[Multiple myeloma with t (8;14) and t (11;14) and extramedullary infiltration of multiple organs].

A 69-year-old man presented with lumbago and was diagnosed with multiple myeloma (IgD-λ type, R-ISS stage II) with bone-destructive lesions in the lumbar spine and sacrum. Chromosome analysis showed t (8;14)(q24;q32) and t (11;14)(q13;q32). Treatment with daratumumab, lenalidomide, and dexamethasone resulted in partial response, but the disease relapsed, with a copy number increase in t (11;14) and abnormal amplification of the 1q21 region. The patient was treated for CMV enteritis, and was admitted to the hospital due to sudden abdominal pain. Gastrointestinal perforation was diagnosed by CT scan showing free air and wall thickening in the small intestine. Emergency surgery was performed, and the tumors in the perforated area were positive for CCND1 but negative for MYC on immunostaining. The patient's general condition did not improve after the surgery and he died. Pathological autopsy revealed extramedullary infiltration of multiple organs in addition to the small intestine. Extramedullary infiltration is thought to be caused by clonal evolution, and further research is warranted to clarify its pathogenesis and establish effective therapeutic strategies in high-risk patients.

[A Patient with CA19-9-Producing Pulmonary Adenocarcinoma Who Responded to Multidisciplinary Therapy and Achieved Complete Response].

The patient, a man in his 60s, visited his physician with hemosputum. The shadow of a large mass, measuring approximately 6 cm in diameter, was observed in the left upper lung field, and the patient was referred to our hospital. After thorough examination, the mass was diagnosed as a pulmonary adenocarcinoma. In addition, serum CA19-9 levels were elevated(608.9 U/mL). Based on the PET-CT scan, the cancer was diagnosed as cT2bN1M0, stage II B disease and surgery was performed. The thorax was opened via a posterolateral incision; left upper lobectomy and lymph node dissection(ND2a-2)were performed. The lesion, measuring 56×59×44 mm, was excised from S1+2. The histopathological diagnosis was poorly-differentiated adenocarcinoma(mucin-producing adenocarcinoma). On immunostaining, the lesion was CA19-9-positive and was confirmed as pT2bN1M0, stage II B disease. The serum CA19-9 level was still elevated after surgery(83.2 U/mL). Therefore, 6 courses of adjuvant chemotherapy(carboplatin plus weekly paclitaxel)were administered. Grade 2 adverse events included hair loss and neutropenia. Thus, the drug withdrawal period was extended. After completion of 2 courses of the therapy, the serum CA19-9 level normalized. Two years after surgery, there has been no sign of recurrence.

Neutrophil depletion protects against zomepirac-induced acute kidney injury in mice.

Acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs have been implicated in drug toxicity. Zomepirac (ZP) is a non-steroidal anti-inflammatory drug that was withdrawn from the market because of anaphylactic reactions and renal injury. We recently established a novel mouse model of ZP-induced kidney injury by increasing zomepirac acyl-glucuronide (ZP-AG) concentration via pretreatment with tri-O-tolyl phosphate, a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine, a glutathione synthesis inhibitor. Although we have shown that ZP-AG is responsible for ZP-induced kidney injury in mice, the exact pathogenic mechanisms of ZP-induced kidney injury have not been investigated yet. In this study, we aimed to investigate the role of immune cells in the pathogenesis of ZP-induced kidney injury, as a representative of AG toxicity. We found that the counts of neutrophils and inflammatory monocytes increased in the blood of mice with ZP-induced kidney injury. However, clodronate liposome- or GdCl3-induced monocyte and/or macrophage depletion did not affect blood urea nitrogen and plasma creatinine levels in mice with ZP-induced kidney injury. Neutrophil infiltration into the kidneys was observed in mice with ZP-induced kidney injury, whereas anti-lymphocyte antigen 6 complex, locus G (Ly6G) antibody pretreatment prevented the renal neutrophil infiltration and partially protected against ZP-induced kidney injury. The mRNA expression of neutrophil-infiltrating cytokines and chemokines, interleukin-1α and macrophage inflammatory protein-2α, increased in mice with ZP-induced kidney injury, whereas pretreatment with anti-Ly6G antibody resulted in a marked reduction of their expression. These results suggest that ZP-AG might be involved in kidney injury, partly via induction of neutrophil infiltration. Therefore, this study may provide an important understanding on toxicological role of ZP-AG in vivo that helps to understand toxicity of AG metabolites.

