A nomogram to predict pathologic complete response (pCR) and the value of tumor-infiltrating lymphocytes (TILs) for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients.

PURPOSE: The value of tumor-infiltrating lymphocytes (TILs) for prediction of pathologic complete response (pCR) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) has received increasing attention. In human epidermal growth factor receptor 2 (HER2)-positive BC, advances in HER2-targeted therapy have not yet clarified the clinical implications of pre-NAC TILs. Likewise, the prognostic role of TILs for long-term survival is not well established. METHODS: Pre- and post-NAC TIL levels were evaluated in 248 pair-matched pre-NAC biopsy and post-NAC resection samples, and analyzed for predictive and prognostic significance with other clinicopathologic parameters. Additional 60 pre-NAC biopsy samples of HER2-positive BC treated with a TCHP regimen (docetaxel, carboplatin, and a combination of trastuzumab and pertuzumab) were also assessed. RESULTS: High pre-NAC TILs, clinical nodal stage 0-1 (cN0-1), and negative ER expression were shown to be strong predictive markers for pCR. A nomogram based on these significant clinicopathologic predictors was developed, providing integrated probability of achieving pCR after NAC. The association between high pre-NAC TIL levels and significantly increased pCR rate was also confirmed in HER2-positive BC patients treated with a TCHP regimen. After chemotherapy, increased quantity of post-NAC TILs was shown to have extended BC-specific survival and disease-free survival in univariable and multivariable analyses. CONCLUSIONS: High pre-NAC TIL levels were significantly predictive of pCR in BC, and can act as a surrogate marker for predicting therapeutic effects of a TCHP regimen for HER2-positive BC. Post-NAC TILs in residual disease were a new prognostic marker of risk stratification for long-term survival.

Prognostic value of cyclin B1 and cyclin B2 expression in breast cancer: A systematic review and updated meta-analysis.

BACKGROUND: Cyclin B1 and cyclin B2 are key regulators of cell cycle progression and have been implicated in the prognostic significance of various cancers. This meta-analysis aimed to evaluate the prognostic value of cyclin B1 and B2 expression in breast cancer. METHODS: A comprehensive literature search was conducted on Pubmed, Embase, MEDLINE, Web of Science, and Cochrane library. Studies with survival data and clinicopathological parameters associated with cyclin B1 and B2 or CCNB1 and CCNB2 genes were included. Survival data and clinicopathological parameters associated with cyclin B1 and B2 expression were extracted. Pooled hazard ratios and odds ratios with 95% confidence intervals were calculated. Subgroup analysis was conducted to assess heterogeneity. Publication bias was evaluated. RESULTS: A total of 23 studies were included in the analysis. High expression of cyclin B1 was significantly associated with worse overall survival (hazard ratio [HR] = 1.69, P < .01), disease-specific survival (HR = 1.71, P < .01), and disease-free survival (HR = 2.01, P = .01). High expression of cyclin B2 was associated with worse disease-specific survival (HR = 2.46, P = .02). Clinicopathological parameters did not show significant associations with cyclin B1 and B2 expressions. When data on cyclin B1 and B2 were combined, a significant age-related difference was found (odds ratio = 0.62, P = .04). CONCLUSIONS: This meta-analysis provides evidence supporting the prognostic significance of cyclin B1 and B2 expression in breast cancer. High expression of cyclin B1 and B2 is associated with worse survival, indicating their potential as prognostic markers in breast cancer.

Complete Hydatidiform Mole with Lung Metastasis and Coexisting Live Fetus: Unexpected Twin Pregnancy Mimicking Placenta Accreta.

