Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG-E8.

The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG-E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor-derived and systemically existing MFG-E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL-dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG-E8, and that such responses were enhanced further with the administration of anti-PD-1 antibody. In mice with decreased levels of systemic MFG-E8, the dominance of regulatory T cells in tumor-infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG-E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG-E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG-E8, but not MFG-E8 expression in tumor cells, before the treatment was associated with objective responses to anti-PD-1 therapy in patients with non-small cell lung cancer. These results suggest that systemic MFG-E8 plays a critical role during the immunological initiation process of antigen-presenting cells to increase tumor-specific CTLs. Regulation of the systemic level of MFG-E8 might induce efficient antitumor immune responses and enhance the potency of anti-PD-1 therapy.

An unusual presentation of dermatofibrosarcoma protuberans: A case of fibrosarcomatous dermatofibrosarcoma protuberans with pleomorphic angiectatic tumor-like changes.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive superficial mesenchymal neoplasm characterized by monomorphic spindle-cell proliferation with a storiform pattern. It can demonstrate pigmentation, myxoid changes, myoid differentiation, plaque-like growth, and fibrosarcomatous features; its varied presentation often complicates diagnosis. We report an extremely rare case of fibrosarcomatous DFSP with features reminiscent of a pleomorphic hyalinizing angiectatic tumor (PHAT) in a 73-year-old male. The diagnosis was confirmed using a reverse transcription polymerase chain reaction. To the best of our knowledge, PHAT-like changes in DFPS have not been described so far. Therefore, this report provides a novel variant of DFSP and expands the differential diagnosis of DFSP and PHAT.

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma.

BACKGROUND: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. METHODS: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. RESULTS: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. CONCLUSIONS: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.

Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases.

ABSTRACT: Information regarding the genetic alterations in extramammary Paget disease (EMPD) is scarce. This study investigated the significance of CDKN2A and MTAP alterations in EMPD progression using immunohistochemistry and panel DNA sequencing. In total, 24 invasive/metastatic EMPD cases were included in this study. The immunoexpression of p16 and MTAP in the primary in situ, primary invasive, and metastatic tumor components was evaluated. Panel DNA sequencing was performed for metastatic tumor components in 5 of the 24 cases. Immunoexpression of p16 in the in situ tumor component was at least partially preserved in all 19 tested cases (100%). By contrast, the invasive tumor component was diffusely or partially lost in 18 (81.8%) of 22 tested cases. Regarding the foci of lymph node metastasis, 13 (81.2%) of the 16 patients showed a significant loss of p16 expression. Loss of MTAP immunoexpression was observed less frequently compared with the loss of p16 expression. CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.

Density and maturity of peritumoral tertiary lymphoid structures in oesophageal squamous cell carcinoma predicts patient survival and response to immune checkpoint inhibitors.

BACKGROUND: Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC). METHODS: In a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody. RESULTS: Tumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138+ plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival. CONCLUSION: The density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients.

Immunoscore Signatures in Surgical Specimens and Tumor-Infiltrating Lymphocytes in Pretreatment Biopsy Predict Treatment Efficacy and Survival in Esophageal Cancer.

OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types. METHODS: In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3, and CD8 were immunostained to evaluate TIL density. RESULTS: In all cases, the IS-high (score 3-4) group tended to have better survival [5-year overall survival (OS) of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722] than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3 + ( P = 0.0106) and CD8 + cells ( P = 0.0729) and, particularly CD3 + cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169). CONCLUSIONS: The IS signature in surgical specimens and TIL density in preNAC- biopsies could be predictive markers of clinical outcomes in EC patients.

Clinicopathologic and genetic characterization of invasive melanoma with BRAF V600K mutation: A study of 16 cases.

