The significance of Hippo pathway protein expression in oral squamous cell carcinoma.

Introduction: The Hippo pathway consists of mammalian sterile 20-like kinase 1/2 (MST1/2), large tumor suppressor 1/2 (LATS1/2), and yes-associated protein (YAP)1. Herein, we present the first report on the significance of major Hippo pathway protein expression in oral squamous cell carcinoma (OSCC). Methods: The analyses included oral epithelial dysplasia (OED, n = 7), carcinoma in situ (CIS, n = 14), and oral squamous cell carcinoma (OSCC, n = 109). Results: Cytoplasmic expression of MST1, LATS1, and LATS2 was low in OED, CIS, and OSCC. The cytoplasmic expression of MST2 was high in OED (5/7 cases), CIS (9/14 cases), and poorly differentiated OSCC (8/8 cases) but was low/lost in a proportion of differentiated OSCC (60/101 cases). The expression of YAP1 was associated with differentiation; low YAP expression was significantly more frequent in well-differentiated OSCC (35/71 cases), compared to moderately and poorly differentiated OSCC (11/38 cases). An infiltrative invasion pattern was associated with a high expression of MST2 and high expression of YAP1. The high expression of YAP1 was associated with features of epithelial-to-mesenchymal transition (EMT), such as the loss of E-cadherin and high expression of vimentin, laminin 5, and Slug. High expression of protein arginine methyltransferase (PRMT) 1 or 5, which positively regulates YAP activity, was associated with the high expression of YAP1 (p < 0.0001). Conclusion: Among the major Hippo pathway proteins, MST2 displayed a distinctive expression pattern in a significant proportion of differentiated OSCC, suggesting a possible differential role for MST2 depending on the course of OSCC progression. A high YAP1 expression may indicate aggressive OSCC with EMT via PRMTs at the invasive front.

H3K27me3 deficiency in dedifferentiated carcinoma and carcinosarcoma of the endometrium.

The present study immunohistochemically investigated trimethylation of lysine 27 of histone 3 (H3K27me3) expression in 769 endometrial carcinomas and 196 uterine mesenchymal tumors. One dedifferentiated endometrial carcinoma (DEC) and one carcinosarcoma showed H3K27me3 deficiency that was limited to undifferentiated and sarcomatous components, respectively. Switch/sucrose nonfermenting (SWI/SNF) complex subunits (SMARCA4, SMARCB1, and ARID1A/1B) and mismatch repair proteins were proficient in both tumors. The dimethylation of H3K27 (H3K27me2) was deficient in the undifferentiated component, whereas the sarcomatous component had scattered H3K27me2-positive cells. CXorf67, which inhibits PRC2 function, was diffusely expressed in the sarcomatous component. CXorf67 was negative in the undifferentiated component, which was submitted to a genetic analysis and showed no alterations in PRC2 core subunits or H3K27. The present results suggest H3K27 methylation dysregulation as a cause of SWI/SNF-proficient DEC and carcinosarcoma and imply differences in their level of and the mechanisms underlying H3K27 methylation dysregulation.

Transduodenal ampullectomy for early ampullary cancer: Clinical management, histopathological findings and long-term outcomes at a single center.