Twin pregnancy with a complete hydatidiform mole and coexisting fetus (CHMCF) is an exceedingly rare condition with an incidence of about 1 in 20,000-100,000 pregnancies. It can be detected by prenatal ultrasonography and an elevated maternal serum beta-human chorionic gonadotropin (BhCG) level. Herein, the author reports a case of CHMCF which was incidentally diagnosed through pathologic examination without preoperative knowledge. The 41-year-old woman, transferred due to preterm labor, delivered a female baby by cesarean section at 28 + 5 weeks of gestation. Clinically, the surgeon suspected placenta accreta on the surgical field, and the placental specimen was sent to the pathology department. On gross examination, focal vesicular and cystic lesions were identified separately from the normal-looking placental tissue. The pathologic diagnosis was CHMCF and considering the fact that placenta accreta was originally suspected, invasive hydatidiform mole was not ruled out. After radiologic work-up, metastatic lung lesions were detected, and methotrexate was administered in six cycles at intervals of every two weeks. The author presents the clinicopathological features of this unexpected CHMCF case accompanied by pulmonary metastasis, compares to literature review findings, and emphasizes the meticulous pathologic examination.

Prognostic Significance of Programmed Cell Death Ligand 1 Expression in High-Grade Serous Ovarian Carcinoma: A Systematic Review and Meta-Analysis.

(1) Background: High-grade serous ovarian carcinoma (HGSOC) is an aggressive subtype of ovarian cancer. Recent advances have introduced prognostic markers and targeted therapies. Programmed cell death ligand 1 (PD-L1) has emerged as a potential biomarker for HGSOC, with implications for prognosis and targeted therapy eligibility; (2) Methods: A literature search was conducted on major databases, and extracted data were categorized and pooled. Subgroup analysis was performed for studies with high heterogeneity. (3) Results: Data from 18 eligible studies were categorized and pooled based on PD-L1 scoring methods, survival analysis types, and endpoints. The result showed an association between high PD-L1 expression and a favorable prognosis in progression-free survival (HR = 0.53, 95% CI = 0.35-0.78, p = 0.0015). Subgroup analyses showed similar associations in subgroups of neoadjuvant chemotherapy patients (HR = 0.6, 95% CI = 0.4-0.88, p = 0.009) and European studies (HR = 0.59, 95% CI = 0.42-0.82, p = 0.0017). In addition, subgroup analyses using data from studies using FDA-approved PD-L1 antibodies suggested a significant association between favorable prognosis and high PD-L1 expression in a subgroup including high and low stage data in overall survival data (HR = 0.46, 95% CI = 0.3-0.73, p = 0.0009). (4) Conclusions: This meta-analysis revealed a potential association between high PD-L1 expression and favorable prognosis. However, caution is warranted due to several limitations. Validation via large-scale studies, with mRNA analysis, whole tissue sections, and assessments using FDA-approved antibodies is needed.

Giant mixed hemangioma of the breast: A case report with imaging findings.

Hemangioma of the breast is an uncommon tumor type that is usually small, superficially located, and impalpable. The majority of cases are cavernous hemangiomas. We describe a rare case of a large, palpable mixed hemangioma of the breast which was located in the parenchymal layer, studied with magnetic resonance imaging, mammography, and sonography. Magnetic resonance imaging findings of slow and persistent enhancement from the center to periphery are useful in characterizing benign breast hemangiomas, where even the lesion presents with a suspicious shape and margin on sonography.

Papillary thyroid cancer with suspicious uterine cervix metastasis: a case report and literature review.

Background: Distant metastasis (DM) of papillary thyroid cancer (PTC) is rare but significantly associated with decreased survival. Accurate clinical staging at initial diagnosis and during follow-up is essential. Case Description: We report the case of a 38-year-old woman diagnosed with PTC in the left isthmus who presented with a suspicious uterine cervix metastasis during follow-up after total thyroidectomy. She had neither medical history nor family history of thyroid cancer. During surgery, extensive central node metastases were found, and bilateral total thyroidectomy was performed. Even after three rounds of radioactive iodine (RAI) ablation, persistently elevated serum thyroglobulin (Tg) levels, combined with a suspicious finding on the whole-body scan (WBS) and fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), led to the clinical suspicion of uterine cervix metastasis from PTC. Hysterectomy confirmed the pathology of chronic cervicitis. No hidden malignancy was observed. After surgery, negative imaging findings and decreased serum Tg levels were observed. Conclusions: This case contributes to the discussion of differential diagnostic problems in the setting of clinical and pathological investigations of PTC. However, based on the relevant rationales, through multidisciplinary discussion, this patient can ultimately obtain a better prognosis. Understanding the pitfalls of imaging modalities and continuous efforts to overcome the limitations of the diagnostic process are crucial for future treatment.

