Increased ratio of FoxP3+ regulatory T cells/CD3+ T cells in skin lesions in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug rash with eosinophilia with systemic symptoms (DIHS/DRESS) is a severe drug eruption accompanied by multiorgan disorders. Several unique aspects of DIHS/DRESS, including herpesvirus reactivation, liver dysfunction and hypogammaglobulinaemia, have similarities to graft-versus-host disease (GVHD). AIM: In this study, we focused on the dynamics of regulatory T cells (Tregs) infiltrating into the skin lesions of DIHS/DRESS and GVHD. METHODS: Skin biopsies were taken from patients with DIHS/DRESS, GVHD, or maculopapular drug eruption. Tregs were detected using immunostaining with anti-FoxP3. RESULTS: The ratio of FoxP3+ T cells to CD3+ T cells was significantly higher in the skin lesions of patients with DIHS/DRESS than in those of patients with GVHD, and was positively correlated with the number of days from disease onset in the acute phase. CONCLUSIONS: The dynamics of Tregs in skin lesions are different between DIHS/DRESS and GVHD, despite there being many similarities between these conditions.

Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren's syndrome.

The regenerating gene (Reg) was isolated originally as a gene specifically over-expressed in regenerating pancreatic islets and constitute a growth factor family. Reg gene product (Reg) is important in the pathophysiology of various human inflammatory diseases. Recently, the possible involvement of human REG in the regeneration of salivary ductal epithelial cells of patients with primary Sjögren's syndrome (SS) was reported. However, the expression of the REG family genes in minor salivary glands (MSG) and the occurrence of anti-REG Iα autoantibodies in SS patients were obscured. In this study, we examined the expression of REG family genes in the MSG of SS and screened anti-REG Iα autoantibodies in SS. The mRNA levels of REG family genes in MSG were quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR) and REG Iα expression in the MSG was analysed by immunohistochemistry. The mRNA level of REG Iα in the MSG of SS patients was significantly higher than that of control. REG Iα protein was expressed highly in SS ductal epithelial cells. Anti-REG Iα autoantibodies in the sera were found in 11% of SS. All the MSG in the anti-REG Iα autoantibody-positive group showed REG Iα expression, whereas only 40% showed REG Iα expression in the anti-REG Iα autoantibody-negative group. The anti-REG Iα autoantibody-positive group showed significantly lower saliva secretion and a higher ratio of grade 4 (by Rubin-Holt) in sialography. These data suggest strongly that autoimmunity to REG Iα might play a role in the degeneration of MSG ductal epithelial cells in primary SS.

Invasive growth of hepatic angiomyolipoma; a hitherto unreported ominous histological feature.

AIMS: Although histological features of hepatic angiomyolipoma (AML) are highly variable, true malignant change is extremely rare. The aim was to review the histological features of invasive growth and clinical outcomes in 39 cases of hepatic AML. METHODS AND RESULTS: An invasive growth pattern into surrounding hepatic parenchyma, portal triads and/or around hepatic veins was found in 24 of 39 tumours (62%). One variant showed tumour cells replacing hepatocytes within the liver cell cords. The other consisted of portal or perivascular invasive growth along blood vessels. In the former pattern, small isolated tumour cell clusters were occasionally found in the vicinity of the main mass, showing a sprouting pattern. Although these histological features suggest malignancy, distant metastases were not found in any of the cases within a mean follow-up period of 6.8 years. CONCLUSIONS: A previously unrecognized histological feature of an invasive growth pattern, which suggests malignancy and might promote an erroneous diagnosis, was frequently found in hepatic AMLs. However, among about 180 reported hepatic AMLs, including the present cases, only one hepatic AML with distant metastasis has been reported to date and nearly all hepatic AMLs behave in a benign fashion. Therefore, pathologists should not overdiagnose malignancy based solely on the histological invasive growth patterns described in this paper.

Intraluminal duodenal diverticulum: MR findings.

We report a case of intraluminal duodenal diverticulum with special reference to its magnetic resonance imaging findings. An intraluminal duodenal fluid collection surrounded by a hypointense rim on T2-weighted or magnetic resonance cholangiopancreatographic images, the shape of which is changed by peristalsis, is considered to be almost diagnostic for intraluminal duodenal diverticulum.

Differentiation of soft tissue haemangioma by 201Tl scintigraphy.