BACKGROUND: The clinicopathologic and genetic features of cutaneous melanoma with a BRAF V600K mutation are not well-known. We aimed to evaluate these characteristics in comparison with those associated with BRAF V600E. METHODS: Real-time polymerase chain reaction (PCR) and/or the MassARRAY® system were used to detect BRAF V600K in 16 invasive melanomas and confirm BRAF V600E in another 60 cases. Immunohistochemistry and panel next-generation sequencing were used to evaluate protein expression and tumor mutation burden, respectively. RESULTS: The median age of melanoma patients harboring the BRAF V600K mutation (72.5 years) was higher than those with the BRAF V600E (58.5 years). The two groups also differed in sex (13/16 [81.3%] male in the V600K group vs. 23/60 [38.3%] in V600E) and in the frequency of scalp involvement (8/16 [50.0%] in V600K vs. 1/60 [1.6%] in V600E). The clinical appearance was similar to a superficial spreading melanoma. Histopathologically, non-nested lentiginous intraepidermal spread and subtle solar elastosis were observed. One patient (1/13, 7.7%) had a pre-existing intradermal nevus. Diffuse PRAME immunoexpression was seen in only one (14.3%) of seven tested cases. Loss of p16 expression was observed in all 12 cases (100%) analyzed. The tumor mutation burden was 8 and 6 mutations/Mb in the two tested cases. CONCLUSIONS: Melanoma carrying the BRAF V600K mutation showed the predominance on the scalp of elderly men, lentiginous intraepidermal growth, subtle solar elastosis, possible existence of intradermal nevus component, frequent loss of p16 immunoexpression, limited immunoreactivity for PRAME, and intermediate tumor mutation burden.

Utility of needle biopsy in centrally located lung cancer for genome analysis: a retrospective cohort study.

BACKGROUND: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. METHODS: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. RESULTS: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. CONCLUSIONS: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

[A Case of Chronic Expanding Hematoma of the Lower Abdomen after Reconstruction of Deep Inferior Epigastric Perforator Flap for Breast Cancer].

A 49-year-old woman who had surgery for left breast cancer and subsequently underwent a two-stage deep inferior epigastric perforator(DIEP)flap reconstruction. One month postoperatively, she became aware of abdominal distention and visited a local hospital. CT scan revealed subcutaneous fluid accumulation with capsular formation in the lower abdomen. Imaging findings and physical examination showed no abdominal wall scar hernia. After multiple puncture aspirations, fluid accumulation was observed again, and the possibility of a chronic expanding hematoma was considered. Later, hematoma removal, including the capsules, was performed; pathological findings showed no evidence of malignancy. No fluid retention was observed postoperatively. In cases where imaging evaluation reveals hematoma formation with capsules, hematoma removal, including the capsules, should be performed to avert the possibility of a chronic expanding hematoma.

Sweat-gland carcinoma with neuroendocrine differentiation (SCAND): a clinicopathologic study of 13 cases with genetic analysis.

Low-grade neuroendocrine carcinoma of the skin (LGNECS) was proposed in 2017 as a new primary cutaneous neoplasm with neuroendocrine differentiation; however, it is not yet well known due to its rarity. Herein, we perform a detailed clinicopathologic analysis of 13 cases as well as panel DNA sequencing in three cases. The study included 12 males and 1 female with a median age of 71 (43-85) years. All lesions occurred on the ventral trunk. The mean tumor size was 2.2 (0.8-11.0) cm. The histopathology resembled that of well-differentiated neuroendocrine tumors (NETs) in other organs, but intraepidermal pagetoid spreading was seen in 8 (61.5%) cases and stromal mucin deposits in 4 (30.8%). Immunoreactivity for CK7, CK19, EMA, BerEP4, CEA, chromogranin A, synaptophysin, INSM1, GCDFP15, GATA3, ER, and bcl-2 were present in varying degrees in all tested cases. PTEN c.165-1G>A splice site mutation was detected by panel sequencing in one case, and GATA3 P409fs*99 and SETD2 R1708fs*4 in another case. Lymph node metastasis was seen significantly in cases with tumor size >2.0 cm [8/8 (100%) vs. 1/5 (20%)]. All three cases with size >3.0 cm were in unresectable advanced-stage [3/3 (100%) vs. 1/10 (10%)], and two of the three patients succumbed to the disease. The two cases of death revealed mild nuclear atypia (mitosis: 1/10 HPFs) and moderate nuclear atypia (2/10 HPFs). Thus, tumor size would be a better prognostic factor than nuclear atypia, mitotic count, and Ki67 index, unlike in NETs. These clinicopathologic and immunohistochemical features would represent the characteristics as skin adnexal tumors with apocrine/eccrine differentiation rather than NETs; therefore, we rename it as sweat-gland carcinoma with neuroendocrine differentiation (SCAND).

Local recurrence after endoscopic resection of sessile serrated lesions: A multicenter prospective study by the Osaka Gut Forum.