Dissecting Gonadoblastoma of the Ovary Coexistent with an Atypical Endometriotic Cyst: Incidental Detection in Cystectomy Specimen of a Woman with 46,XX Karyotype.

Dissecting gonadoblastoma (DGB) of the ovary, a recently described terminology, defines a unique distribution of neoplastic germ cells. Here, we report a case of incidental DGB coexistent with an atypical endometriotic cyst occurring in a 23-year-old woman. The ovarian cyst was lined by endometrial-like glands and stroma. Some glands displayed nuclear enlargement and hyperchromasia, and abundant eosinophilic cytoplasm with occasional intracytoplasmic hemosiderin and mucin vacuoles. The neoplastic germ cells resembled those of ovarian dysgerminoma and were diffusely distributed within the ovarian stroma, which was stretched around the wall of the endometriotic cyst. These cells were arranged in nests and cords, possessing clear cytoplasm and centrally located round nuclei with prominent nucleoli and occasional mitoses. Chromosomal analysis revealed a 46,XX karyotype. We describe the clinical, histological, immunophenotypical, and genetic features of ovarian DGB incidentally detected in the ovarian cystectomy specimen of a woman with normal female karyotype.

Clinicopathological Characteristics of Primary Pulmonary Hodgkin Lymphoma (PPHL): Two Institutional Experiences with Comprehensive Literature Review of 115 PPHL Cases.

Primary pulmonary Hodgkin lymphoma (PPHL) is an extremely rare condition. Its clinicopathological characteristics remain unclear because of the limited number of patients with PPHL. The aim of this study was to comprehensively analyze the clinicopathological characteristics of PPHL. We reviewed the electronic medical records and pathology slides of our 10 PPHL patients. The female-to-male ratio was 6:4, and the mean age was 41 years. Although three patients had no symptoms, seven had localized or generalized symptoms, including cough, sputum, chest discomfort/pain, and weight loss. Some cases had not been diagnosed as PPHL in the initial needle biopsy. Four patients underwent surgical resection. With chemotherapy, eight patients achieved complete remission. We also conducted a thorough literature review on 105 previously reported PPHL cases. Among a total of 115 PPHL cases, the most common subtype was nodular sclerosis (37.4%). More than half of the cases (55%) were clinically suspected as infectious pneumonia. Of 61 patients whose biopsies were available, 27 (44.3%) were diagnosed correctly as Hodgkin lymphoma, whereas the misdiagnoses included tuberculosis, Langerhans cell histiocytosis, solitary fibrous tumor, and adenocarcinoma. We demonstrated that PPHL represents a diagnostic challenge on small biopsies. Recognizing that this rare tumor can mimic infectious and inflammatory diseases as well as malignancies is important because the accurate diagnosis of PPHL is essential for adequate clinical management.

Incidental paratracheal air cyst in papillary thyroid cancer patient: a case report.

Paratracheal air cyst (PTAC) is a collection of air in the right posterior side of the trachea with an uncertain etiology. We report a papillary thyroid cancer patient with a PTAC that was removed during thyroid cancer surgery. A 68-year-old woman was diagnosed with right papillary thyroid cancer with suspicion of central lymph node metastasis. She had a history of hypertension and a rear-end collision car accident 20 years prior. On computed tomography, an ovoid cyst was incidentally found in the paratracheal region at the thoracic inlet level. Emphysematous lung with an obstructive lung defect was noted without any symptoms. Bilateral total thyroidectomy with ipsilateral central compartment neck dissection was indicated for the patient. During surgery, removal of the cyst was inevitable for complete central neck dissection. Histopathologic analysis revealed an etiology of tracheal mucus sprouting through weak trachea points. No postoperative complications occurred. The patient continued on levothyroxine medication without further radioactive iodine therapy. After 6 months, follow-up ultrasound showed no evidence of recurrence. We hypothesized that obstructive lung disease with impaired lung function or trauma history might have contributed to the development of PTAC. Future studies are needed to determine if PTACs have any association with obstructive lung disease or trauma.