Radiological diagnosis of deep soft tissue is often difficult. In the present study, thallium-201 ( Tl) uptake into haemangiomas and deep malignant soft tissue tumours was investigated in order to assess its clinical utility. Tl scintigraphy was reviewed in four patients presenting with soft tissue haemangiomas. Early and delayed planar images, obtained at 15 min and 3 h following the intravenous injection of Tl (111 MBq), were examined. The Tl uptake ratio was calculated by dividing the count density of the tumour region of interest (ROI) by that of the background ROI. Results were compared with those of five cases of rhabdomyosarcoma and a single instance of angiosarcoma. All haemangioma lesions demonstrated increased Tl uptake in early images. However, Tl uptake in delayed images was markedly decreased. No significant differences were observed in the early uptake ratio between haemangiomas (1.60-2.72) and reference malignant tumours (1.48-2.45); however, the difference was significant in delayed images (range, 1.01-1.26 vs. 1.43-2.03, respectively) ( P<0.02). Deep soft tissue haemangiomas revealed Tl accumulation in early images; however, a rapid washout was observed in delayed images. This distinctive feature may facilitate the use of Tl scintigraphy in the diagnosis of haemangiomas.

Mapping sentinel nodes in patients with early-stage gastric carcinoma.

BACKGROUND: Nodal status in gastric carcinoma is related not only to prognosis but also to the extent of nodal dissection. However, a method for accurate assessment of nodal status during operation has not been established. This study aimed to map the sentinel nodes of gastric carcinoma and to estimate the clinical usefulness of sentinel node biopsy. METHODS: Following laparotomy, a vital dye (0.2 ml 2 per cent patent blue) was injected through a gastroscope into the submucosal layer at four sites around a clinical T1 gastric carcinoma. The dye immediately appeared at the serosal surface and stained lymphatic vessels and nodes. The stained nodes were removed and examined by frozen sectioning. RESULTS: The assay was successful in mapping the lymphatic basins in 203 (96.2 per cent) of 211 patients. The dye stained one or more metastatic nodes in 31 patients, but failed to indicate a metastatic node in four patients with a large involved node. Meticulous postoperative examination of all resected nodes in the standard paraffin slices revealed no new metastases. The accuracy of the assay was 98.0 per cent. CONCLUSION: The method was accurate in predicting nodal status in patients with early-stage gastric carcinoma.

Intraoperative lymphatic mapping and sentinel lymph node biopsy in patients with papillary carcinoma of the thyroid gland.

We examined the feasibility of sentinel lymph node biopsy for thyroid cancer. Thirty-eight patients with papillary thyroid carcinoma underwent intraoperative lymphatic mapping and sentinel lymph node biopsy. At surgery, we exposed the thyroid gland and used a tuberculin syringe to inject 0.2 ml of 1% patent blue dye directly into the thyroid mass. The lymphatics and the lymph node dyed with blue dyes, was excised as a sentinel lymph node. Modified radical neck dissection was performed following sentinel lymph node biopsy and the diagnostic ability of sentinel lymph node biopsy was examined. A sentinel lymph node was identified successfully in 27 (71%) of 38 patients. Sentinel lymph node biopsy removed one to three lymph nodes (median, two nodes). Eighteen patients had paratracheal sentinel lymph nodes, five patients had jugular sentinel lymph nodes, and four patients had both. Histological nodal metastasis was recognized in 16 of 27 cases. The positive rate of cancer metastases in sentinel lymph nodes was 58%, which was significantly higher than 11% in non-sentinel lymph nodes. Diagnostic ability of sentinel lymph node biopsy showed that accuracy was 89%, sensitivity was 84%, and specificity was 100%. Our preliminary study indicated that sentinel lymph node biopsy was available on detection of non-palpable nodal metastasis in the patients with thyroid cancer; however, further experience and refinement are needed.

[Treatment for bilateral multiple lung cancers].

During a 27-year period 1,839 patients with lung cancer were treated at Kanazawa University Hospital. Of these 1,839 patients, 25 (1.3%) were classified as bilateral multiple lung cancers by Martini's criteria. They consisted of 14 synchronous carcinomas and 11 metachronous carcinomas. For the patients with synchronous carcinomas, 5 underwent bilateral operation, and 5 underwent ipsilateral operation and contralateral combination therapy (Nd:YAG, irradiation or chemotherapy). Four did not undergo operation. While for the patients with metachronous carcinomas, 9 underwent operation for bilateral lesions, 2 were treated by radiotherapy for the second primary lung cancer. When a pulmonary resection for bilateral multiple lung cancers is required, radicality and the need to preserve residual respiratory function and cardiac function (FEV1.0 more than 500 ml/DSA, performance status) must be considered in making the decision to operation. The 5-year survival rate was 67%, 41%, and 33% in cases treated by operation for bilateral lesions, ipsilateral operation and contralateral combination therapy, and non-surgical therapy. Multidisciplinary treatment based on surgical resection contributed to good prognosis of bilateral multiple lung cancers. A long-term detailed follow-up is necessary to detect second lung carcinoma after the first operation as soon as possible.