Reverse adipofascial flap after resection of a malignant perineurioma of the forearm.

The authors describe a patient with recurrent perineurioma arising in the subcutaneous tissue of the dorsal forearm and extending along the forearm fascia. Soft tissue perineurioma is a rare, originally benign peripheral nerve sheath neoplasm arising from the perineurium, a protective cell barrier surrounding the individual fascicles in peripheral nerves. Perineurioma has only recently been recognized as an entity distinct from other nerve sheath tumors, such as schwannoma and neurofibroma, with unique morphologic, ultrastructural, and immunoreactive features. The recurrent tumor had converted into malignant perineurioma, defined as increased nuclear pleomorphism and cellularity. The ill-marginate feature extending along the fascia required wide resection, leaving a substantial defect on the distal forearm. Surgical repair of large forearm skin defects is challenging because of limited skin extensibility for flap creation, the prominence of the site in terms of aesthetic outcome, and the risk of damage to extrinsic muscles that control delicate hand movements. The reverse forearm adipofascial flap, which was based on distal perforators of the radial artery, was suitable for the current case to cover the exposed myotendinous junctions of the forearm extensor muscles. This flap did not sacrifice skin, a major vessel, or skeletal muscles, and preserved function at both the donor and the recipient sites. The texture of the graft was similar to that of the surrounding skin. The clinical and histopathologic features of this rare tumor are also described to aid in the differential diagnosis and as a reference for surgeons who treat soft tissue neoplasms and may encounter this type of soft tumor.

Clinicopathological characterization of TSH-producing adenomas: special reference to TSH-immunoreactive but clinically non-functioning adenomas.

Thyrotropin (thyroid-stimulating hormone (TSH))-producing pituitary adenomas have been known to be quite variable in clinical features covering from typical functioning TSH-producing adenomas (FTSHomas) associated with hyperthyroidism to clinically silent TSH cell adenomas (STAs) that are apparently unassociated with hyperthyroidism. It is important to distinguish STAs from other types of clinically non-functioning adenomas for adequate postoperative managements. However, because of rareness of TSH-producing adenomas, their histopathological features linking to the clinical manifestations have not been well characterized. Herein, we investigated clinical and histopathological findings to characterize 29 TSH-producing adenomas including 20 FTSHomas and nine STAs. Clinical symptoms of the patients with STAs included headache, visual defect, vertigo, and nausea. All STAs and 19 FTSHomas were macroadenoma. The average tumor size of STAs was significantly larger than that of FTSHomas (P < 0.05). The invasiveness was detected in 33% STAs and in 20% FTSHomas. Both STAs and FTSHomas showed a variety of morphological features and immunohistochemical profiles. Chromophobic polygonal or short-spindled tumor cells usually proliferated in a diffuse pattern, while they exhibited globoid or whorl-like appearance with intertwined cytoplasmic processes in both subgroups. Stromal fibrosis and calcification were often noted. Their nuclei were somehow pleomorphic. Ultrastructural features of all four STAs examined were similar to those of normal thyrotrophs. Thus, STAs and FTSHomas were indistinguishable by histology alone. Immunohistochemically, the number of TSH-positive cells in individual FTSHomas was highly various. Six tumors showed only a few TSH-positive cells (1-5%), and three were negative for TSH by conventional method without antigen retrieval. After proteinase K treatment, these tumors turned out TSH positive. As defined, STAs were TSH positive in more than 20% of tumor cells and three of them in more than 50%. Growth hormone- and/or prolactin-positive cells were detected in 55% STAs and 63% FTSHomas. Both pituitary-specific transcription factor 1 and GATA-binding protein 2 were expressed in all STAs and 20 FTSHomas. Membranous somatostatin receptor (SSTR)-2A immunoreactivity was found in 89% STAs and 94% FTSHomas, whereas SSTR5 was positive in 78% of both STAs and FTSHomas. MIB-1 labeling index was related to tumor invasiveness and tumor size (P < 0.05, P = 0.09, respectively). Thus, although both STAs and FTSHomas showed unique histopathological features distinct from other type adenomas, these two subgroups were indistinguishable by histopathology. Immunohistochemistry for TSH by use of antigen retrieval, transcription factors, and SSTRs may be useful to confirm STAs and to determine the postoperative therapy among various kinds of clinically non-functioning adenomas.

