Mixed hepatocellular carcinoma and high-grade neuroendocrine neoplasm with ambiguous histopathological features: a case report.

Well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC) are distinct entities with different biological behavior. However, difficult cases showing equivocal morphology have been reported in some organs. Herein, we report a case of primary hepatic neuroendocrine neoplasm (NEN) with ambiguous histopathological features admixed with conventional hepatocellular carcinoma (HCC). A 70-year-old man with untreated chronic hepatitis B underwent left medial sectionectomy because of two incidental liver masses. On pathological examination, one of the resected tumors had intermingling NEN and HCC components. The NEN component consisted of relatively uniform tumor cells proliferating in trabecular, cord-like, or solid patterns with peripheral nuclear palisading. The tumor cells were immunopositive for synaptophysin, chromogranin A, cluster of differentiation 56 (CD56), and focally hepatocyte paraffin 1. p53 showed wild-type expression. The Ki-67 labeling index was 27% at the hot spot. Eleven months after the surgery, he died of a cerebral hemorrhage without evidence of recurrent liver cancer. The intermediate degree of differentiation and the modest proliferative activity can challenge the distinction between NEC and NET G3. While the coexisting HCC indicates NEC rather than NET in a pathogenetic viewpoint, such ambiguous tumor may not be as aggressive as typical NECs.

A Case of GATA3 Positive Pleomorphic Liposarcoma, Epithelioid Variant: A Diagnostic Pitfall.

Pleomorphic liposarcoma is a rare malignant adipocytic tumor showing undifferentiated pleomorphic sarcoma morphology with various degrees of epithelioid features. It is sometimes difficult to distinguish from carcinoma metastasis. Immunohistochemical panel is very important for differential diagnosis; however, there is a risk that unexpected staining could lead to misinterpretation. We report a pleomorphic liposarcoma, epithelioid variant, in an 88-year-old man, with tricky-positive staining for GATA3. Histological examination revealed a tumor with epithelioid morphology. The tumor consists of solid sheets of epithelioid tumor cells with focal aggregates of pleomorphic lipoblasts. Immunohistochemically, the adipocytic tumor cell areas were positive for S100 protein, and the epithelioid tumor cells showed CAM 5.2 positivity. GATA3 was diffusely positive. The combination of CAM 5.2 and GATA3 staining suggested the possibility of metastatic cancer, but systemic clinical examinations did not detect any presence of a primary tumor, including urinary bladder, breasts, and salivary glands. The pathological diagnosis of pleomorphic liposarcoma, epithelioid variant, was made because of the presence of malignant lipoblasts. Our report may contribute for differential diagnosis of pleomorphic liposarcoma, epithelioid variant, with unexpected positive immunoreaction for GATA3.

Rapid progression of a granulocyte colony-stimulating factor-producing liver tumor metastasized from esophagogastric junction cancer: A case report and literature review.

The current study presents the case of a 72-year-old woman with a rapidly enlarged liver metastasis from esophagogastric junction (EGJ) cancer, accompanied by progressive leukocytosis (47,680/µl) and elevated serum granulocyte colony-stimulating factor (G-CSF; 779 pg/ml). The patient underwent right hemihepatectomy 26 months after a total gastrectomy. On the seventh post-operative day the patient's leukocyte count and serum G-CSF level decreased to 4,280/µl and ≤19.5 pg/ml, respectively. Histologically, the lesion was a well to moderately differentiated adenocarcinoma similar to the primary lesion. Therefore, this tumor was clinically diagnosed as a G-CSF-producing liver metastasis from EGJ cancer, although immunohistochemical staining for G-CSF was negative. A right pulmonary nodule detected simultaneously with the hepatic mass was resected four months following the hepatectomy and was diagnosed as a pulmonary metastasis. The patient's leukocyte count was normal at the time of her initial surgery for EGJ cancer, and her clinical course varied for different metastatic sites. The liver metastasis was accompanied by progressive leukocytosis and elevated serum G-CSF and demonstrated rapid tumor growth during a six-month period, whereas the non-G-CSF-producing pulmonary metastasis grew slowly during the same period. In addition 21 reported cases of G-CSF-producing upper gastrointestinal tract cancer were reviewed to elucidate the clinicopathological features of this disease.

