Eiichi Konishi

Extraskeletal osteosarcoma arising in myositis ossificans

Abstract A 53-year-old woman had extraskeletal osteosarcoma that developed from a soft tissue bony mass present on the volar aspect of the left wrist for 4 years. Initially, the bony mass was soft and movable, but during the first year it became hard and fixed. The patient had no history of trauma. Because the lesion did not grow or cause any symptoms, the patient did not come to the hospital until 4 years after she first noticed the lesion. Radiologically, the bony mass had features characteristic of mature myositis ossificans, showing ”eggshell” ossification. A nonmineralized soft tissue mass occurred between the surface of the radius and the bony shell. Histologically, a high-grade osteosarcoma was present between the surface of the radius and the well-differentiated bone tissue, which included fatty and hematopoietic marrow. All the findings indicated that our patient had an extremely rare case of malignant transformation of myositis ossificans.

Characterization of FN1-FGFR1 and novel FN1-FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors.

Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1–FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1–FGF1 fusion gene was identified in two cases without FN1–FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1–FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1–FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1–FGFR1 and FN1–FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary fibrous tumors (positive in 40%), chondroblastomas (40%), and giant cell tumors of bone (38%), suggesting a possible role for FGFR1 immunohistochemistry in the diagnosis of phosphaturic mesenchymal tumor. With the exception of one case reported in our prior study, none of the remaining tumors resembling phosphaturic mesenchymal tumor had either fusion type or expressed significant FGFR1. Our findings provide insight into possible mechanisms underlying the pathogenesis of phosphaturic mesenchymal tumor and imply a central role of the FGF1-FGFR1 signaling pathway. The novel FN1–FGF1 protein is expected to be secreted and serves as a ligand that binds and activates FGFR1 to achieve an autocrine loop. Further study is required to determine the functions of these fusion proteins.

Clear cell carcinoid tumor of the gallbladder: A case without von Hippel-Lindau disease

A golden yellow polyp was detected in the gallbladder of a 64-year-old man who presented with epigastric pain. The lesion was composed of clear polygonal cells arranged in a trabecular and glandular pattern. The tumor invaded through the wall into the perimuscular subserosal layer. Immunohistochemical stains showed that neoplastic cells were positive for chromogranin A, synaptophysin, somatostatin, gastrin, and pancreatic polypeptide and negative for glucagon, serotonin, insulin, S100 protein, and inhibin. This tumor resembles the recently described clear cell endocrine tumors of the gallbladder and pancreas that are associated with von Hippel-Lindau disease. Our patient, however, had neither personal nor family history indicative of von Hippel-Lindau disease. Furthermore, published accounts of clear cell endocrine tumors in von Hippel-Lindau disease describe immunoreactivity for inhibin; the current case was negative for the disease. There may be a subtype of clear cell carcinoid tumor not associated with von Hippel-Lindau disease, which is characterized by its lack of immunoreactivity against inhibin.

The role of breast MR imaging in pre-operative determination of invasive disease for ductal carcinoma in situ diagnosed by needle biopsy

ObjectivesTo evaluate whether magnetic resonance (MR) imaging features can predict the presence of occult invasion in cases of biopsy-proven pure ductal carcinoma in situ (DCIS).MethodsWe retrospectively reviewed 92 biopsy-proven pure DCIS in 92 women who underwent MR imaging. The following MR imaging findings were compared between confirmed DCIS and invasive breast cancer (IBC): lesion size, type, morphological and kinetic assessments by ACR BI-RADS MRI, and findings of fat-suppressed T2-weighted (FS-T2W) imaging.ResultsSixty-eight of 92 (74%) were non-mass-like enhancements (NMLE) and 24 were mass lesions on MR imaging. Twenty-one of 68 (31%) NMLE and 13 of 24 (54%) mass lesions were confirmed as IBC. In NMLE lesions, large lesions (P = 0.007) and higher signal intensities (SI) on FS-T2W images (P = 0.032) were significantly associated with IBC. Lesion size remained a significant independent predictor of invasion in multivariate analysis (P = 0.032), and combined with FS-T2W SIs showed slightly higher observer performances (area under the curve, AUC, 0.71) than lesion size alone (AUC 0.68). There were no useful findings that enabled the differentiation of mass-type lesions.ConclusionsBreast MR imaging is potentially useful to predict the presence of occult invasion in biopsy-proven DCIS with NMLE.Key PointsMR mammography permits more precise lesion assessment including ductal carcinoma in situA correct diagnosis of occult invasion before treatment is important for cliniciansThis study showed the potential of MR mammography to diagnose occult invasionTreatment and/or aggressive biopsy can be given with greater confidenceMR mammography can lead to more appropriate management of patients

Irritated seborrheic keratosis of the external ear canal

Although a seborrheic keratosis is not rare on the skin of the trunk, extremities, head and neck of an elderly person, it is uncommon to originate in the external ear canal. Even rarer, an irritated subtype may arise in this location. We report the case of a 63‐year‐old man with an irritated seborrheic keratosis arising in the right external ear canal, who first presented with a bloody discharge from his right ear canal 3 years and 10 months before the subsequent operation. Macroscopically, a dome‐like, black elevation was found at the anterior wall of the right external ear canal. A biopsy showed an exophytic papillomatous, hyperkeratotic growth of basaloid cells which revealed some nuclear atypism and mitosis. Squamous eddies and moderate inflammatory infiltrate were noted. Some cellular atypism made us suspect an irritated seborrheic keratosis. Because the patient hated the extirpation, he remained untreated for 3 years and 3 months following his first presentation. The biopsy and a surgical resection of his second presentation confirmed the diagnosis of irritated seborrheic keratosis. Immunohistochemical analysis of Ki‐67, p53 and papillomavirus was performed to elucidate its character. We emphasize that irritated seborrheic keratosis does occur in the external ear canal and may cause some diagnostic difficulty. Pathologists should be aware of this fact and avoid overdiagnosis.