BACKGROUND: Transduodenal ampullectomy has been attempted in ampullary tumors, including early ampullary cancer. However, the indication and extent of transduodenal ampullectomy with curative intent remain controversial. Herein, we address the perioperative and long-term outcomes of patients with early ampullary cancer who underwent transduodenal ampullectomy at a single center. METHODS: We retrospectively enrolled 10 early ampullary cancer patients who underwent transduodenal ampullectomy and 11 early ampullary cancer patients who underwent subtotal stomach-preserving pancreatoduodenectomy at Saitama Cancer Center between October 2008 and May 2021. Among this cohort, we analyzed the perioperative outcomes and long-term outcomes. RESULTS: In terms of the perioperative outcomes between the transduodenal ampullectomy and subtotal stomach-preserving pancreatoduodenectomy groups, the transduodenal ampullectomy group exhibited a shorter operating time (244 minutes vs 390 minutes, P = .003), less intraoperative blood loss (67.5 grams vs 774 grams, P = .006) and shorter length of postoperative hospital stay (15 days vs 33 days). With respect to the postoperative nutrition status, the transduodenal ampullectomy group exhibited less postoperative weight loss (0.67% vs 8.95%, P = .021), a better Controlling Nutritional Status score (1.0 vs 2.1, P = .011) and a better Prognostic Nutritional Index score (42.9 vs 40.9, P = .018). The 5-year survival in the adenoma with high-grade dysplasia and T1 ampullary cancer which invaded the mucosal layer groups was 100%, whereas the median survival time in the T1 ampullary cancer which invaded the sphincter of Oddi group was 20.7 months (P = .0028). CONCLUSION: Transduodenal ampullectomy is assumed to be a feasible and effective surgical procedure for the treatment of selected patients with early ampullary cancer, including patients with adenoma with high-grade dysplasia or T1 ampullary cancer which invaded the mucosal layer ampullary cancer.

Genetic and phenotypic determinants of morphologies in 3D cultures and xenografts of lung tumor cell lines.

We previously proposed the classification of lung adenocarcinoma into two groups: the bronchial epithelial phenotype (BE phenotype) with high-level expressions of bronchial epithelial markers and actionable genetic abnormalities of tyrosine kinase receptors and the non-BE phenotype with low-level expressions of bronchial Bronchial epithelial (BE) epithelial markers and no actionable genetic abnormalities of tyrosine kinase receptors. Here, we performed a comprehensive analysis of tumor morphologies in 3D cultures and xenografts across a panel of lung cancer cell lines. First, we demonstrated that 40 lung cancer cell lines (23 BE and 17 non-BE) can be classified into three groups based on morphologies in 3D cultures on Matrigel: round (n = 31), stellate (n = 5), and grape-like (n = 4). The latter two morphologies were significantly frequent in the non-BE phenotype (1/23 BE, 8/17 non-BE, p = 0.0014), and the stellate morphology was only found in the non-BE phenotype. SMARCA4 mutations were significantly frequent in stellate-shaped cells (4/4 stellate, 4/34 non-stellate, p = 0.0001). Next, from the 40 cell lines, we successfully established 28 xenograft tumors (18 BE and 10 non-BE) in NOD/SCID mice and classified histological patterns of the xenograft tumors into three groups: solid (n = 20), small nests in desmoplasia (n = 4), and acinar/papillary (n = 4). The latter two patterns were characteristically found in the BE phenotype. The non-BE phenotype exhibited a solid pattern with significantly less content of alpha-SMA-positive fibroblasts (p = 0.0004) and collagen (p = 0.0006) than the BE phenotype. Thus, the morphology of the tumors in 3D cultures and xenografts, including stroma genesis, reflects the intrinsic properties of the cancer cell lines. Furthermore, this study serves as an excellent resource for lung adenocarcinoma cell lines, with clinically relevant information on molecular and morphological characteristics and drug sensitivity.

Conversion surgery for initially unresectable advanced biliary tract cancer treated with gemcitabine plus cisplatin combination chemotherapy: a case report and literature review.

Recently, the number of reports describing patients with initially unresectable biliary tract cancer (BTC) who underwent resection in the form of conversion surgery is increasing. Gemcitabine plus cisplatin (GC) combination therapy has been reported to significantly prolong the median survival time from 8.1 to 11.7 months compared with conventional gemcitabine therapy in patients with unresectable BTC. We report the case of a patient with unresectable BTC who underwent conversion surgery with a partial response to GC combination therapy. A 78-year-old woman was diagnosed with unresectable BTC with invasion of the right hepatic artery by lymph node metastasis and liver metastases. The patient received GC combination therapy. After 6 cycles of chemotherapy, the patient achieved a partial response. The radiological findings revealed a marked shrinkage in the primary lesion and the disappearance of lymph node and liver metastases. Therefore, the patient underwent conversion surgery, including biliary tract resection and regional lymph node dissection. For postoperative follow-up, the patient was monitored without receiving adjuvant chemotherapy. The patient had not exhibited recurrence during the 12-month follow-up period. We report the case of a patient with unresectable BTC who underwent conversion surgery with a partial response to GC combination therapy.

