Jun-ichi Tanuma

Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats

Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats.

Intraneural perineurioma arising in the lateral border of the tongue

To the Editor: The term perineurioma (PN) was first suggested by Lazarus and Trombetta in 1978 to describe a rare peripheral nerve sheath tumor consisting of the proliferation of neoplastic perineurial cells. It is divided into four types on the basis of histological findings: soft tissue, sclerosing, reticular and intraneural PN. Soft tissue PN generally occurs as a nodular mass subcutaneously, especially in the extremities of adults. Sclerosing PN prefers the fingers of adults and reticular PN is generally observed within the upper limbs of adult women. Intraneural PN causes enlargement of the affected nerve, especially the thick nerves of the extremities of infants and young adults. Although the etiology of this lesion is unknown, the possibility of a clonal neoplastic disorder has been supported by a previous report. Intraneural PN in oral regions is extremely rare; only six cases have been reported in the literature. This report describes an unusual case of intraneural PN in the lateral border of the tongue with histological and immunohistochemical findings. A 14-year-old boy presented at his primary dental clinic because of a painless nodule in the right lateral border of the tongue. The patient had first noticed the nodule on the surface of the tongue 2 years ago and reported that it was gradually increasing in size. He had no prior history of trauma; intraoral examination revealed an elastic, wellcircumscribed nodule on the right lateral surface of the tongue (Fig. 1a). The lesion was approximately 4 × 3 mm in size, and the overlying epithelium was whitish and smooth. An excisional biopsy of the nodule was performed under local anesthesia (Fig. 1b). Histopathologically, the preparation disclosed a sessilebased and relatively well-circumscribed lesion composed of spindle-shaped cells arranged concentrically around the axons of a small peripheral nerve, forming numerous pseudo-onion bulb structures (Fig. 1c). In addition, there were many small peripheral nerves continuously from the bottom of the excisional fragment of the lesion (Fig. 1d). The pseudo-onion bulb structures consisted of a fibrous connective tissue with increased irregular collagen bundles with many capillary blood vessels and few inflammatory cells (Fig. 2a,b). Immunohistochemically, the spindle-shaped cells were positive for epithelial membrane antigen (EMA) (Fig. 2c). Glucose transporter 1 was positive within the tumor cell population, and Vimentin positivity was observed throughout. In contrast, S-100 protein immunostaining was positive in the Schwann cells and centrically located axons but negative in the pseudo-onion bulb structures (Fig. 2d). The tissue showed no positive staining for the other antigens tested (cytokeratin and CD34). These findings completely confirm a diagnosis of intraneural PN. The postoperative course was uneventful and 6 months after the operation there was no sign of recurrence. PN is a rare peripheral nerve sheath tumor usually affecting the extremities of infants to adults. Only six cases in the oral region have been reported and five of these cases occurred in the tongue. Four of the previous six cases were located in the lateral border of the tongue. Intraneural PN commonly involves a thick nerve. Among the described cases of oral intraneural PN, the mandibular cases involved the inferior alveolar nerve, while the other cases affecting the tongue and buccal mucosa arose from an unnamed nerve. Generally, intraneural PN causes several symptoms, such as sensory or motor deficits, muscle weakness and muscle atrophy. The present patient did not show any symptoms; this is observed in most cases arising in oral soft tissue suggesting that these cases including the present case had no relationship to major nerves. Most peripheral nerve sheath tumors in the oral region are Schwannoma and neurofibroma, and PN is extremely rare. Histopathologically, soft tissue PN shows bundles, whorls or storiform arrangement composed of spindle-shaped and/or wavy cells with long, tapered cytoplasmic processes and elongated nuclei, within a dense collagenous stroma. Sclerosing PN reveals a proliferation of cords, storiform or small island-like arrangements composed of the cuboidal or epithelioid tumor cells within an abundantly dense collagenous stroma. Reticular PN shows a proliferation of the reticularlike tumor cells within a myxoid or fibrous stroma. Intraneural PN reveals numerous pseudo-onion bulb structures composed of whorled proliferation of spindle-shaped cells around central axons, as observed in the present case. Immunohistochemically, the spindle-shaped cells are positive for EMA but negative for S-100 protein, indicating that PN is derived from perineural cells. Although Schwann cells are positive for S-100 protein, the ratio of S-100-positive cells is lower than that for EMA. These immunohistochemical findings are useful for distinguishing between PN and other peripheral nerve sheath tumors. In the differential diagnosis of intraneural PN, the hereditary hypertrophic neuropathies of Charcot-Marie-Tooth disease and Déjerine-Sottas should be considered. In these diseases, true onion-bulb structures Pathology International 2013; 63: 619–621 doi:10.1111/pin.12121 bs_bs_banner

Inflammatory Myofibroblastic Tumor Mimicking Apical Periodontitis

Inflammatory myofibroblastic tumors (IMTs) are rare. IMTs of the head and neck occur in all age groups, from neonates to old age, with the highest incidence occurring in childhood and early adulthood. An IMT has been defined as a histologically distinctive lesion of uncertain behavior. This article describes an unusual case of IMT mimicking apical periodontitis in the mandible of a 42-year-old man. At first presentation, the patient showed spontaneous pain and percussion pain at teeth #28 to 30, which continued after initial endodontic treatment. Panoramic radiography revealed a radiolucent lesion at the site. Cone-beam computed tomographic imaging showed osteolytic lesions, suggesting an aggressive neoplasm requiring incisional biopsy. Histopathological examination indicated an IMT. The lesion was removed en bloc under general anesthesia, and the patient manifested no clinical evidence of recurrence for 24 months. Lesions of nonendodontic origin should be included in the differential diagnosis of apical periodontitis. Every available diagnostic tool should be used to confirm the diagnosis. Cone-beam computed tomographic imaging is very helpful for differential diagnosis in IMTs mimicking apical periodontitis.

Pthlh, a promising cancer modifier gene in rat tongue carcinogenesis.

Susceptibly to the induction of rat tongue cancer (TC) by oral 4-nitroquinoline 1-oxide (4NQO) exposure is a polygenic trait. Among several quantitative trait loci identified by crosses between TC-susceptible Dark Agouti (DA) rats and TC-resistant Wistar-Furth (WF) rats, we focused on tongue cancer susceptibility locus (Tcas3) of chromosome 4. We examined tongue carcinogenesis in the reciprocal congenic strains DA.WF-Tcas3 and WF.DA-Tcas3 and in their parental strains. The Tcas3DA allele, and not the Tcas3WF allele, significantly favored tumor latency, incidence and TC number/size. In genomic DNA of TCs induced in (DA × WF) F1 rats, the resistant Tcas3WF allele was frequently and selectively lost, particularly in larger tumors. Thus, we searched the possible candidate genes in the Tcas3 region using microarray analysis of TCs in F1 rats and revealed significant upregulation of 2 cancer-related genes, parathyroid hormone-like hormone (Pthlh) and Kras2. The relevance of the WF allele of Pthlh as a cancer modifier was indicated by 3 single nucleotide polymorphisms specific to this strain. In contrast, no consistent strain-specific variations were found in Kras2. Moreover, the plasma Ca2+ level was consistently higher in DA rats when compared to the level in WF rats bearing TCs; moreover, the Pthlh-mRNA expression level was >30-fold higher in TCs when compared to this level in the normal tongue mucosa. Immunostaining experiments showed strong PTHrP protein expression in TCs of DA rats, and the signal was intensified in larger TCs. Kras2 was also upregulated in TCs, but to a lesser degree than PTHrP. Thus, Pthlh is a promising candidate modifier gene in the development and progression of rat TCs.