BACKGROUND AND AIM: Sessile serrated lesions (SSLs) act as precursors to colorectal cancer, sometimes harbor carcinomas, and are sometimes incompletely resected. We aimed to evaluate local recurrence after endoscopic resection of SSL ≥10 mm. METHODS: This prospective, single-arm, observational study was performed at eight Japanese tertiary institutions. Colorectal lesions ≥10 mm were resected endoscopically, and the pathological diagnosis was either an SSL or hyperplastic polyp (HP). Follow-up colonoscopy was performed 1 year later, and the local recurrence was evaluated by biopsy. RESULTS: From October 2018 to September 2021, 104 cases with 123 lesions were registered. Among the pathologically diagnosed 105 SSLs and 18 HPs, 95 and 7 lesions were diagnosed as SSLs and HPs, respectively, by central pathological review. Among the 104 endoscopically diagnosed SSLs, 86 were diagnosed as SSLs, whereas among the 11 endoscopically diagnosed HPs, two were diagnosed as HPs by central pathological review (the rest were SSLs). Among the 95 patients with 113 lesions who underwent follow-up colonoscopy, resection scars were identified in 95 (84%) lesions. Three (3.1%; 95% confidence interval 0.6-8.7%) local recurrences were diagnosed pathologically among 98 pathologically diagnosed SSLs. Two (6%) local recurrences were diagnosed in patients with SSLs ≥20 mm. CONCLUSIONS: The local recurrence rate after endoscopic resection of SSLs ≥10 mm was 3.1%. Careful follow-up is recommended after endoscopic resection of large SSLs. Endoscopically diagnosed HPs ≥10 mm were sometimes pathologically diagnosed as SSL and should be considered for resection.

Categorization of cutaneous epithelioid angiomatous nodule as epithelioid hemangioma or angiolymphoid hyperplasia with eosinophilia: Clinicopathologic, immunohistochemical, and molecular analyses of seven lesions.

BACKGROUND: The status of cutaneous epithelioid angiomatous nodule (CEAN) as a distinct entity remains controversial. This study investigated the relationship between CEAN and epithelioid hemangioma/angiolymphoid hyperplasia with eosinophilia (ALHE). METHODS: Data of seven lesions with CEAN features from four cases (Cases 1-4: 61-year-old, 76-year-old, 53-year-old, and 21-year-old men, respectively) were investigated. RESULTS: Cases 1 and 2 showed multiple lesions in the head and neck region, but Cases 3 and 4 showed solitary lesions on the back and scalp, respectively. Moreover, the histopathologic findings of the lesions of Cases 1 and 2 were consistent with those of conventional epithelioid hemangioma or classic cutaneous ALHE. Diffuse immunoexpression of FOSB was observed in Cases 1 and 2, but FOSB split signals were absent in break-apart fluorescence in situ hybridization (FISH). In contrast, the histopathologic findings of the lesions of Cases 3 and 4 were consistent with those of cellular-type epithelioid hemangiomas. Diffuse immunoreactivity for c-FOS was observed in Cases 3 and 4, and split signals of FOS were present in break-apart FISH in Case 3. CONCLUSIONS: This study showed that the seven tumors with CEAN features could be reclassified under the epithelioid hemangioma/ALHE group, although the small sample size is a limitation.

Spindle Cell Carcinoma of the Breast: Investigation of Magnetic Resonance Imaging Features of 26 Cases.

OBJECTIVE: The aim of the study was to retrospectively investigate the fat-saturated T2-weighted sequences (FST2WI) and 3-dimensional dynamic contrast-enhanced sequence (DCE) of magnetic resonance imaging (MRI) findings of breast spindle cell carcinoma (SpCC). METHODS: Twenty-six women with surgically confirmed breast SpCC, who underwent breast MRI in 2 institutions, were enrolled in this study (mean age, 54 years; range, 27-81 years). Two breast radiologists determined the MRI findings by consensus after independent interpretations. Each MRI finding was analyzed. RESULTS: Most lesions of SpCC showed a solitary mass (92.2%). Most masses were round/oval (76.0%), had an irregular margin (88.0%), rim enhancement (72.0%), washout kinetic analysis (96.0%), hyperintensity on FST2WI (84%), hyperintensity on FST2WI and fast enhancing component on DCE (56%), and hypointense rim on FST2WI (72.0%). CONCLUSIONS: Most breast SpCC showed a solitary mass, round/oval shape, irregular margin, rim enhancement, washout kinetics, and intratumoral hyperintensity on FST2WI; a hypointense rim on FST2WI; and hyperintensity on FST2WI and fast enhancing component on DCE.