Clinicopathological and Prognostic Significance of Stromal Patterns in Oral Squamous Cell Carcinoma.

Background: Stromal patterns (SP), especially desmoplastic reactions, have recently gained attention as indicators of malignant potential in cancer. In this study, we explored the clinicopathological and prognostic significance of the SP in oral squamous cell carcinoma (OSCC). Materials and Methods: We reviewed 232 cases of surgically resected OSCC that were not treated with neoadjuvant chemoradiotherapy. We categorized the SP of the OSCC into four groups: immune/inflammatory (84 cases), mature (14 cases), intermediate (78 cases), or immature (56 cases). Results: The SP category was significantly associated with various clinicopathological factors, such as the histological grade, lymphovascular invasion, neural invasion, and a diffuse invasion pattern. For each of the factors, the immune/inflammatory type was associated with favorable categories, while the immature type was associated with unfavorable categories (p ≤ 0.001). The SP category was also shown to be a prognostic predictor: the 5-year relapse-free survival (RFS) rate was 72.0% for the immune/inflammatory type, 66.7% for the intermediate/mature type, and 31.2% for the immature type (p < 0.0001), and the 5-year overall survival (OS) rate was 85.1% for the immune/inflammatory type, 76.4% for the intermediate/mature type, and 50.0% for the immature type (p < 0.0001). In multivariate analyses, the SP category was identified as an independent prognostic factor for RFS and OS. Conclusion: Our SP categorization method provides valuable prognostic information in OSCC.

ZEB1 expression is frequently detected in undifferentiated and de-differentiated carcinomas, but is not specific among endometrial carcinomas.

AIMS: The pathological diagnosis of undifferentiated and de-differentiated endometrial carcinomas (UC/DCs) is prognostically important. However, undifferentiated components may be confused with other subtypes, particularly grade 3 endometrioid carcinomas (G3ECs). Zinc finger E-box binding homeobox 1 (ZEB1) has recently been identified as a promising marker because it is frequently expressed in the undifferentiated components of UC/DCs, but not in other carcinomas. Therefore, we herein evaluated the diagnostic utility of ZEB1 with an emphasis on distinguishing between UC/DCs and G3ECs using an expanded cohort of endometrial carcinomas and carcinosarcomas. METHODS AND RESULTS: Immunostaining for ZEB1 was performed on whole-tissue sections of 19 UC/DCs, 194 non-UC/DC endometrial carcinomas and 29 carcinosarcomas. Staining was defined as negative (< 5%), focal (5-50%) and diffuse expression (> 50%). ZEB1 was expressed in 84% of the undifferentiated components of UC/DCs (diffuse in 14, focal in two). Focal expression was observed in eight non-UC/DC endometrial carcinomas and diffuse expression in seven, with the latter comprising G3ECs (four of 76), serous carcinoma (one of 37), clear cell carcinoma (one of 21) and neuroendocrine carcinoma (one of three). Epithelial differentiation was morphologically and immunohistochemically less evident in G3ECs and neuroendocrine carcinoma with diffuse ZEB1 expression. All carcinosarcomas showed diffuse ZEB1 expression in their sarcomatous components. CONCLUSION: Immunostaining for ZEB1 was sufficiently sensitive to detect undifferentiated components. Diffuse ZEB1 expression showed high specificity for distinguishing between undifferentiated components and G3ECs; however, ZEB1 expression was not entirely specific to UC/DCs. The integration of ZEB1 into the diagnosis of UC/DCs requires careful examination to exclude other tumours, such as less differentiated G3ECs, neuroendocrine carcinomas and carcinosarcomas.