Vulvar epithelioid sarcoma: A case report with literature review.

OBJECTIVE: To report a case of vulvar epithelioid sarcoma, a rare type of tumor that has been reported in 37 cases in the English literature to date. CASE REPORT: We report three cases of vulvar epithelioid sarcoma, proximal type. Wide excisions of the mass were performed with margins free of tumor in all three cases. CONCLUSION: Due to its low incidence, there are no evidence-based diagnostic algorithms or published recommendations for treatment. Locoregional lymph node involvement, vascular invasion, tumor size larger than 2 cm, deep localization, presence of necrosis, and a high mitotic index are known as poor prognostic factors. Adjuvant radiotherapy is advisable in the presence of a high-grade tumor or positive margins. The beneficial effect of adjuvant chemotherapy is not well established. Treatment decisions should be made based on the individual case presentation and pathology evaluation.

Clinicopathological and Molecular Differences Between Gastric-type Mucinous Carcinoma and Usual-type Endocervical Adenocarcinoma of the Uterine Cervix.

BACKGROUND/AIM: We investigated differences in the clinicopathological and molecular characteristics between gastric-type mucinous carcinoma (GMC) and usual-type endocervical adenocarcinoma (UEA). PATIENTS AND METHODS: We collected the clinicopathological information and performed targeted genomic sequencing analysis. RESULTS: GMCs exhibited significantly deeper invasion depth, larger horizontal spread, more advanced stage, more frequent distant metastasis, and more frequent parametrial and vaginal extension. Disease-free survival time of GMC patients was significantly shorter than that of UEA patients. GMCs displayed mutant p53 immunostaining pattern, whereas UEAs exhibited p16 block positivity. GMCs harbored mutations in KRAS, TP53, NF1, CDKN2A, STK11, and ARID1A. One GMC exhibited MDM2 amplification. In contrast, UEAs harbored mutations in HRAS, PIK3CA, and BRCA2. Two UEAs were found to have novel TP53 mutations. CONCLUSION: GMC is associated with more aggressive behavior than UEA. Distinctive p53 and p16 immunostaining patterns enable differential diagnosis. GMC and UEA exhibit genetic heterogeneity with potentially actionable molecular alterations.

Hepatic Angiosarcoma: Clinicopathologic Study With an Investigation of ROS1 Gene Rearrangements.

BACKGROUND/AIM: Primary hepatic angiosarcoma (PHA) is a rare disease entity with variable morphologic features. Recent findings regarding ROS1 gene rearrangements in PHA may lead to new targeted therapies. PATIENTS AND METHODS: Thirteen cases (4 resected specimens and 9 biopsy samples) underwent histologic review and morphologic patterns were classified according to a previous study as 1) sinusoidal, 2) peliotic, 3) vasoformative, and 4) solid (epithelioid/spindled). ROS1 immunohistochemistry and investigation of the presence of a ROS1 fusion gene by reverse transcription-polymerase chain reaction were performed in available cases. RESULTS: Eight of 13 cases (62%) showed vasoformative patterns. Three cases (23%) were classified as sinusoidal and two (15%) as solid patterns. Mortality rate was 90% (9/10) except for three patients lost in follow up. Only one patient is still alive and has survived for 8 months with the disease. All cases tested did not have ROS1 expression (0/9) or a ROS1 fusion gene (0/4). CONCLUSION: We report 13 cases of PHA with 90% mortality. Vasoformative PHA is the most common histologic type. New findings on ROS1 fusion gene rearrangements could lead to the development of novel targeted therapeutics for PHA patients with dismal prognosis.

Clinicopathologic characteristics of HER2-positive pure mucinous carcinoma of the breast.

