Ameloblastic fibrosarcoma of the maxilla with EGFR exon 20 insertions: Relevance of whole-exome sequencing in molecular understanding and therapeutic proposals for rare cancers.

Ameloblastic fibrosarcoma (AFS) is the most common odontogenic sarcoma, but the incidence is relatively low, and its molecular biology is poorly understood. We experienced a young female patient with a rapidly growing soft tissue tumor of the left maxilla, which eventually occupied the left side of the oral cavity. Histologically, the tumor mainly consisted of a proliferation of atypical spindle to polygonal cells without any specific differentiation, but a small number of benign odontogenic epithelial foci mainly in the tumor periphery were also noted; thus, a diagnosis of AFS was made. We performed whole-exome sequencing (WES) on the tumor to investigate its molecular features and identify therapeutic options. We found that the tumor harbored EGFR exon 20 insertions and MDM2 amplification; the former may be a target for newly developed tyrosine kinase inhibitors in case of recurrence. To the best of our knowledge, this is the first case of AFS for which WES was performed and with EGFR mutation. Our case provides new genetic information on AFS and suggests that comprehensive genetic analysis can clarify the molecular biology in rare cancers, potentially leading to the proposal of therapeutic strategies.

Giant cell tumor of bone - Analysis of 213 cases involving extra-craniofacial bones.

We elucidated clinicopathological characteristics of giant cell tumor of bone (GCTB) in Japan, and significant clinicopathological factors for predicting local recurrence. Clinicopathological profiles of 213 patients with GCTB (100 male, 113 female) involving extra-craniofacial bones were retrieved. Pathological slides obtained at the initial surgery were reviewed. Fourteen pathological and five clinical features were statistically analyzed to disclose prognostic significance. Patient age ranged from 12-80 years (Average 38.7). Long bones were most frequently affected (86.4%), especially around the knee (62.9%). Histological features are basically similar to those previously reported. Within a follow-up period (24-316 months, average 106.1 months), the local recurrence rate is 29.1%. Metastasis has occurred in 9 patients. Cox regression analysis of representative clinicopathological features shows that younger age, higher mitotic count, smaller zones of stromal hemorrhage, considerable vascular invasion and absence of ischemic necrosis are significant predictors for local recurrence. Initial operative method (curettage) is a significant risk factor in univariate analysis but not by multivariate analysis (P = 0.053). Denosumab administration increases risk but not significantly (P = 0.053). Histone 3.3 G34W immunopositivity is not significant for predicting local recurrence.

Hypertrophic obstructive cardiomyopathy and mitral regurgitation in Libman-Sacks endocarditis.

Hypertrophic obstructive cardiomyopathy in Libman-Sacks endocarditis is quite rare and the correct etiological relationship between them is unknown. Some changes may cause a secondary disorganization of the ordinary muscle structure, making a disarray pattern with irregular interwoven myocyte fibers. This case report describes one of the first cases of ventricular septal myectomy and mitral valve replacement for hypertrophic obstructive cardiomyopathy and mitral valve regurgitation associated with Libman-Sacks endocarditis.

Hepatic epithelioid hemangioendothelioma with metastasis to the mesentery of the small intestine: A case report.

Epithelioid hemangioendothelioma (EHAE) is a vascular tumor which, due to its rarity, is often misdiagnosed as other hepatic tumors based on radiological characteristics. We herein report a case of EHAE in the liver and the mesentery of the small intestine. A 64-year-old asymptomatic woman was admitted to the hospital due to a hepatic tumor identified using computed tomography (CT). An enhanced CT scan revealed multiple tumors in the liver and a tumor in the mesentery. One of the hepatic tumors and the mesenteric tumor were resected and histologically examined. The two tumors exhibited similar histological characteristics and were diagnosed as EHAE. When multiple tumors are found in the liver, EHAE should be included in the differential diagnosis, as the prognosis of EHAE differs from that of carcinoma or benign tumors.

Chondroblastoma of extra-craniofacial bones: Clinicopathological analyses of 103 cases.