BRAF Immunoexpression Can Be Intralesionally Heterogeneous but BRAF V600E Mutation Status Is Intralesionally Homogeneous and Interlesionally Concordant in Melanoma: A Study of 140 Lesions From 98 Patients.

ABSTRACT: This study sought to confirm the homogeneity of BRAF V600E mutation status in melanoma. BRAF immunohistochemistry was performed on 102 lesions from 60 patients of melanoma with BRAF V600E mutation and 38 negative-control melanoma lesions from 38 patients, both of which were confirmed by real-time PCR or the MassARRAY System. In the positive-control lesions, 9 lesions from 7 patients with preceding BRAF-inhibitor therapy were included. Of the 102 BRAF-mutant lesions, 101 (99.0%) showed diffuse BRAF immunoexpression, but 39 (38.2%) of them showed various heterogeneous intensities. The heterogeneous intensity of immunostaining was due to necrosis (n = 10), minimal or clear cytoplasm (n = 5), tissue crush (n = 8), insufficient fixation (n = 24), or technical error (n = 4). Only 1 lesion (1.0%) with nondiffuse immunoexpression harbored 80% weakly BRAF-positive tumor area and 20% BRAF-negative area with tissue damage. Sanger sequencing performed on the weak or negative regions in 7 lesions revealed BRAF V600E mutation in all the tested lesions. By contrast, all 38 negative-control lesions demonstrated no BRAF immunoexpression. This study demonstrated intralesional homogeneity and interlesional concordance for BRAF V600E mutation status and intralesional frequent heterogeneity for BRAF immunoexpression. The abovementioned 5 phenomena caused substantial reduction in BRAF immunostaining intensity. In 9 lesions within this study, BRAF immunoexpression and BRAF V600E point mutation status were not affected by preceding BRAF inhibitor therapy. Our data would also support the position that it does not matter whether we select primary or metastatic samples for BRAF mutation analysis.

Seborrheic Keratosis With Malignant Transformation (Invasive or Noninvasive Squamous Cell Carcinoma Arising in Seborrheic Keratosis): A Clinicopathologic and Immunohistochemical Study of 11 Cases.

ABSTRACT: Seborrheic keratosis is a common benign neoplasm composed of basaloid keratinocytes. However, little is known about the malignant transformation of the tumor. Eleven cases of seborrheic keratosis with malignant transformation were analyzed. The 11 patients included 5 male patients and 6 female patients with a median age of 75 years at diagnosis (68-90 years). The tumors arose at various sites from the scalp (n = 3) to the lower leg (n = 2). The median tumor size was 12 (10-32) and 40 (20-75) mm in 7 noninvasive and 4 invasive cases, respectively. One patient exhibited in-transit skin metastasis. Histopathology of the malignant components resembled porocarcinoma or inverted follicular keratosis. Bowenoid and pagetoid spreading was frequently observed. The malignant components expressed cytokeratin 5/6 (100%) and GATA3 (73%), but not cytokeratin 7 (0%), cytokeratin 19 (9%), BerEP4 (0%), c-kit (0%), and NUT (0%). No significant immunoreactivity of YAP1 was observed in any of the cases. Mutant-type immunostaining of p53 and PTEN was observed in 91% and 82% of the cases, respectively. An increase in p16 expression was seen in 6 (86%) of the 7 cases with noninvasive carcinoma, although a loss of p16 immunoexpression was seen in the invasive carcinoma component in 3 (75%) of the 4 cases. This study demonstrated that seborrheic keratosis can undergo malignant transformation, particularly in large-sized lesions in elderly patients. Malignant components mimic porocarcinoma or inverted follicular keratosis. Malignant transformation induced by TP53 and PTEN mutations and tumor invasion by CDKN2A inactivating mutations are suggested in this study.

Positive predictive value of the clinical diagnosis of T1a-epithelial/lamina propria esophageal cancer depends on lesion size.