Intense 201 Tl uptake in giant-cell tumour of bone.

The aim of this study was to determine the characteristics and clinical usefulness of 201Tl scintigraphy in giant-cell tumour of bone (GCT). Twenty-one patients with histopathologically proven benign GCT (22 lesions; 18 primary and four recurrent) underwent 201Tl scintigraphy. We also studied conventional osteosarcoma (10 lesions), a very common primary malignant bone tumour; and chordoma in the sacrum (four lesions), an entity requiring differential diagnosis from GCT of the sacrum. Early and delayed planar imaging was performed at 15 min (early) and 3 h (delayed) after the intravenous injection of 201Tl chloride (111 MBq). The Tl uptake ratio was calculated by dividing the count density of the tumour region of interest (ROI) by that of the background ROI. All GCT lesions showed increased Tl uptake in both early and delayed images. The mean Tl uptake ratios of primary GCT were 4.7 (range, 2.0-11.1) in the early images and 2.2 (range, 1.4-3.6) in the delayed images, and those of recurrent lesions were 5.8 (range, 2.4-11.5) in the early images and 2.7 (range, 2.0-4.3) in the delayed images. There were no significant differences between the uptake ratios in GCT and osteosarcoma, but the values of GCT tended to be higher than those of osteosarcoma, 3.1 (range, 1.7-4.4) in the early images and 1.8 (range, 1.3-2.3) in the delayed images. Chordoma did not show appreciable Tl uptake: the uptake ratio was 1.19 (range, 0.98-1.5) in the early images and 1.1 (range, 1.0-1.3) in the delayed images. In GCT, a benign lesion, Tl scintigraphy demonstrated marked uptake in both primary and recurrent lesions with no exceptions, precluding the use of Tl scintigraphy for the differential diagnosis of GCT from malignant tumours. However, the Tl scintigraphy can be used for excluding GCT when no lesional Tl uptake is observed, and diagnosing recurrent lesions on post-operative follow-up.

Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessment from the point of view of nodal micrometastasis.

OBJECTIVE: We sought to determine the critical diameter of a peripheral non-small cell lung cancer tumor less than which no evidence of nodal micrometastasis is present. METHODS: Samples of 3081 lymph nodes from 181 patients with stage I peripheral lung cancer (155 with adenocarcinoma and 26 with squamous cell carcinoma) who had undergone complete resection with systematic lymphadenectomy were used in the study. In the samples immunohistochemical staining for cytokeratin was performed. The expression of vascular endothelial growth factor (VEGF) at primary sites was also immunohistochemically assessed. RESULTS: Nodal micrometastasis was detected in 44 patients. The mean tumor sizes were 2.2 +/- 1.3 cm (range, 1.0-7.0 cm) in nodal micrometastasis-positive adenocarcinoma, 2.1 +/- 0.9 cm (range, 0.5-6.0 cm) in nodal micrometastasis-negative adenocarcinoma, 4.8 +/- 2.3 cm (range, 2.2-10.0 cm) in nodal micrometastasis-positive squamous cell carcinoma, and 3.2 +/- 2.1 cm (range, 0-9.0 cm) in nodal micrometastasis-negative squamous cell carcinoma. The tumor size in the nodal micrometastasis-positive group tended to be greater than that in the nodal micrometastasis-negative group in squamous cell carcinomas, but there was no significant difference in adenocarcinomas. Nodal micrometastasis was not found in patients with squamous cell carcinoma of 2.0 cm or less in diameter. However, nodal micrometastasis was found in 20% (19/95) of the patients with adenocarcinoma of 1.1 to 2.0 cm in diameter and even in 4 of 11 patients with adenocarcinoma of 1.0 cm or less. Among the patients with nodal micrometastasis, survival of patients with vascular endothelial growth factor overexpression was worse than that of patients without it. The survival of patients with nodal micrometastasis without vascular endothelial growth factor overexpression was comparable with that of patients without nodal micrometastasis. CONCLUSION: A limited surgical intervention without lymphadenectomy is validated for squamous cell carcinoma of 2.0 cm or less without pleural involvement. In adenocarcinoma the tumor size itself is not a reliable guide for nodal micrometastasis status. In patients with nodal micrometastasis with vascular endothelial growth factor overexpression, the risk of systemic disease should be considered.