We elucidated clinicopathological characteristics of chondroblastoma (CB) in Japan, and reliable clinicopathologic parameters predicting local recurrence and/or metastasis. Clinicopathological profiles of 103 CB (80 male, 23 female) in extra-craniofacial bones were retrieved. Numerical scoring of nine pathological and five radiological features was statistically analyzed to determine prognostic significance. Age ranged 8-61 years (average 19.6 years). Frequently involved sites were femur, tibia, calcaneus, patella and humerus. Radiologically, tumors were 2-80 mm (average 31.1 mm) in size. Marginal sclerosis and calcification were common. Histologically, pink cartilage, mitoses, and chicken-wire calcification were often seen. Within a follow-up period [2-260 months (average 53.5 months)], the local recurrence rate was 15.5%. No patient had metastasis. Recurrence was most frequently observed at the femur. By log-rank analysis, only cyst formation in images was significant for predicting recurrence free survival (RFS). By Cox hazard analysis with representative clinico-radiological and pathological features, only age (≥16 years) and cyst formation were significant predictors for RFS. Pathological features were not significant in both uni- and multivariate analyses.

Primary central chondrosarcoma of long bone, limb girdle and trunk: Analysis of 174 cases by numerical scoring on histology.

The aims of this study were: (i) to elucidate clinicopathological characteristics of pcCHS of long bones (L), limb girdles (LG) and trunk (T) in Japan; (ii) to investigate predictive pathological findings for outcome of pcCHS of L, LG and T, objectively; and (iii) to elucidate a discrepancy of grade between biopsy and resected specimens. Clinicopathological profiles of 174 pcCHS (79 male, 95 female), of L, LG, and T were retrieved. For each case, a numerical score was given to 18 pathological findings. The average age was 50.5 years (15-80 years). Frequently involved sites were femur, humerus, pelvis and rib. The 5-year and 10-year disease-specific survival (DSS) rates [follow-up: 1-258 months (average 65.5)] were 87.0% and 80.4%, respectively. By Cox hazards analysis on pathological findings, age, sex and location, histologically higher grade and older age were unfavorable predictors, and calcification was a favorable predictor in DSS. The histological grade of resected specimen was higher than that of biopsy in 37.7% (26/69 cases). In conclusion, higher histological grade and older age were predictors for poor, but calcification was for good prognosis. Because there was a discrepancy in grade between biopsy and resected specimens, comprehensive evaluation is necessary before definitive operation for pcCHS.

Screening of BCOR-CCNB3 sarcoma using immunohistochemistry for CCNB3: A clinicopathological report of three pediatric cases.

BCOR-CCNB3 sarcoma is a recently recognized tumor morphologically and clinically simulating Ewing sarcoma. We herein retrospectively collected clinicopathologic data on BCOR-CCNB3 sarcoma in the Kyoto University Hospital over the last 10 years. Three (20%) bone sarcomas were revealed to be diffusely positive for CCNB3 immunohistochemistry among 15 pediatric cases of undifferentiated sarcoma morphologically similar to Ewing sarcoma, while the other cases showed completely negative staining. The three patients with immunohistochemically CCNB3-positive tumors were all male, aged between 11 and 17, and confirmed to have the BCOR-CCNB3 fusion transcript by RT-PCR. Radiologically, all cases had well-demarcated solid masses with bone destruction. Although the tumors were basically small round cell tumors, less monomorphic histological patterns such as short spindle cells, a myxoid matrix, and hemangiopericytoma-like pattern were also observed in both biopsy and resected specimens. Two patients achieved a complete response after chemotherapy for Ewing sarcoma and osteosarcoma, respectively. These results demonstrated that the application of CCNB3 immunostaining was useful for differentiating BCOR-CCNB3 from a group of 'Ewing-like sarcomas' and may contribute to the evaluation of treatment strategies for bone sarcomas.

Ewing's sarcoma with an uncommon clinical course: A case report.

Here, a case of Ewing's sarcoma family of tumors (ESFT) of the femur with an unusual clinical course is reported. At 20 years of age, the patient had undergone curettage of a bone tumor of the right femur which was diagnosed as ESFT. One cycle of chemotherapy with vincristine and cyclophosphamide and radiotherapy for a total dose of 40 Gy was administered. The patient did not develop any recurrence or metastases for the following 18 years, in spite of the inadequacy of the initial treatment. At 38 years of age, he was referred to our institution with right thigh pain that had persisted for several months. Radiographs and magnetic resonance imaging findings showed a mass lesion in his proximal femur extending to the soft tissue. An open biopsy was performed and the lesion was diagnosed as recurrence of ESFT, although a molecular biological investigation did not reveal any expression of the characteristic fusion genes that have previously been reported. The patient received standard multimodal therapy employing standard combination chemo-therapy for ESFT and wide surgical excision. The patient has been disease-free for 9 years since the treatment. This patient may have a rare subtype of ESFT with an unknown chromosomal translocation and relatively non-aggressive biological behavior.