Expression and localisation of methylthioadenosine phosphorylase (MTAP) in oral squamous cell carcinoma and their significance in epithelial-to-mesenchymal transition.

Methylthioadenosine phosphorylase (MTAP) is a rate-limiting enzyme in the methionine salvage pathway, which recycles one carbon unit that is lost during polyamine synthesis back into the methionine cycle. Although MTAP deficiency has been reported in various tumours, MTAP is overexpressed and might promote oncogenesis in other cancers, including prostate and colon cancer. Currently, little is known about the MTAP status of oral squamous cell carcinoma (OSCC). In this study, we immunohistochemically examined the expression of MTAP in surgically resected oral epithelial dysplasia (OED, n=7), carcinoma in situ (CIS) (n=16), and OSCC (n=118). In the normal epithelium, MTAP was only weakly expressed in the cytoplasm of the basal layer cells. In OED, CIS, and OSCC, MTAP was uniformly expressed in the cytoplasm of the dysplastic and cancer cells. In addition to cytoplasmic MTAP expression, 45 of 118 cases (38.1%) exhibited increased nuclear expression of MTAP in the cancer cells at the invasive front. Statistical analysis showed that the concomitant nuclear and cytoplasmic expression of MTAP was associated with a high budding score (p=0.0023); poor differentiation (p=0.0044); aggressive invasion patterns (p=0.0001); and features of epithelial-to-mesenchymal transition (EMT), such as loss of E-cadherin expression (p=0.0003) and upregulated expression of vimentin (p=0.0002), slug (p=0.0002), and laminin 5 (p<0.0001). High expression of protein arginine methyltransferase 1 or 5, the functions of which are reported to be inhibited in MTAP-deficient cancer, was associated with the concomitant nuclear and cytoplasmic expression of MTAP (p<0.0001). Concomitant nuclear and cytoplasmic expression of MTAP was marginally significantly associated with worse 5-year relapse-free survival (p=0.045). These findings suggest that MTAP not only plays a role in the oncogenesis of OSCC, but that it might also make it more aggressive by inducing EMT through its activity in the methionine salvage pathway.

Colloid carcinoma derived from intraductal papillary mucinous neoplasm of the pancreatic head with calcification: A case report and literature review.

BACKGROUND: Colloid carcinoma derived from intraductal papillary mucinous neoplasm (IPMN) of the pancreatic head with prominent calcification is exceedingly rare. Only a few studies about this entity have been reported in the literature. Therefore, its biological behavior, appropriate treatment modalities, and overall patient prognosis remain largely unclear. In this report, we present a case of a resected colloid carcinoma derived from IPMN with prominent calcification. In addition, we review the relevant literature and discuss the clinical management of colloid carcinoma derived from IPMN with prominent calcification, including the histopathological features. CASE PRESENTATION: A 75-year-old man presented with a pancreatic tumor measuring 58 mm on the head of the pancreas that was incidentally detected by abdominal ultrasonography. Abdominal computed tomography and endosonography revealed a multilobular cystic lesion with a 17 mm mural nodule in the pancreatic head. Furthermore, prominent calcification was observed on part of the cyst wall. Magnetic resonance cholangiopancreatography showed a multilobular cyst in the branch duct lacking communication between the cystic lesion and the main pancreatic duct. Thus, the lesion was diagnosed as intraductal papillary mucinous carcinoma (IPMC) with a preoperative classification of T1N0M0 stage IA according to the 8th Union for International Cancer Control (UICC) guidelines, and the patient underwent conventional pancreatoduodenectomy. The resected specimen was microscopically found to contain colloid carcinoma, probably derived from IPMN. In addition, marked calcification was confirmed in the partition wall of the cystic mass. The postoperative course was uneventful, and no evidence of recurrence or metastasis was observed after 10 months of follow-up. CONCLUSIONS: We consider that colloid carcinoma derived from IPMN should be differentially diagnosed as a pancreatic multilobular cystic lesion with prominent calcification that shows no sign of systemic chronic pancreatitis.