Clinical implications of the proliferative ability of the squamous component regarding tumor progression of adenosquamous carcinoma of the pancreas: A preliminary report.

OBJECTIVES: The objectives of this study were to examine the clinicopathological characteristics of patients with adenosquamous carcinoma of the pancreas (ASCP) and assess whether the proliferative ability of the squamous cell carcinoma (SCC) component contributes to either its proportion within the tumor or tumor progression. METHODS: We retrospectively reviewed 12 patients with resected ASCP and compared their clinicopathological characteristics with those of 161 patients with adenocarcinoma of the pancreas (ACP). The Ki-67 indexes of the separate ASCP components were assessed. RESULTS: All the clinicopathological characteristics and outcomes were similar between the ASCP patients and ACP patients. Among the 12 ASCP cases, nine exhibited higher Ki-67 levels in the SCC component than in the corresponding adenocarcinoma (AC) component at primary sites (P = 0.022). The component with a higher Ki-67 level coincided with the predominant component at the primary site in nine of 11 patients. In all 10 patients who presented lymph node metastasis, the metastases almost entirely consisted of either the SCC or AC component. The SCC component was absent from metastatic lymph nodes in five of 10 patients even though the Ki-67 levels at the primary site in four of these patients were higher in the SCC component than in the AC component. CONCLUSIONS: The enhanced proliferative ability of the SCC component of ASCP is reflected by its proportion within the tumor. However, other biological factors might contribute to metastasis in ASCP.

Adenosquamous carcinoma in the biliary tract: association of the proliferative ability of the squamous component with its proportion and tumor progression.

OBJECTIVES: The purpose of this study was to evaluate the association of the proliferative ability of squamous cell carcinoma (SCC) component with its proportion and tumor progression in adenosquamous carcinoma (ASC) in the biliary tract. METHODS: Nine patients with ASC in the biliary tract (four each in the gallbladder and the extrahepatic bile duct and one in the ampulla of Vater) who underwent surgical resection were retrospectively reviewed. RESULTS: The proportion of the SCC component in the primary sites ranged from 30% to 95%. The Ki-67 index of the SCC component was higher than that of the adenocarcinoma component in all cases, regardless of the component ratio in the patients' primary lesions. Predominance of the SCC component in the advancing region of the tumor, in angiolymphatic invasion and in perineural invasion was observed in most of the cases. The component ratio in metastatic lymph nodes differed from that in the corresponding primary lesions in all six cases with lymph node metastasis. Among these cases, the proportion of the SCC component was increased in the metastatic lymph nodes compared with that in the corresponding primary lesion in two cases, whereas the proportion was decreased in four cases. CONCLUSIONS: The SCC component of ASC in the biliary tract displayed a relatively higher proliferative ability, which might be associated with local invasiveness. However, not only the high proliferative ability of the SCC component but also other biological factors might contribute to tumor progression and metastasis in ASC of the biliary tract.

Prognostic significance of intraoperative peritoneal washing cytology for patients with potentially resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The prognostic significance of intraoperative peritoneal washing cytology (IPWC) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the treatment strategy for PDAC patients with positive cytology has not been established. OBJECTIVES: The objective of this study was to evaluate the clinical significance of IPWC in PDAC patients. METHODS: This study included a retrospective cohort of 166 patients with curatively resected PDAC who underwent IPWC. RESULTS: Overall, 17 patients (10%) had positive cytology (CY+), and 149 (90%) patients were negative (CY-). Tumor location in the pancreatic body and/or tail and pancreatic anterior capsular invasion were independent predictors of a CY+ status (P = 0.012 and 0.041, respectively). The initial recurrence occurred at the peritoneum with a significantly higher frequency in CY+ patients (50%) than in CY- patients (12%) (P = 0.003). The median overall survival (OS) for CY+ patients was 12 months. The OS rates at 1 and 3 years were significantly higher for CY- patients (75.1% and 35.3%, respectively) versus CY+ patients (47.1% and 17.6%, respectively; P = 0.012). However, one CY+ patient survived for 66 months, and another two CY+ patients have survived for more than three years after surgery without evidence of peritoneal recurrence. In the multivariate analysis, the independent predictors of OS were a CY+ status, lymph node metastasis, and adjuvant chemotherapy. CONCLUSIONS: This study demonstrates that positive IPWC predicts early peritoneal recurrence and a poor prognosis for PDAC patients. However, a small but not insignificant subset of CY+ patients with PDAC may avoid peritoneal carcinomatosis.