Dedifferentiated liposarcoma with lipoma-like well-differentiated liposarcoma: clinicopathological study of 30 cases, with particular attention to the comingling pattern of well- and dedifferentiated components: a proposal for regrouping of the present subclassification of well-differentiated liposarcoma and dedifferentiated liposarcoma.

Dedifferentiated liposarcoma (DDL) is defined as nonlipogenic sarcoma, with an abrupt transition from coexisting well-differentiated liposarcoma (WDL). However, intermingled transition in a mosaic pattern between WDL and DDL is not infrequently encountered. Here, the authors review clinicopathological features of 30 cases of DDL associated with lipoma-like WDL. Histological examination revealed 20 tumors that showed an abrupt transition between WDL and DDL. Among these, 13 tumors showed high-grade spindle-cell sarcoma having histological features of unclassified malignant fibrous histiocytoma (MFH)-like sarcoma (high-grade DDL [HDDL]). The remaining 7 tumors showed moderate cellular spindle-cell proliferation with mild nuclear atypia and scant mitotic figures (low-grade DDL [LDDL]). The other 10 tumors showed intermingled transition between WDL and DDL. The interface between these 2 components overlapped, resulting in frequent occurrence of a lipogenic spindle-cell component (comingling DDL). Based on the cellularity and nuclear atypia of the spindle-cell components, there were 7 comingling HDDLs and 3 comingling LDDLs. The histology of comingling LDDL simulated an admixture of spindle-cell liposarcoma and LDDL, and distinction from each other was practically difficult. The histology of comingling HDDL simulated pleomorphic liposarcoma. Follow-up data, available for 23 patients (median, 39 months), showed that 2 patients died of tumor (both had HDDL), and 1 patient died of unrelated disease; 8 patients were alive with recurrent or metastatic diseases (3 HDDLs, 3 LDDLs, and 2 comingling HDDLs). Statistical analysis by Fisher's exact test showed no correlation between histological subtypes (HDDL and LDDL, and typical DDL and comingling DDL).

The ß1-integrin-dependent function of RECK in physiologic and tumor angiogenesis.

Vascular endothelial cells produce considerable amounts of matrix metalloproteinases (MMP), including MMP-2, MMP-9, and membrane type 1 (MT1)-MMP. However, little is known about the regulatory mechanisms of these protease activities exhibited during vascular development. A glycosylphosphatidylinositol-anchored glycoprotein, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), has been shown to attenuate MMP-2 maturation by directly interacting with MT1-MMP. Here, we show that an angiogenic factor angiopoietin-1 induces RECK expression in human umbilical vein endothelial cells (HUVEC), and RECK depletion in these cells results in defective vascular tube formation and cellular senescence. We further observed that RECK depletion downregulates beta1-integrin activation, which was associated with decreased autophosphorylation of focal adhesion kinase and increased expression of a cyclin-dependent kinase inhibitor p21(CIP1). In agreement, significant downregulation of beta1-integrin activity was observed in vascular endothelial cells in Reck-/- mouse embryos. In HUVECs, specific inhibition of MMP-2 significantly antagonized the effect of RECK depletion on beta1-integrin signaling, cell proliferation, and tube elongation. Furthermore, we observed that hypervascular tumor-derived cell lines can induce high RECK expression in convoluted vascular endothelial cells, and this in turn supports tumor growth. Targeting RECK specifically in tumor-associated vascular endothelial cells resulted in tumor regression. Therefore, we propose that RECK in tumor vascular endothelial cells can be an interesting target of cancer treatment via abortion of tumor angiogenesis.

Immunohistochemical analysis for Sox9 reveals the cartilaginous character of chondroblastoma and chondromyxoid fibroma of the bone.

Chondroblastoma, which is histologically composed of mononuclear cell proliferation and lobules of immature cartilage, and chondromyxoid fibroma, which is composed of myxoid lobules with spindle or stellate cells and a cellular fibrous rim with spindle cells, are both rare tumors. Based on histogenetic investigation including immunohistochemistry, matrix biochemistry, and electron microscopy, chondroblastoma is thought to contain chondrogenic cells, whereas chondromyxoid fibroma is considered to contain myofibroblastic cells, as well as chondrogenic cells, and chondroid matrix. In this study, we performed immunohistochemical analysis for Sox9, which is an essential transcriptional factor for chondrogenesis, to examine the possible chondrogenic nature of chondroblastoma and chondromyxoid fibroma. Formalin-fixed, paraffin-embedded tissues obtained from 10 cases of chondroblastoma and 11 cases of chondromyxoid fibroma were immunostained with antibody to Sox9. In addition, immunohistochemical study for collagen type II, which is a major component of cartilaginous matrix, was performed. Sox9 was positive in 8 chondroblastomas and 10 chondromyxoid fibromas. Positive staining was observed in the nuclei of the tumor cells. The matrices of 7 chondroblastomas and of 8 chondromyxoid fibromas were immunopositive for collagen type II. The findings suggest the cartilaginous differentiation of chondroblastoma and chondromyxoid fibroma.