Primary mediastinal germ cell tumor in a middle-aged woman: case report and literature review.

Although primary mediastinal germ cell tumors are found much more frequently among young males than among other people, we recently encountered a middle-aged woman with the disease. The patient was a 59-year-old woman who complained mainly of anterior chest pain. Chest CT scans revealed a nonhomogeneous mass measuring 7 x 7 cm in the anterior mediastinal area, accompanied by signs suggestive of mediastinal invasion of the tumor. Reduction surgery was performed. The pathologic diagnosis was mediastinal dysgerminoma. The patient received postoperative radiochemotherapy but died due to liver metastasis 11 months after surgery.

Thymic lesions in patients with myasthenia gravis: characterization with thallium 201 scintigraphy.

PURPOSE: To assess thallium 201 ((201)Tl) single photon emission computed tomography (SPECT) for evaluation of thymic lesions associated with myasthenia gravis (MG), including lymphoid follicular hyperplasia (LFH) and thymoma. MATERIALS AND METHODS: (201)Tl SPECT and computed tomography (CT) were performed preoperatively in 46 patients with MG who had undergone thymectomy. SPECT was conducted 15 (early image) and 180 (delayed image) minutes after (201)Tl injection. Results were visually assessed, and (201)Tl uptake ratios (thymic lesion count density/lung count density) were measured for quantitative analysis. Uptake was analyzed among the normal thymus, LFH, and thymoma patient groups. RESULTS: Histopathologic results indicated a normal thymus, LFH, and thymoma in 19, 16, and 11 patients, respectively. Mean uptake ratios in the normal thymus, LFH, and thymoma were 0.96 (95% CI: 0.90, 1.03), 1.14 (95% CI: 1.04, 1.25), and 1.87 (95% CI: 1.56, 2.25), respectively, on early images and 1.09 (95% CI: 1.00, 1.18), 1.65 (95% CI: 1.48, 1.85), and 2.03 (95% CI: 1.65, 2.50), respectively, on delayed images. Thymoma showed more intense (201)Tl accumulation than did the normal thymus (P <.001) and LFH (P <.001) on early images. Both thymoma (P <.001) and LFH (P <.001) displayed more intense uptake than did the normal thymus on delayed images. CONCLUSION: (201)Tl SPECT can enable differentiation between normal thymus, LFH, and thymoma in patients with MG.

[Primary small cell carcinoma of the kidney: a case report].

A 43-year-old male visited our hospital with the complaint of right flank colicky pain. Computed tomographic (CT)-scan and angiography showed large renal tumor with liver invasion and tumor thrombosis in the vena cava. Multiple lung and bone tumors were also recognized. Percutaneous biopsy of the renal tumor revealed small cell carcinoma. Multiple lung masses were diagnosed as metastatic tumors according to the results of bronchoscopic biopsy. Chemotherapy including cisplatinum and etoposide was performed without success. He died 6 months after the diagnosis. Autopsy specimen revealed primary small cell carcinoma of the right kidney. To our knowledge, this is the seventh case as primary renal small cell carcinoma in the world literature.

Immunohistochemical detection of cytokeratin 18 and its neo-epitope in Warthin's tumor (adenolymphoma) of the parotid glands.

An immunohistochemical method using a monoclonal antibody M30 (MAb M30), which reacts with the product released by cleavage of cytokeratin 18 (CK18) by activated caspase, was used to investigate the presence and extent of apoptosis in 36 cases of Warthin's tumor (WT) of the parotid glands. The distribution of CK18 in WT was also determined and compared with that of the product detected by MAb M30. In WT, CK18 was observed mainly in the tumor cells of duct-like structures, but not in the cells of lymphatic tissues. Positive MAb M30 reaction products were found in luminal contents, duct-like structures and the cytoplasm of some macrophages in lymphatic areas near the duct-like structures in WT. These findings indicated that apoptotic cells are phagocytosed and eliminated as waste by macrophages. It is suggested that a mechanism which regulates the balance of proliferative activity and apoptosis may be closely linked to the growth of WT.

Blockade of eosinophil migration and airway hyperresponsiveness by cPLA2-inhibition.