Collision tumors of hepatocellular carcinoma and malignant peritoneal mesothelioma.

We report a case of synchronous hepatocellular carcinoma (HCC) and malignant peritoneal mesothelioma (MM-per). A 56-year-old man with no past history of asbestos exposure, chronic viral hepatitis, or alcoholic liver injury was admitted to our hospital with left flank pain and abdominal tumor. Partial hepatectomy, splenectomy, partial diaphragm resection, and partial gastrectomy were performed. The tumor in the lateral segment of the liver was gray to white, massive in appearance, and contained focal bile-producing nodules and extensive fibrous firm lesion. It had directly invaded the spleen and diaphragm. Liver cirrhosis was not found. The peritoneum contained multiple small nodules especially around the diaphragm, which mimicked carcinoma dissemination. After histological examination, the liver tumor was diagnosed as HCC. It had trabecular and scirrhous patterns and positive immunoreactivities for Hep-Par-1 and α-fetoprotein. The peritoneal nodules were diagnosed as MM-per, epithelioid type, with positive immunoreactivities for calretinin and cytokeratin 5/6. The two tumors collided around the diaphragm. Cases of MM synchronous with other primary malignant tumors have been reported, but most had a history of asbestos exposure unlike the present case. The carcinogenic background was unclear for two tumors in this case. This is an extremely rare and valuable case.

Primary peripheral T-cell lymphoma, not otherwise specified of the thyroid with autoimmune thyroiditis.

Primary peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) of the thyroid is an extremely rare neoplasm. Six cases of primary PTCL-NOS of the thyroid were analysed for clinicopathological features and genomic alteration patterns using oligo-array comparative genomic hybridization. All patients had a diffusely enlarged thyroid and three cases showed leukaemic manifestation. Five of the six cases had anti-thyroid antibodies and the remaining case showed hypothyroidism, suggesting that all cases had autoimmune thyroiditis. Except for one early relapsed case, the remaining five patients are alive and three of these five individuals have survived for 70 months or more. Interestingly, two cases showed spontaneous regressions after partial thyroid biopsy without any therapy. Leukaemic manifestation disappeared after irradiation of the thyroid mass in another two cases. The tumour cells were positive for CD3, CD4 and CXCR3 in all cases, suggesting that the tumour cells are of a type 1 helper T-cell origin. All six cases showed genomic alterations that were different from those previously reported for PTCL-NOS. The loss of 6q24·2 was characteristic and was detected in four of the six cases. These results suggest that primary PTCL-NOS of the thyroid arising from autoimmune thyroiditis is a distinct disease entity among heterogeneous PTCL-NOS.

[An autopsy case of unresectable colon cancer who developed lung injury by cetuximab].

We report the case of a woman in her 60s with unresectable advanced colon cancer. After the first course of cetuximab as second-line therapy, she had developed drug-induced lung injury. Steroid pulse therapy had been ineffective, and she died of respiratory failure on day 9. The pathological examination of autopsy lung specimens revealed diffuse alveolar damage(DAD). Details of the cetuximab-induced lung injury are unclear. However, in 3 previous reports of lung injury by cetuximab, the postmortem findings were similar to this case. We concluded that DAD seems to be one of the pathological features of lung injury caused by cetuximab.

[Clinical analysis of 3 cases with primary splenic diffuse large B-cell lymphoma].