Intracerebral schwannoma in a child with infiltration along perivascular spaces resembling meningioangiomatosis.

Schwannoma arising within brain parenchyma is a rare lesion, usually found in children. Reported herein is a case of intracerebral schwannoma in a 5-year-old boy, with a review of the English-language literature on the subject, in which 47 cases were found. Few detailed histological reviews of intracerebral schwannoma exist. The tumor had a distinctive plexiform growth pattern, and small aggregates of Schwann cells spread extensively into the surrounding brain tissue along perivascular spaces adjacent to the tumor nodule. Histological differential diagnoses included perivascular schwannosis and meningioangiomatosis. A few intratumoral axons, seen on immunostaining for neurofilament protein, were trapped at the periphery of the main lesion, but there was no evidence of intralesional axons in the multiple nodules of Schwann cell proliferations that extended into the perivascular spaces, suggesting that the lesions are neoplastic. Because Schwann cells are not a natural component of the central nervous system, the origin of intracerebral schwannomas remains unknown. The histology suggests that Schwann cells of the perivascular nerve plexus are a likely site of origin.

Clear cell carcinoma of the minor salivary gland: an autopsy case with multiple metastases 29 years after the initial surgery and a review of the literature.

Clear cell carcinoma of the salivary gland is an uncommon tumor comprising about 1% of neoplasms of minor salivary glands. We report an autopsy case of a tumor with widespread metastases 29 years after initial surgery. At the initial presentation, the patient was a 48-year-old man with a small ulcerative tumor in the right hard palate, and the tumor was excised. Twenty-four years after the initial excision, the first recurrence was detected in the lung. Five years later, the patient died of widespread metastases of the disease at the age of 77. Specimens obtained at the initial excision and at autopsy were very similar histologically and immunohistochemically, and both were clear cell carcinoma of the salivary gland. The patient died of the disease after a very long disease-free period, which reinforces the classification of this tumor as a low-grade malignancy.

High ratio of IgG4-positive plasma cell infiltration in cutaneous plasmacytosis--is this a cutaneous manifestation of IgG4-related disease?

Cutaneous plasmacytosis is a rare condition affecting middle-aged individuals, characterized by multiple red-brown papules and plaques over the trunk. It has been reported mainly in Japan. The condition is accompanied by polyclonal hypergammaglobulinemia and superficial lymphadenopathy. Lung or retroperitoneal involvement occurs rarely. In the present study, 3 consecutive cases of cutaneous plasmacytosis were observed histologically to have abundant infiltration of IgG4-bearing plasma cells. All 3 were associated with superficial lymphadenopathy, one with interstitial lung involvement showing ground-glass opacity on computed tomography and the others with bone marrow plasmacytosis, showing histologic evidence of more IgG4-positive plasma cells. All 3 had polyclonal hypergammaglobulinemia, one had high serum concentration of IgG4, and all had elevated serum IL-6. The ratios of IgG4+ to IgG+ plasma cells were assessed using skin biopsy specimens with pemphigus (n = 7), discoid lupus erythematosus (n = 5), and morphea (n = 2) (mean ratios, 19%, 0%, and 0%, respectively); we noted the proportion of IgG4-positive plasma cells in cutaneous plasmacytosis (mean, 48%). IgG4-related sclerosing disease is a newly recognized systemic disorder characterized by lymphoplasmacytic infiltration and fibrosis and by a high serum IgG4 level and increased IgG4-positive plasma cells in the tissues. Skin manifestations of this disorder have not been described. Although cutaneous plasmacytosis could be a chronic allergic hypersensitivity reaction, our findings raise the possibility of a relationship in pathogenesis between cutaneous plasmacytosis and IgG4-related sclerosing disease.

Esophageal metastasis of breast carcinoma.

Esophageal metastasis from primary breast cancer is an unusual manifestation. We recently treated a patient with dysphagia, whose breast cancer had been treated in the distant past. A 70-year-old woman had been followed regularly in our outpatient clinic for 14 years after her primary breast cancer treatment, with no apparent tumor recurrence. After 2 years absence, she consulted our clinic with progressive dysphagia. Contrast esophagography and endoscopic examination with ultrasonography revealed a protruding submucosal tumor that was histopathologically diagnosed as esophageal metastasis of breast cancer. Radiation therapy involving a total of 60 Gy in combination with aromatase inhibitor was given. The patient's dysphagia was greatly relieved, concomitant with marked improvement of the stenotic lesion on imaging. Since treatment for recurrent breast cancer is generally palliative, systemic (chemo- and/or endocrine-) therapy in combination with radiotherapy is the first-line option for esophageal metastasis of breast cancer.