We examined the role of a cytosolic phospholipase A2 (cPLA2) in antigen-induced eosinophil infiltration of airways and in airway hyperresponsiveness to methacholine. Inhibition of cPLA2, or blockade of the platelet-activating factor (PAF) receptor, blocked antigen-induced airway hyperresponsiveness and suppressed eosinophil infiltration. Neither cyclooxygenase nor 5-lipoxygenase inhibition had either effect. We show here that, in antigen-sensitized guinea pigs, cPLA2 inhibition prevents both eosinophilic infiltration and subsequent airway hyperresponsiveness after antigen challenge. We also show that this effect is mediated by first-step hydrolysis of membrane phospholipid into lysophospholipid rather than by prostanoid or leukotriene metabolites of arachidonate.

Malignant transformation of a giant cell tumor 25 years after initial treatment.

The current authors report a patient in whom a malignant fibrous histiocytoma developed long after a benign giant cell tumor of bone was removed from the same site. Twenty-five years after a benign giant cell tumor of the lateral condyle of the proximal tibia had been treated by curettage and iliac bone grafting without radiotherapy, a 53-year-old woman noted progressive pain and an enlarging mass in the same area. Radiographs showed osteolytic change, whereas magnetic resonance imaging indicated a tumor arising at the site of the giant cell tumor and extending beyond the bone. Examination of an open biopsy specimen showed a high-grade malignant fibrous histiocytoma with some areas rich in giant cells. After five courses of caffeine assisted intraarterial chemotherapy, the tumor was resected with an adequate margin, and the defect was reconstructed with an implanted prosthesis of corresponding shape. The extensor mechanism of the knee was reinforced using an allograft of fascia from the tensor fascia lata muscle. The resected specimen showed a good histologic response (95% tumor necrosis) to preoperative chemotherapy. Excellent function in the knee has been regained with no evidence of disease recurrence. Caffeine potentiated chemotherapy was effective in minimizing the extent of tumor excision, in this case of high-grade malignant fibrous histiocytoma representing transformation from a benign giant cell tumor.

Sentinel lymph node biopsy in breast cancer using blue dye with or without isotope localization.

BACKGROUND: The purpose of this study was to determine the feasibility of sentinel lymph node (SLN) biopsy using blue dye with or without isotope localization to predict the presence of axillary and internal mammary lymph node (IMN) metastases in patients with breast cancer. We also investigated whether multiple sectioning of the SLN could improve the accuracy of frozen section examination. METHOD: One-hundred twenty-six patients underwent dye-guided or dye- and gamma probe-guided SLN biopsy followed by complete axillary lymph node dissection (ALND). No ALND was performed in the 14 patients with small tumors and a negative SLN. In addition, 69 patients underwent IMN biopsy. RESULTS: The axillary SLN was identified in 123 of 140 (88%) patients. An accuracy rate of 90% was obtained by frozen section examination of the SLN, which increased to 100% in patients examined with a greater number of sections. Lymphatic flow to the IMN and/or a radioactive hot spot in the IMN was found in 9 of 102 (9%) patients, while a hot node was detected using a gamma probe in only 2 of these patients. No involvement of the IMNs was found histologically in these 9 patients. IMN involvement was found in 7 of 61 (11%) patients without lymphatic flow to the IMNs or a hot spot by lymphoscintigraphy or who did not undergo lymphoscintigraphy. CONCLUSION: ALND can be avoided in patients with small breast cancers and a negative SLN. SLN biopsy guided by lymphatic mapping is unreliable for identifying metastases to IMNs.

[A case of adenocarcinoma complicated with massive leukocytosis and hypercalcemia].

A 66-year-old man was admitted to our hospital complaining of non-productive cough and low-grade fever. Chest X-ray examination revealed a mass shadow in the right hilum. Transbronchial lung biopsy of the tumor mass yielded a diagnosis of adenocarcinoma. Despite repeated chemotherapy using CDDP and VDS, metastasis to the right adrenal gland and right femur occurred, and was accompanied by hypercalcemia and hypophosphatemia. Serological study revealed elevated levels of PTH-rP and G-CSF. Six months after adenocarcinoma was diagnosed, multiple skin metastases of the cancer were observed. Immunohistochemical staining for PTH-rP and G-CSF indicated that production of cytokines had caused a paraneoplastic syndrome including hypercalcemia and leukocytosis. It appeared that the elevation of G-CSF was induced by IL-6 produced from PTH-rP in cancer tissue. Documentation of similar cases is required.