BACKGROUND: Pure mucinous carcinoma (PMC) is a rare type of breast cancer, estimated to represent 2% of invasive breast cancer. PMC is typically positive for estrogen receptors (ER) and progesterone receptors (PR) and negative for human epidermal growth factor receptor 2 (HER2). The clinicopathologic characteristics of HER2-positive PMC have not been investigated. METHODS: Pathology archives were searched for PMC diagnosed from January 1999 to April 2018. Clinicopathologic data and microscopic findings were reviewed and compared between HER2-positive PMC and HER2-negative PMC. We also analyzed the differences in disease-free survival (DFS) and overall survival according to clinicopathologic parameters including HER2 status in overall PMC cases. RESULTS: There were 21 HER2-positive cases (4.8%) in 438 PMCs. The average tumor size of HER2-positive PMC was 32.21 mm (± 26.55). Lymph node metastasis was present in seven cases. Compared to HER2-negative PMC, HER2-positive PMC presented with a more advanced T category (p < .001), more frequent lymph node metastasis (p = .009), and a higher nuclear and histologic grade (p < .001). Microscopically, signet ring cells were frequently observed in HER2-positive PMC (p < .001), whereas a micropapillary pattern was more frequent in HER2-negative PMC (p = .012). HER2-positive PMC was more frequently negative for ER (33.3% vs. 1.2%) and PR (28.6% vs. 7.2%) than HER2-negative PMC and showed a high Ki-67 labeling index. During follow-up, distant metastasis and recurrence developed in three HER2-positive PMC patients. Multivariate analysis revealed that only HER2-positivity and lymph node status were significantly associated with DFS. CONCLUSIONS: Our results suggest that HER2-positive PMC is a more aggressive subgroup of PMC. HER2 positivity should be considered for adequate management of PMC.

PD-L1 expression in gastric cancer determined by digital image analyses: pitfalls and correlation with pathologist interpretation.

Programmed death ligand-1 (PD-L1) immunohistochemistry is used to predict response to anti-PD-L1 therapy. However, intra- and inter-observer variability influence the prediction of PD-L1 expression. Unlike evaluations of non-small cell lung cancer according to PD-L1 expression determined by tumor proportion score, gastric cancer is evaluated using combined positive scores. We aimed to compare the results of digital image analysis and pathologists' interpretations for predicting response to pembrolizumab in gastric cancer patients. Gastric cancer tissues from patients enrolled in a clinical trial of pembrolizumab were reviewed, and 39 cases were analyzed. PD-L1 22C3 PharmDx (Dako) immunohistochemistry slides were interpreted by digital image analysis and by the consensus of two pathologists, and the results of interpretations were compared with the eventual clinical responses to pembrolizumab. In direct comparisons of digital image analyses and pathologists' interpretations, 33 (84.6%) out of 39 cases showed concordant results. In 6 (15.4%) cases, weak staining of PD-L1, anthracotic pigment deposits, or decalcification artifacts caused discordant results, and all the cases were challenging. In statistical analyses, PD-L1 expression as interpreted by pathologists and digital image analysis did not differ significantly for predicting responses to pembrolizumab (P = 0.1856). Digital image analyses and pathologists' interpretations showed concordant results for PD-L1 combined positive scores in most cases, and the prediction performances of each were not significantly different.

CAMTA-1 Expression in 24 Cases of Hepatic Epithelioid Hemangioendothelioma in a Single Institute: Diagnostic Utility for Differential Diagnosis from Hepatic Angiosarcoma.

BACKGROUND/AIM: Epithelioid hemangio-endothelioma (EHE) of the liver is an uncommon vascular tumor with variable clinical courses ranging from stable disease to fatal outcome. EHE can mimic epithelioid angiosarcoma, which has a more aggressive behavior, especially in a small biopsy sample. EHEs are known to have the WWTR1-CAMTA1 fusion gene, and nuclear expression of CAMTA1 by immunohistochemistry (IHC) has been reported in about 90% of EHEs in multiple organs. Our study aimed to validate the diagnostic utility of CAMTA1 expression in EHEs, especially in the liver. PATIENTS AND METHODS: IHC was performed using anti-CAMTA1 antibody in 34 tumors (24 hepatic EHEs and 10 angiosarcomas). In CAMTA1-negative EHEs, TFE3 IHC was performed. RESULTS: Of the 24 hepatic EHEs, 22 (91.6%) showed nuclear staining for CAMTA1. One of two CAMTA1-negative cases showed TFE3 positivity. The other case was negative for TFE3. Meanwhile, all 10 angiosarcoma cases had no CAMTA1 expression. CONCLUSION: CAMTA1 is a highly sensitive and specific marker for diagnosis of hepatic EHE. It is helpful for differentiation of hepatic EHE and angiosarcoma, especially in small biopsy samples.

