The clinicopathologic features of two Japanese sisters with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) are described. Neither patient had a history of hypertension, and both experienced cerebrovascular events before reaching their forties. Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs. MRI showed extensive cerebral white matter lesions, which revealed remarkable arteriosclerotic changes on autopsy.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a distinctive clinicopathologic entity characterized by young adult-onset non-hypertensive vasculopathic encephalopathy accompanied by alopecia and disco-vertebral degeneration. CARASIL arteriopathy is histopathologically characterized by intense arteriosclerosis without the deposition of granular osmiophilic materials. Until now, the obliterative arteriosclerosis is the presumptive cause of subcortical ischemia in CARASIL; however, a detailed vascular pathology leading to diffuse leukoencephalopathy remains unclear. In this study, we examined two autopsied CARASIL brains in comparison with an autopsy case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Intensity of arterial sclerotic changes of CARASIL was evaluated by sclerotic index analysis. Immunohistochemical investigations were performed using a battery of primary antibodies, which recognized vascular cellular and extracellular components. As a result, sclerotic changes were disclosed to be mild and infrequent in CARASIL, in contrast to CADASIL that showed severe obliterative arterial changes. In CARASIL, conversely, most of the arteries were centrifugally enlarged and some were collapsed. We further revealed that arterial medial smooth muscle cells (SMCs) in patients with CARASIL were extensively lost, even in arteries without sclerotic changes. Arterial adventitia in CARASIL was conspicuously thin and immunoreactivities for type I, III, and VI collagens and fibronectin were appreciably weak in this region, indicating a reduction in the mural extracellular matrix (ECM). Because of the medial and adventitial degeneration, CARASIL brains likely receive marked fluctuations in blood flow because of deviations in the structural and functional basis of autoregulation mechanisms. We thus consider that diffuse leukoencephalopathy in CARASIL may be caused by arterial medial SMC loss with mural ECM reduction. We speculate that the abnormalities in the ECM are causatively related to the SMC degeneration, since the ECM is a crucial signal determining the biophysiological properties of arterial SMCs.

Ciliated muconodular papillary tumor (CMPT) is a rare papillary tumor that arises in the peripheral lung fields and is associated with the proliferation of ciliated and goblet cells and increased mucin production. We report a case of CMPT involving the rearrangement of the anaplastic lymphoma kinase (ALK) gene. The patient was an 84-year-old Japanese female who had exhibited a small nodular shadow on chest computed tomography during a regular checkup 10 years ago. She underwent a partial resection of segment S10 of the right lung. The cut surface of the surgical specimen revealed a well-circumscribed, jelly-like mass measuring 8 Â 8 Â 10 mm. Histologically, the tumor was composed of a mixture of ciliated, goblet, and basal cells arranged in a papillary pattern together with pools of mucin. A diagnosis of CMPT was made. The lung tumor cells were subjected to fluorescent in situ hybridization and highly sensitive immunohistochemical staining for the ALK protein, both of which produced positive results. CMPT usually follows a favorable course, but the exact nature of this tumor; i.e., whether it is benign or malignant, has not been established. This is the first reported case of an ALK-positive CMPT.

Two familial cerebro-vascular diseases characterized by different cerebral arterial pathologies and presenting in non-hypertensive young and middle-aged adults are described. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the deposition of smudged periodic acid-Schiff (PAS)-positive granules known as granular osmiophilic materials (GOM) in the media of small arteries and arterioles. The medial smooth muscle cells are completely lost, and intense adventitial fibrosis is present. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), or Maeda syndrome, is characterized by intense arteriolosclerosis without GOM deposition. Fibrous intimal proliferation, hyaline degeneration of the media, thickening and splitting of the internal elastic lamina, and concentric narrowing of the lumen are characteristic features. In PAS preparation, small arteries are occasionally stained homogeneously due to exudative changes, but never exhibit granular appearance in CARASIL (Maeda syndrome). Each of the small arterial changes is intense in the cerebral medullary and leptomeningeal arteries, leading to multifocal, confluent, or diffuse ischemic changes in the cerebrum. The authors suggest that CARASIL be referred to as 'Maeda syndrome' or 'CARASIL (Maeda syndrome)' to avoid confusion with CADASIL.

The postoperative outcome (including clinicopathologic features) in 19 patients with differentiated thyroid cancer of the isthmus was investigated to develop more appropriate surgical strategies for these lesions. The extent of thyroidectomy, including neck dissection, tumor size, nodal involvement, and other clinical features were evaluated. The incidence of intraglandular dissemination was about 16% in all patients. Analysis of regional node metastatic distribution revealed no definite metastatic pattern. In addition, there was no apparent correlation between tumor size and nodal involvement. Two of the six patients who underwent total thyroidectomy suffered permanent postoperative hypoparathyroidism. It is thus recommended that isthmusectomy, including an adequate edge of surrounding normal thyroid tissues of each lobe and modified or limited neck dissection when cervical nodes are palpably enlarged, is sufficient as an appropriate primary surgical procedure for differentiated carcinoma of the thyroid isthmus.