The definition of primary splenic lymphoma is controversial, but it has been reported to be a rare disease that comprises less than 1% of all malignant lymphomas. Three cases of primary splenic diffuse large B-cell lymphoma treated at our institution are described here. Median follow-up was 34.6 months (range 8.7∼39.2) and median age at diagnosis was 72 years old (range 65∼73). In all three cases, the diagnosis was definitively established not by splenectomy but by ultrasonically guided percutaneous splenic tissue core biopsy. Using the Hans classifier, one of the cases was subclassified as the germinal center B-cell like (GCB) subtype and two as non-GCB subtype. One case was CD5-positive diffuse large B-cell lymphoma. Two patients were in Ann Arbor stage II and one was in stage III. Using the International Prognostic Index, one was categorized as Low/intermediate risk, one as high/intermediate risk, and one as high risk. All patients underwent eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone followed by irradiation therapy. These three patients attained complete response. Although the follow-up period to date has been short, all patients have maintained a complete response and are currently alive. To determine whether our management protocol is valid, further observations are needed.

[A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment].

The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital.

Successfully resected intrathoracic low-grade fibromyxoid sarcoma.

A low-grade fibromyxoid sarcoma (LGFMS), an Evans tumor, is highly unusual. It is rarely described as a primary neoplasm in the thoracic cavity. We experienced a case of a 20-year-old woman with a right intrathoracic tumor that was surgically treated. Postoperative pathology of the resected specimen revealed the tumor to be LGFMS based on its histological appearance, immunohistological staining, and evidence of fused in sarcoma (FUS) translocation by fluorescence in situ hybridization. Tumor resection was performed with a free surgical margin, and the resultant chest wall defect was repaired using prosthetic mesh. The patient has been well without any recurrence for 18 months since surgery.

Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice.

NKX2-1 is a homeodomain transcription factor that is critical for genesis of the thyroid and transcription of the thyroid-specific genes. Nkx2-1-thyroid-conditional hypomorphic mice were previously developed in which Nkx2-1 gene expression is lost in 50% of the thyroid cells. Using this mouse line as compared with wild-type and Nkx2-1 heterozygous mice, a thyroid carcinogenesis study was carried out using the genotoxic carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN), followed by sulfadimethoxine (SDM) or the non-genotoxic carcinogen amitrole (3-amino-1,2,4-triazole). A significantly higher incidence of adenomas was obtained in Nkx2-1-thyroid-conditional hypomorphic mice as compared with the other two groups of mice only when they were treated with DHPN + SDM, but not amitrole. A bromodeoxyuridine incorporation study revealed that thyroids of the Nkx2-1-thyroid-conditional hypomorphic mice had >2-fold higher constitutive cell proliferation rate than the other two groups of mice, suggesting that this may be at least partially responsible for the increased incidence of adenoma in this mouse line after genotoxic carcinogen exposure. Thus, NKX2-1 may function to control the proliferation of thyroid follicular cells following damage by a genotoxic carcinogen.

Primary adenocarcinoma of the minor duodenal papilla.

A 70-year-old man was admitted to our institution due to aggravation of blood-sugar level control and because an abdominal CT showed dilatation of the main pancreatic duct. Upper gastrointestinal endoscopy revealed a flat elevated tumor with central ulceration in the second portion of the duodenum. Subsequent duodenoscopy for a more detailed examination showed that the tumor had originated in the minor duodenal papilla. A biopsy specimen showed moderately differentiated adenocarcinoma. Endoscopic retrograde pancreatography via the major duodenal papilla revealed a slightly dilated main pancreatic duct and obstruction of the accessory pancreatic duct. Endoscopic ultrasonography showed a hypoechoic mass in the minor duodenal papilla with retention of the muscularis propria of the duodenum. These findings suggest that the tumor existed only to a limited extent in the minor duodenal papilla, and that the tumor did not infiltrate into the pancreas. For treatment, pylorus-preserving pancreatoduodenectomy was performed, and histological findings revealed a well-differentiated adenocarcinoma that originated in the minor duodenal papilla. Primary adenocarcinoma of the minor duodenal papilla is extremely rare. Our case is the first report of primary adenocarcinoma of the minor duodenal papilla at an early stage with no infiltration into muscularis propria of the duodenum and pancreas.

Thyroid-specific enhancer-binding protein/NKX2.1 is required for the maintenance of ordered architecture and function of the differentiated thyroid.

Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12-13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl);TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl);TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl);TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl);TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.