Infrequent loss of SMARCA4, SMARCA2, and SMARCB1 expression in uterine mesenchymal tumors.

SMARCA4-deficient uterine sarcoma (SMARCA4-DUS) was recently proposed as a new entity of uterine sarcoma. Reported cases of SMARCA4-DUS showed the loss of SMARCA4 and SMARCA2 expression. However, the prevalence of their deficiency in uterine mesenchymal tumors remains unclear. This study immunohistochemically examined the expression of SMARCA4, SMARCA2, and SMARCB1 in 206 uterine mesenchymal tumors and detected a round cell tumor with the loss of SMARCA4 and SMARCA2 and a low-grade endometrial stromal sarcoma with SMARCA4 deficiency. The remaining 204 cases, including 170 smooth muscle tumors, 22 endometrial stomal nodule/sarcomas, seven undifferentiated uterine sarcomas, two adenosarcomas, one uterine tumor resembling ovarian sex cord tumor, and two perivascular epithelioid cell tumors, retained the expression of both SMARCA4 and SMARCA2. All tumors retained SMARCB1 expression. The round cell tumor with the loss of SMARCA4 and SMARCA2 was composed of diffuse small round cell growth with follicle-like spaces, which resembled small cell carcinoma of the ovary, hypercalcemic type. Immunohistochemically, the tumor showed the proficient expression of mismatch repair proteins and wild-type p53 expression, which favored SMARCA4-DUS; however, the tumor harbored the PIK3CA mutation, and thus, was reclassified as undifferentiated endometrial carcinoma. In conclusion, SMARCA4, SMARCA2, and SMARCB1 were rarely deficient in uterine mesenchymal tumors. SMARCA4 immunohistochemistry has potential in the diagnosis of SMARCA4-DUS with the exclusion of some tumors showing its deficiency, such as endometrial stromal sarcoma and undifferentiated carcinoma. Undifferentiated carcinoma may show an indistinguishable morphology and immunophenotype from SMARCA4-DUS, and thus, molecular analysis is required for their distinction in diagnostic practice.

Ovarian clear cell carcinoma with an immature teratoma component showing ARID1A deficiency and an identical PIK3CA mutation.

We herein report a case of ovarian clear cell carcinoma with an immature teratoma component that exhibited aggressive behavior. A 47-year-old woman presented with abdominal distention, and computed tomography detected a cystic mass on the right ovary. The resected mass had mural nodules, most of which showed a pale-yellow appearance; some nodules had a heterogeneous cut surface with bright yellow and white areas. Histologically, the former nodules were composed of clear cell carcinoma, while the latter contained teratomatous tissues, such as immature skeletal muscle, adipose tissue, and enteric glands. The tumor was staged as pT1c. Despite adjuvant chemotherapy and additional lymph node dissection, she had local recurrence and multiple liver metastasis 6 months after the first surgery. The disease rapidly progressed, and she died 9 months after the first surgery. Clear cell carcinoma and immature teratoma both showed ARID1A deficiency and an identical PIK3CA mutation, which suggested their clonal relationship.

Pancreas-preserving double pancreaticogastrostomy after traumatic injury to the head of the pancreas: a case report.

Traumatic injury to the main pancreatic duct requires surgical treatment, but optimal management strategies have not been established. In patients with isolated pancreatic injury, the pancreatic parenchyma must be preserved to maintain long-term quality of life. We herein report a case of traumatic pancreatic injury with main pancreatic duct injury in the head of the pancreas. Two years later, the patient underwent a side-to-side anastomosis between the distal pancreatic duct and the jejunum. Eleven years later, he presented with abdominal pain and severe gastrointestinal bleeding from the Roux limb. Emergency surgery was performed with resection of the Roux limb along with central pancreatectomy. We attempted to preserve both portions of the remaining pancreas, including the injured pancreas head. We considered the pancreatic fluid outflow tract from the distal pancreatic head and performed primary reconstruction with a double pancreaticogastrostomy to avoid recurrent gastrointestinal bleeding. The double pancreaticogastrostomy allowed preservation of the injured pancreatic head considering the distal pancreatic fluid outflow from the pancreatic head and required no anastomoses to the small intestine.