The pathogenesis of slippage and deformity in the pediatric lumbar spine: a radiographic and histologic study using a new rat in vivo model.

STUDY DESIGN: Rat lumbar spines with posterior destabilizing surgery were evaluated radiographically and histologically. OBJECTIVES: To create an appropriate rat model showing the vertebral slippage and deformities frequently observed in pediatric patients with spondylolysis, and to clarify their pathogenesis. SUMMARY OF BACKGROUND DATA: There are controversial hypotheses regarding the pathogenesis of slippage and deformities of the pediatric spine with pars defects. Furthermore, there is no appropriate animal model mimicking those conditions. METHODS: After posterior destabilizing surgery, the lumbar spines of young (4-week-old) and adult (26-week-old) rats were radiographically examined at weekly intervals during 3 weeks, and histologically 3 weeks after the surgery. RESULTS: Slippage occurred in the young rats, but not in the adult rats. In the young rats, 7.2% slippage was observed 1 week after the surgery, whereas the slippage in the adult rats was 0%. The difference in percentage of slippage between the two groups was significant (P < 0.05). Lumbar deformity also was seen in the young rats, but not in the adult rats. The lumbar index of L6, as an indicator of L6 rounding, was 91.7% immediately after surgery. It had decreased to 87.7, 84.6, and 74%, respectively, 1, 2, and 3 weeks after surgery. Histologic examination showed growth plate injury in the young group and pronounced disc degeneration in the adult group. CONCLUSIONS: The young rat with posterior destabilizing surgery was an appropriate animal model, mimicking the slippage and deformities radiographically seen in pediatric patients with spondylolysis. The histologic examination indicated that vertebral growth plate impairment was the basic lesion causing such slippage and deformities in pediatric spines.

Unique cell membrane expression of topoisomerase-II alpha as a useful diagnostic marker of liposarcoma.

Topoisomerase-II alpha (Topo-II alpha) is known as a cell cycle-related intranuclear marker. To the best of our knowledge, the expression of Topo-II alpha on extranuclear sites has not been reported. The aim of the present study was to determine the usefulness of Topo-II alpha immunostaining for detecting the lipoblasts that are essential to diagnosing liposarcoma. Surgical specimens, including benign lipomatous tumors (four cases), well-differentiated liposarcomas (three cases), myxoid liposarcomas (six cases), pleomorphic liposarcomas (two cases), dedifferentiated liposarcomas (two cases), myxoid malignant fibrous histiocytomas (six cases), and one case of mesenteric panniculitis, were studied. Samples were immunostained using antibodies for Topo-II alpha, S-100 protein and Ki-67. In addition, we used the western blot method to investigate immunohistochemical-affinity in adipocytes. Mature adipocytes and lipoblasts in all of the benign and malignant lipomatous tumors intensively expressed cell contours positivity for Topo-II alpha. Cytoplasm of the lipoblasts occasionally reacted to the antibody and highlighted intracytoplasmic small unilocular, multivacuolated, or bubble-like patterns. Western blot analysis confirmed a 70 kDa product reactive to Topo-II alpha in the cell membrane fragment of mature adipocytes. S-100 protein expressed adipocytes and lipoblasts, but the detection of lipoblasts was not as easy as in Topo-II alpha immunostaining. Immunoreactivity of Ki-67 was limited to the nuclei, and the nuclear labeling index of Ki-67 correlated with that of Topo-II alpha. The immunoreactivity of Topo-II alpha for lipoblasts was more sensitive and obvious than those of S-100 protein. Immunostaining using the antibody for Topo-II alpha seems to be useful in recognizing lipoblasts that have been overlooked in hematoxylin-eosin-stained preparations, and is a useful marker for diagnosing liposarcoma.