A rare case of hyperfunctioning papillary carcinoma of the thyroid gland.

We report a rare case of hyperfunctioning papillary carcinoma of the thyroid. A 32-year-old man was referred to our hospital for the treatment of a painless mass in the left neck, which had been detected on routine physical check-up. Cervical ultrasonography and computed tomography showed a solid tumor with calcification in the left lobe of the thyroid gland. Serum examinations demonstrated hyperthyroidism with a high level of thyroglobulin. Fine needle aspiration biopsy revealed a cytological diagnosis of class II. Tc-99m scintigraphy showed a hot nodule in the left lobe, which implied that the tumor was a hyperfunctioning thyroid tumor. Left lobectomy of the thyroid gland was performed to treat the hyperfunctioning tumor. Postoperative pathological examinations revealed a follicular variant papillary carcinoma. Postoperative thyroid function became within the normal range. Although hyperfunctioning thyroid carcinomas are rare, it is important to correctly diagnose them and to perform appropriate surgical interventions.

Evaluation of primary brain tumors with FLT-PET: usefulness and limitations.

PURPOSE OF THE REPORT: The purpose of this report was to investigate the potential of positron emission tomography using F-18 fluorodeoxythymidine (FLT-PET) in evaluating primary brain tumors. MATERIALS AND METHODS: FLT-PET was performed in 25 patients with primary brain tumors. FLT uptake in the lesion was semiquantitatively evaluated by measuring the maximal standardized uptake value (SUVmax) and the tumor-to-normal tissue ratio (TNR). SUVmax and TNR were compared with the histologic grade and the expression of the proliferation marker (Ki-67). RESULTS: FLT uptake in normal brain parenchyma was very low, resulting in the visualization of brain tumors with high contrast. Both SUVmax and TNR significantly correlated with the malignant grade of brain gliomas, in which high SUVmax/TNR was obtained for high-grade gliomas. Patients with primary lymphoma also showed SUVmax/TNR equivalent to glioblastoma. There was a positive correlation between SUVmax/TNR and the Ki-67 index. In contrast, spuriously high SUVmax and TNR were obtained in 3 of 6 patients with suspected recurrent tumors (2 patients with recurrent grade 2 glioma and one patient with postoperative granuloma), all of which showed lesion enhancement on MRI after Gd administration. CONCLUSIONS: FLT-PET can be used to evaluate the malignant grade and proliferation activity of primary brain tumors, especially malignant brain tumors. However, the presence of benign lesions showing blood-brain barrier disruption cannot be distinguished from malignant tumors and needs to be carefully evaluated.

Expression of claudin7 is tightly associated with epithelial structures in synovial sarcomas and regulated by an Ets family transcription factor, ELF3.

Synovial sarcoma, a soft tissue sarcoma that develops in adults, is pathologically subclassified into monophasic spindle synovial sarcoma and biphasic synovial sarcoma with epithelial components. The molecular mechanism building the epithelial components in biphasic synovial sarcoma is totally unknown. Here we investigated claudins, critical molecules in the tight junction, in biphasic synovial sarcoma. Expression profiles of 21 claudins in 17 synovial sarcoma tumor samples, including 9 biphasic tumors, identified claudin4, claudin7, and claudin10 as biphasic tumor-related claudins, and immunohistochemical analyses demonstrated the localization of these claudins in the epithelial component in biphasic tumors, with claudin7 the most closely associated with the epithelial component. The mRNA expression and protein localization of claudin7 coincided with those of the ELF3, an epithelia-specific member of the Ets family of transcription factors. Luciferase reporter assays demonstrated that the presence of the Ets-binding site at -150 in the promoter region of the claudin7 gene was critical for the transcriptional activity, and gel shift and chromatin immunoprecipitation assays confirmed the binding of ELF3 to the Ets site at -150. Inhibition of ELF3 expression by small interfering RNA simultaneously down-regulated the mRNA expression of the claudin7 gene, and the introduction of ELF3 expression in claudin7-negative cell lines induced mRNA expression of the claudin7 gene. Therefore, the induction of claudin7 expression by ELF3 appears critical to the formation of the epithelial structures in biphasic synovial sarcoma.