섬유성 종양 기질이 있는 non-VETC는 상피-간엽 이행적 특징과 K19 및 PD-L1 발현이 높고, 염증세포의 침윤이 풍부하였으며, 분자적으로는 p53(-), glutamine synthetase/β-catenin (-)이 많았다 (모두 p<0.05). 반면 섬유성 기질이 없는 non-VETC는 VETC 아형과 비교했을 때, K19과 PD-L1 발현 정도가 비슷하고 섬유성 기질이 있는 non-VETC에 비하여서는 p53 발현이 높았다 (모두 p<0.05). 생존 분석에서 VETC 환자군이 가장 불량한 예후를 보였고, 섬유성 기질이 없는 non-VETC 환자군이 최상의 예후를 보였으며, 섬유성 기질이 있는 non-VETC가 그 중간의 예후를 보였다. 간외로 전이된 간세포암은 원발성 간세포암에 비해 조직학적으로는 거대 기둥형이 더 많았고, 미세 환경적 측면에서는 저산소성, 상피-간엽 이행성, K19의 발현이 높았다 (모두 p<0.05). 간외로 전이된 간세포암을 상피-간엽 이행성 마커의 발현정도에 따라 나누면, 상피-간엽 이행성이 낮은 간외전이 그룹은 VETC와 연관이 있었고, 상피-간엽 이행성이 높은 간외 전이 그룹은 섬유성 종양기질이 풍부하고, K19 발현, 염증세포 침윤과 PD-L1 발현율이 높았다 (모두 p< 0.05). 간외 전이가 일어난 장기별 특성으로서 폐로 전이된 간암은 거대 기둥형 및 VETC 아형이 많았고, 림프절로 전이된 종양은 K19 및 상피-간엽 이행성 표지자의 발현이 높았다. 원발 간암과와 대응되는 간외 전이 간암의 비교에서, VETC를 포함하여 종양의 병리학적 특성은 대체로 유지되는 경향을 보였다. 본 연구는 VETC가 공격적인 생물학적 특성과 연관된 간세암종의 아형으로서 종양 미세환경적으로 상피-간엽 이행성이 낮고 섬유성 종양 기질 및 염증세포 침윤이 적고, PD-L1 발현이 낮고, 저산소성의 특성을 보였다. 또한 VETC 형태를 보이는 간외전이 간암에서는 상피-간엽 이행성이 낮으며, 폐로의 전이가 많은 특성을 보였다. 결론적으로 본 연구에서 VETC 아형은 불량한 예후 예측하며, 간암의 맞춤치료를 위한 표지자로서의 가능성을 제시하였다. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The concept of tumor microenvironment (TME) has been established as an integrated and essential component of the cancer development and progression. Among the heterogeneous population comprising TME, endothelial cells in HCC are of particular interest because they are strikingly involved in the tumor growth and represent a potential therapeutic target (transarterial chemoembolization, drugs). Recently, Fang et al. reported a distinct pattern of HCC vascularization that predicted rapid tumor dissemination and high recurrence rates. This pattern is characterized by the presence of CD34+ vessels completely encapsulating tumor clusters (VETC). In this study, we tried to refine the clinico-pathological features of VETC phenotype, especially in terms of TME. This study was performed on surgically resected primary liver (cohort 1, n=322) and extrahepatic metastatic (cohort 2, n=130) HCC tissue samples, obtained from Severance Hospital (Seoul, Korea), from 2006 to 2012. The tissue microarray was constructed, of which 96 cases of cohort 1 were stained with CD34 in the whole sections. The full spectrum of clinical and pathological variables was collected and fibrous tumor stroma and immune cell infiltration was assessed in each tumor. The following immunostaining was performed: tumor vessel (CD34), cancer-associated fibroblast (αSMA, FAP), tumor-associated macrophage (CD163), epithelial-mesenchymal transition (EMT; Zebl, IL-6, Snail, Ezrin, S100A4, E-cadherin), tumor immunity (PD-L1), hypoxia (CAIX), stemness (K19), molecular phenotypic markers (p53, glutamine synthetase, and β-catenin). The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small-sized tissues of tissue microarray. VETC-HCCs represented 23.0% of the cases and was significantly associated with several clinical and pathological features such as high alpha-fetoprotein (AFP) and PIVKA-II level, tumor size greater than 5 cm, macrovascular invasion, poor differentiation, macrotrabecular pattern, frequent microvascular invasion, multinucleated cells (p<0.05 for all). VETC phenotype was associated with early recurrence (HR 1.91 [1.20-3.02]; p=0.006), shorter DFS (HR 1.55 [1.07-2.24]; p=0.233), OS (HR 2.84 [1.29-6.26]; p=0.010), and extrahepatic metastasis (HR 2.38 [1.21-4.64]; p=0.011), in multivariable analysis. This distinct vascular pattern was enriched in