OBJECTIVES: Endoscopic resection (ER) is a minimally invasive treatment for esophageal squamous cell carcinoma (ESCC). However, stricture may develop after ER for widespread lesions. Application of ER is justified if these cancers are pathological T1a-epithelial/lamina propria (pEP/LPM) cancers that can be cured by ER. We conducted a study to clarify the association between pathological invasion depth and lesion size or circumference in clinical (c) EP/LPM cancers. METHODS: From our database, we identified patients diagnosed with cEP/LPM ESCC via endoscopic examination who underwent endoscopic or surgical tumor resection. The accuracy of the cEP/LPM ESCC diagnosis was determined by histologically diagnosing cancer invasion depth as a reference standard. RESULTS: Between January 2015 and December 2019, 1271 cancer patients were diagnosed with cEP/LPM ESCC, of which 1195 (94.0%) were correctly diagnosed with pEP/LPM cancer. The positive predictive value (PPV) classified according to lesion sizes of ≤25, 26-49, and ≥50 mm was 95.8% (981/1024 lesions), 89.7% (191/213 lesions), and 67.6% (23/34 lesions), respectively. PPV according to the circumferential extent of <3/4, ≥3/4, and <1, and whole was 94.6% (1164/1230 lesions), 75.0% (24/32 lesions), and 77.8% (7/9 lesions), respectively. In multivariate analysis, the PPV of cEP/LPM ESCC was significantly associated with lesion size (P < 0.001) and male sex. CONCLUSIONS: Between January 2015 and December 2019, 1271 cancer patients were diagnosed with cEP/LPM ESCC, of which 1195 (94.0%) were correctly diagnosed with pEP/LPM cancer. The PPV of cEP/LPM ESCC was related to lesion size. Treatment should be determined considering the high risk of cancer invasion into the muscularis mucosa or deeper in cEP/LPM cancers with a lesion size of ≥50 mm.

Prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer: comparison of diagnostic performances of dedicated breast PET, whole-body PET, and dynamic contrast-enhanced MRI.

PURPOSE: To compare the diagnostic performance of ring-type dedicated breast PET (dbPET), whole-body PET (WBPET), and DCE-MRI for predicting pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). METHODS: This prospective study included 29 women with histologically proven breast cancer on needle biopsy between July 2016 and July 2019 (age: mean 55 years; range 35-78). Patients underwent WBPET followed by ring-type dbPET and DCE-MRI pre- and post-NAC for preoperative evaluation. pCR was defined as an invasive tumor that disappeared in the breast. Standardized uptake values corrected for lean body mass (SULpeak) were calculated for dbPET and WBPET scans. Maximum tumor length was measured in DCE-MRI images. Reduction rates were calculated for quantitative evaluation. Two radiologists independently evaluated the qualitative findings. Reduction rates and qualitative findings were compared between the pCR (n = 7) and non-pCR (n = 22) groups for each modality. Differences in quantitative and qualitative data between the two groups were analyzed statistically. RESULTS: Significant differences were observed in the reduction rates of dbPET and DCE-MRI (P = 0.01 and 0.03, respectively) between the two groups. Univariate and multiple logistic regression analyses revealed that SULpeak reduction rates in WBPET and dbPET (P = 0.02 and P = 0.01, respectively) and in dbPET (odds ratio, 16.00; 95% CI 1.57-162.10; P = 0.01) were significant indicators associated with pCR, respectively. No between-group differences were observed in qualitative findings in the three modalities. CONCLUSION: SULpeak reduction rate of dbPET > 82% was an independent indicator associated with pCR after NAC in breast cancer.

Signet-ring cell/histiocytoid carcinoma of the axilla: a clinicopathological and genetic analysis of 11 cases, review of the literature, and comparison with potentially related tumours.

AIMS: The aim of this study was to determine the clinicopathological and genetic characteristics of axillary signet-ring cell/histiocytoid carcinoma (SRCHC) and the relationship between axillary SRCHC, eyelid SRCHC, and conventional apocrine carcinoma (AC). METHODS AND RESULTS: Eleven cases of axillary SRCHC, four cases of eyelid SRCHC, eight cases of axillary AC and five cases of invasive lobular carcinoma (ILC) were retrieved. Additionally, 14 axillary and 43 eyelid SRCHC cases from the literature were reviewed. Male predominance was prominent for axillary SRCHC (24:1) and eyelid SRCHC (42:5). Axillary SRCHC formed a circumscribed plaque or nodule, unlike eyelid SRCHC. Lymph node metastasis was predominantly seen in axillary SRCHC cases (72%, 18/25), but not in eyelid SRCHC cases (19%, 9/47). Axillary SRCHC and eyelid SRCHC were histopathologically similar and showed rare tubular formations. Immunoexpression of cytokeratin 7, cytokeratin 19, mucin 1, mucin 5AC, BerEP4 and androgen receptor was seen in all tested cases of the four diseases. Oestrogen and progesterone receptors were negative in both types of SRCHC and AC, but were strongly positive in ILCs. Complete loss of E-cadherin expression was seen in approximately one-quarter of both types of SRCHC and in all ILCs. PIK3CA mutations were detected in all three sequenced cases (two axillary SRCHCs and one eyelid SRCHC). CONCLUSION: The histopathological, immunohistochemical and genetic findings suggest that both types of SRCHC are phenotypic variants of AC, although there are differences in sex, macroscopic findings and the frequency of lymph node metastasis among the three. In contrast, ILC differs from the other three tumour types.