BRG1, INI1, and ARID1B Deficiency in Endometrial Carcinoma: A Clinicopathologic and Immunohistochemical Analysis of a Large Series From a Single Institution.

Switch/sucrose nonfermenting complex subunits, such as BRG1, INI1, and ARID1B, are inactivated in a subset of endometrial undifferentiated carcinoma and dedifferentiated carcinoma (DC). Limited information is currently available on their prevalence in other subtypes or the nosological status of endometrial carcinoma with their deficiencies. This study immunohistochemically examined the expression status of BRG1, INI1, and ARID1B using 570 archived cases of endometrial carcinoma and carcinosarcoma resected at a single institution. We identified 1 BRG1-deficient undifferentiated carcinoma, 8 BRG1/INI1/ARID1B-deficient DC, and 3 BRG1-deficient clear-cell carcinomas. None of the cases of endometrioid and serous carcinomas or carcinosarcoma showed deficiencies of these subunits. We then compared 8 BRG1/INI1/ARID1B-deficient DC with 6 BRG1/INI1/ARID1B-intact DC and 28 carcinosarcomas, the latter of which was often confused with DC. Histologically, BRG1/INI1/ARID1B-intact and BRG1/INI1/ARID1B-deficient DC shared a monotonous solid appearance with rhabdoid and epithelioid cells and a myxoid stroma; however, abrupt keratinization and cell spindling was absent in BRG1/INI1/ARID1B-deficient tumors. The median overall survival of patients with BRG1/INI1/ARID1B-deficient DC was 3.8 months, which was worse than those with BRG1/INI1/ARID1B-intact DC (P=0.008) and with carcinosarcoma (P=0.004). BRG1/INI1/ARID1B-deficient DC may be a separate entity with an aggressive behavior to be distinguished from BRG1/INI1/ARID1B-intact DC and carcinosarcoma. Regarding clear-cell carcinoma (n=12), BRG1 deficiency appeared to be mutually exclusive with abnormal ARID1A, BRM, and p53 expression. Further studies are needed to clarify whether BRG1 deficiency plays a role in the pathogenesis of clear-cell carcinoma.

Preoperative diagnosis of a gastric extremely well-differentiated adenocarcinoma: A case report.

INTRODUCTION: Gastric adenocarcinomas with low grade atypia may be difficult to diagnose as gastric cancer by preoperative biopsy. We report an extremely well-differentiated adenocarcinoma (EWDA) of the stomach which appeared like a submucosal tumor diagnosed by preoperative endoscopic submucosal dissection. PRESENTATION OF CASE: A 70-year-old male was referred with a 3-month history of a submucosal-appearing lesion in the gastric wall found on endoscopy. Biopsies of the lesion were performed and were inconclusive for neoplasia. Endoscopic ultrasonography showed a low echoic tumor growing into the fourth layer of the gastric wall. It was difficult to identify the tumor by repeat biopsy. Endoscopic submucosal dissection of the lesion was performed and revealed adenocarcinoma, and laparoscopic total gastrectomy was performed. Histopathologic evaluation showed that the tumor was stage IIA (T3N0M0). There is no recurrence 12 months after resection. DISCUSSION: Gastric EWDAs are rare lesions, accounting for 0.6% of all gastric cancers. It is difficult to diagnose gastric EWDA especially if it appears like a submucosal tumor. This lesion was finally diagnosed by endoscopic submucosal dissection. CONCLUSION: Endoscopic submucosal dissection may facilitate establishing the preoperative diagnosis of a tumor thought to be a gastric EWDA based on its endoscopic appearance and pathological findings.