Pathologic analyses of peritoneal nodules in gastric cancer patients during surgery-A single cancer center experience with diagnostic pitfalls.

BACKGROUND: Gastric carcinoma (GC) is the second most common cause of cancer-related deaths worldwide. During operations, nodular lesions of the peritoneum are often sent for frozen section (FS). For pathologists, FS of the peritoneum is challenging due to sparse and discohesive tumor cells in a fibrotic background. METHODS: To explore diagnostic accuracy and diagnostic pitfalls of FS in this setting, we retrospectively collected 252 peritoneal biopsies in cases with GC from January 2006 to May 2017 and compared corresponding permanent sections and patient prognosis. After review, 6 cases (2.4%) were discrepant: positive conversion was identified in 5 cases due to scarce tumor cells associated with severe fibrosis and inflammation; negative conversion was identified in one case due to papillary mesothelial cell proliferation masquerading as carcinoma. RESULTS: Two hundred cases were finally confirmed as positive for tumor cells. Of these, 185 (92.5%) patients died of GC, with survival times ranging from 7 to 3574 (mean 415) days after operation. Fifty-two (20.6%) cases were negative for tumor, and pathologic findings included chronic inflammation with fibrosis (N = 25: associated with previous operation, 10; idiopathic, 15) and papillary mesothelial cell proliferation (N = 9). All 5 patients with frozen diagnosis converted to positive results died of GC during follow up. A total of 19 patients with peritoneal nodules diagnosed as benign on FS died with GC (79.0%), and their survival times ranged from 87 to 3649 (mean 833) days. CONCLUSIONS: Peritoneal biopsies in patients with GC were mostly carcinoma, followed by chronic inflammation with fibrosis and papillary mesothelial cell proliferation. Deeper sections or intradepartmental consultations were helpful to reduce false negative diagnosis on FS.

Correlations between Janus kinase 2 V617F allele burdens and clinicohematologic parameters in myeloproliferative neoplasms.

BACKGROUND: This study evaluated potential correlations between the allele burden of the Janus kinase 2 (JAK2) V617F mutation and clinicohematologic characteristics in patients with myeloproliferative neoplasms (MPN). METHODS: Clinical and hematologic features were reviewed for 103 MPN patients, including patients with polycythemia vera (PV, 22 patients), essential thrombocythemia (ET, 64 patients), and primary myelofibrosis (PMF, 17 patients). JAK2 V617F allele status and allele burdens were measured by allele-specific PCR and pyrosequencing, respectively. RESULTS: The JAK2 V617F mutation was detected in 95.5%, 68.8%, and 52.9% of PV, ET, and PMF patients, respectively. JAK2 V617F-positive ET patients were significantly older and exhibited higher neutrophil fractions, a higher frequency of thrombotic events, and a higher myelofibrosis rate than JAK2 V617F-negative patients (P <0.05). PV patients carried the highest mean T allele burden (66.0%±24.9%) compared with ET (40.5%±25.2%) and PMF patients (31.5%±37.0%) (P =0.00). No significant correlations were detected between V617F allele burden and patient age, white blood cell count, Hb, Hct, or the platelet count for PV, ET, or PMF patients. ET patients with organomegaly had a higher JAK2 V617F allele burden (53.4%±23.7%) than patients without organomegaly (35.6%±24.3%) (P =0.03). CONCLUSIONS: The JAK2 V617F mutational status and its allele burden correlate with the clinicohematologic phenotypes of ET patients, including older age, higher neutrophil count, and greater rates of organomegaly, thrombotic events, and myelofibrosis. For PV and PMF patients, larger-scale studies involving more MPN patients are needed.