Bcl-2-negative IGH-BCL2 translocation-negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl-2-positive IGH-BCL2 translocation-positive follicular lymphoma.

AIMS: Follicular lymphoma (FL), comprising a minor subset of primary thyroid lymphomas, is divided into two groups based on Bcl-2 expression and IGH-BCL2 translocation. The clinicopathological features exhibited by Bcl-2-negative IGH-BCL2 translocation-negative FL of the thyroid (Bcl-2- /IGH-BCL2- tFL) are different from those of conventional FL; however, its lymphomagenesis remains unclear. Here, we collected samples from seven patients with Bcl-2- /IGH-BCL2- tFL to investigate their epigenetic and genetic aberrations. METHODS AND RESULTS: The immunohistochemical profiles of epigenetic modifiers and the methylation status of histones were examined, including EZH2, MLL2/KMT2D, CBP/CREBBP, EP300, H3K27me3 and H3K4me3, in Bcl-2- /IGH-BCL2- tFL and Bcl-2-positive IGH-BCL2 translocation-positive FL of the thyroid (Bcl-2+ /IGH-BCL2+ tFL). Most Bcl-2- /IGH-BCL2- tFLs retained the positivity of epigenetic modifiers and lower expression of H3K27me3, although Bcl-2+ /IGH-BCL2+ tFLs exhibited aberrant immunohistochemical patterns of EZH2 and CBP/CREBBP and overexpression of H3K27me3. Samples from seven cases were further analysed using targeted sequencing, focusing on the exons of 409 key tumour suppressor genes and oncogenes. Bcl-2- /IGH-BCL2- tFLs do not have pathogenic mutations of epigenetic modifiers, such as EZH2, MLL2/KMT2D, MLL3/KMT2C, EP300 and ARID1A, which have been reported in FLs in the literature, whereas Bcl-2+ /IGH-BCL2+ tFLs are probably pathogenic/pathogenic missense mutations or frameshift mutations of these genes. Additionally, novel mutations in TET2 and EP400 were detected in Bcl-2- /IGH-BCL2- tFLs. CONCLUSIONS: Different genetic and epigenetic abnormalities might be involved in the oncogenesis of Bcl-2- /IGH-BCL2- tFLs from Bcl-2+ /IGH-BCL2+ tFLs and other FLs.

Favorable long-term outcomes of endoscopic resection for nonampullary duodenal neuroendocrine tumor.

BACKGROUND AND AIM: The long-term outcomes of endoscopic resection for nonampullary duodenal neuroendocrine tumors are limited. We aimed to clarify it. METHODS: Consecutive patients with nonampullary duodenal neuroendocrine tumors endoscopically treated at our institute between January 2005 and June 2020 were included in this retrospective study. En bloc and R0 resection rates and adverse events were evaluated as short-term outcomes of endoscopic resection. The 5-year overall and recurrence-free survival rates of patients after endoscopic resection were calculated as long-term outcomes. RESULTS: Of 34 patients with 34 lesions, 33 patients (97%) underwent endoscopic mucosal resection, and one (3%) underwent endoscopic submucosal dissection. En bloc resection was achieved in 33 lesions (97%). R0 resection was achieved in 20 lesions (59%). The median tumor size was 6 mm (range: 3-13). Thirty-one lesions (91%) and three lesions (9%) were classified as G1 and G2, respectively. Lymphovascular invasion was observed in six lesions (18%). Intraprocedural perforation occurred in four patients (12%) who were conservatively treated with endoscopic closure. All 34 patients were followed up without additional treatment after endoscopic resection, and no recurrence or metastasis developed during the median follow-up period of 47.9 months (range: 9.0-187.1). The 5-year overall survival and recurrence-free survival rates were 87.1% and 100%, respectively. CONCLUSIONS: Endoscopic resection provided a favorable long-term prognosis for patients with nonampullary duodenal neuroendocrine tumors without lymph node metastasis.