Goblet cell carcinoid of the rectum: a case report.

BACKGROUND: Goblet cell carcinoid (GCC) is a neuroendocrine tumor usually found in the appendix. GCCs exhibit characteristic findings with mixed endocrine-exocrine features such as staining positive for neuroendocrine markers and producing mucin. The primary GCC of the rectum is exceedingly rare. CASE PRESENTATION: A 77-year-old Japanese male presented with hematochezia. Anal tenderness and a hard mass in the anal canal were found on the digital rectal examination, and colonoscopy was performed. Colonoscopy showed an irregularly shaped mass in the anal canal. Biopsy showed mixed features including adenocarcinoma in situ, well-differentiated adenocarcinoma, and mucinous carcinoma with invasive proliferation. No metastatic lesions were found on the computed tomography scan. Pelvic magnetic resonance imaging scan showed extramural growth of a tumor on the ventral side of the rectum without invasion to the prostate. Laparoscopic abdominoperineal resection was performed. The final diagnosis was well-differentiated adenocarcinoma in the mucosa and goblet cell carcinoid from the submucosa to the adventitia of the rectum. The patient was discharged from the hospital on postoperative day 16. Six months after resection, a computed tomography scan revealed multiple metastatic lesions in the liver. Several chemotherapy regimens were given, and the patient has stable disease 27 months after surgery. CONCLUSION: We present a patient with rectal GCC with metachronous liver metastases. Since GCC grows intramurally and is biologically aggressive compared to typical carcinoid lesions, the disease is usually diagnosed at an advanced stage. The development of optimal adjuvant chemotherapy is needed for those patients.

Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas.

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor-1 (TTF-1)/NK2 homeobox 1 (NKX2-1)-positive terminal respiratory unit (TRU) types and rarely in non-TRU types. To elucidate the molecular characteristics of the major subtypes of non-TRU-type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non-TRU types). A characteristic of non-TRU-type cell lines was the strong expression of TFF-1 (trefoil factor-1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF-1 was positive in 31 cases (13%). Expression of TFF-1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF-1 correlated with the expression of HNF4-α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF-1/NKX2-1 (P < .0001). These results indicate that TFF-1 is characteristically expressed in non-TRU-type adenocarcinomas with gastrointestinal features. The TFF-1-positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF-1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF-1 inhibited cell proliferation and soft-agar colony formation and induced apoptosis in a TFF-1-high and KRAS-mutated lung adenocarcinoma cell line. These results indicate that TFF-1 is not only a biomarker, but also a potential molecular target for non-TRU-type lung adenocarcinomas.

Desmoplastic small round cell tumor showing solid proliferation with limited desmoplasia and confusing immunohistochemical findings: an autopsy report.

We herein report a variant case of desmoplastic small round cell tumor (DSRCT) showing limited desmoplasia and confusing immunohistochemical findings. A 26-year-old male was referred for multiple abdominal masses. Laparoscopic biopsy showed only the solid proliferation of small round cells, and he was initially diagnosed with small cell carcinoma. At autopsy, the tumor spread diffusely throughout the abdominal and pelvic cavities. Although the tumor was composed of a predominantly solid pattern of small round cells, multiple samples revealed a fibrous stroma in limited areas only. While immunohistochemistry showed the diffuse expression of desmin, CD99, and bcl-2, epithelial differentiation was unclear with few cytokeratin-positive cells and no staining for the epithelial membrane antigen. Although fluorescence in situ hybridization analysis indicated the EWSR1 gene rearrangement, we were unable to exclude Ewing sarcoma considering the morphological and immunohistochemical findings. The diagnosis of DSRCT was confirmed with a reverse transcription-polymerase chain reaction for EWSR1-WT1 fusion transcripts. DSRCT must be included in a differential diagnosis of small round cell tumors even if desmoplasia is not immediately detected, and thorough sampling and a molecular analysis are mandatory.