the macrotrabecular massive HCC subtype, which was seen in 10.6% of patients. The VETC pattern was found to be easily detectable and a powerful pathological finding affecting survival. In terms of TME, VETC-HCCs showed less immune cell infiltration, scarce fibrous stroma, less PD-L1 expression, and increased CAIX expression. As non-VETC type HCCs, which are 77.0% of HCCs, had heterogenous TME, we further divided into groups of VETC-HCCs (n=74), non-VETC-HCCs with (n=117) or without fibrous stroma (n=131). Non-VETC type HCCs with fibrous stroma showed higher frequency of EMT-high, K19 expression, rich immune cell infiltration, PD-L1 expression, and double negative phenotype, compared to other groups. Non-VETC type HCCs without fibrous stroma showed similar level of K19 expression, macrophage infiltration and PD-L1 expression compared to VETC type HCC and higher frequency of p53 phenotype than Non-VETC type HCCs with fibrous stroma. On survival analysis, overall, the patients with VETC-HCC had the worst outcome, patients with non-VETC-HCCs without fibrous tumor stroma had the best prognosis, patients with non-VETC-HCCs with fibrous tumor were in the middle. Extrahepatic metastatic HCCs demonstrated more MTM subtype with CAIX expression and EMT-high and K19-expressing TME, than intrahepatic primary HCCs. Extrahepatic metastatic HCCs with EMT-low group (74%) were associated with VETC type HCCs. Extrahepatic metastatic HCCs with EMT-high group (26%) were associated with abundant fibrous stroma, K19 expression, rich immune cell infiltration and high level of PD-L1 expression. The metastatic tumors in lungs are associated with MTM subtype with VETC type HCCs. The metastatic tumors in LNs are more likely to express stemness- and EMT- related markers and PD-L1. In analysis for matched pair of primary and metastasis, overall, various features of HCCs including VETC were conserved during metastasis. This study suggests that VETC phenotype is a distinct aggressive subtype with CAIX expression, EMT-low TME, and may predict response to immune checkpoint inhibitors.open박

Clinicopathological Characteristics of Microscopic Tubal Intraepithelial Metastases from Adenocarcinoma and Small Cell Neuroendocrine Carcinoma of the Uterine Cervix

Background/aim: Some metastatic tumors that involve the fallopian tube show intraepithelial spread, mimicking primary tubal neoplasm and representing a potential diagnostic pitfall. In this study, we aimed to investigate the clinicopathological characteristics of tubal intraepithelial metastasis (IEM) from cervical carcinoma. Patients and methods: We analyzed the clinical features, histological features, and immunophenotypes of IEMs in five patients with cervical carcinoma. Results: This study included usual-type (1/5), mucinous-type (1/5), and gastric-type (2/5) endocervical adenocarcinomas and small cell neuroendocrine carcinoma (1/5) cases. None of the patients had ovarian metastasis, but metastatic tumor cells spread along the tubal mucosal surface and partially replaced the lining epithelium. Histological features of metastatic tumors closely resembled those of the primary tumors in all cases. Conclusion: Tubal IEM can mimic various tubal lesions including serous tubal intraepithelial carcinoma. Morphological consistency between the primary and metastatic tumors and immunostaining help guide the differential diagnosis of challenging intraepithelial lesions of the fallopian tube.ope