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.

Podoplanin expression in cancer-associated fibroblasts predicts aggressive behavior in melanoma

Recent studies have showed podoplanin expression in several tumors, which has been associated with lymph node metastasis and poor prognosis. Podoplanin expression in cancer‐associated fibroblasts also correlates with tumor progression. However, the association of podoplanin expression with melanomas remains unclear.

A novel serine protease highly expressed in the pancreas is expressed in various kinds of cancer cells

We have isolated a cDNA that encodes a novel serine protease, prosemin, from human brain. The cDNA of human prosemin is 1306 bp, encoding 317 amino acids. It showed significant homology with the sequence of a chromosome 16 cosmid clone (accession no. NT_037887.4). The prosemin gene contains six exons and five introns. The amino acid sequence of prosemin shows significant homology to prostasin, γ‐tryptase, and testisin (43%, 41%, and 38% identity, respectively), the genes of which are also located on chromosome 16. Northern hybridization showed that prosemin is expressed predominantly in the pancreas and weakly in the prostate and cerebellum. However, western blot and RT‐PCR analyses showed that prosemin is expressed and secreted from various kinds of cancer cells, such as glioma, pancreas, prostate, and ovarian cell lines. Prosemin is secreted in the cystic fluid of clinical ovarian cancers. Furthermore, immunohistochemistry showed prosemin protein localized in the apical parts of ovarian carcinomas. Recombinant prosemin was expressed in COS cells and was purified by immunoaffinity chromatography. Recombinant prosemin preferentially cleaved benzyloxycarbonyl (Z)‐His‐Glu‐Lys‐methylcoumaryl amidide (MCA) and t‐butyloxycarbonyl (Boc)‐Gln‐Ala‐Arg‐MCA. Our results suggest that prosemin is a novel serine protease of the chromosome 16 cluster that is highly expressed in the pancreas. The usefulness of this serine protease as a candidate tumor marker should be further examined.

A novel PAX3 rearrangement in embryonal rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft tissue tumor seen in children and young adults, and it can be classified into 2 major histological subtypes, alveolar and embryonal. In the alveolar subtype, 2 recurrent chromosomal translocations, t(2;13)(q35;q14) and its variant t(1;13)(p36;q14), have been identified as the specific cytogenetic abnormalities. These translocations produce the PAX3-FOXO1 and PAX7-FOXO1 fusion genes, respectively. In the embryonal subtype, however, no recurrent chromosomal abnormalities have been identified. In this study, we analyzed the complex chromosomal translocation in one case with embryonal rhabdomyosarcoma by means of spectral karyotyping (SKY) and identified a novel translocation involving chromosome band 2q35, which is the locus of PAX3 gene. Furthermore, we identified the novel PAX3 rearrangement using fluorescence in situ hybridization (FISH) analysis. Additional identification of the partner gene may help disclose the molecular mechanism of the development of this embryonal subtype.

Intratumoral heterogeneity of MIB-1 labelling index in gastric gastrointestinal stromal tumor (GIST)

BackgroundThe MIB-1 labelling index (LI) is used as a prognostic indicator for gastrointestinal stromal tumors (GISTs). However, whether a biopsy-based LI represents the entire tumor is uncertain, because the LI is not always homogeneous. In this study, we examined the extent and characteristics of LI heterogeneity in gastric GISTs.MethodsWe analyzed ten c-kit-positive gastric GISTs with diameters exceeding 3 cm, of which six were multilobular and four were unilobular. For MIB-1-immunostained sections, continuous digital images were obtained through the maximum diameter of the lobules. We obtained LIs for images by carrying out computer-assisted image analysis, and calculated the means and standard deviations (SDs) of the LIs for the lobules. For each lobule, intralobular heterogeneity was evaluated on the basis of the SD. For multilobular tumors, interlobular heterogeneity was assessed on the basis of the mean LI difference between lobules.ResultsThe SDs, which ranged from 0.8% to 9.8%, indicated intralobular heterogeneity. Moreover, considerable interlobular heterogeneity was noted in five (83%) of the six multilobular GISTs, in which the maximum interlobular mean LI difference ranged from 9.6% to 27.2%. Notably, although the high maximum mean LI (14.1%–32.3%) showed that these five GISTs were high-grade tumors, they also contained at least one lobule showing a low-grade mean LI value (2.7%–5.1%).ConclusionGastric GISTs often show intralobular or interlobular MIB-1 LI heterogeneity. In multilobular GISTs, multiple biopsy samples may be required for the accurate evaluation of tumor grade.