Taku Homma

Airspace enlargement with fibrosis shows characteristic histology and immunohistology different from usual interstitial pneumonia, nonspecific interstitial pneumonia and centrilobular emphysema

The histologic characteristics of air space enlargement with fibrosis (AEF) are compared with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) and centrilobular emphysema (CLE) to determine similarities and differences. Lung specimens from 39 patients were studied; 9 with AEF, 13 with UIP and 5 with CLE identified in lobectomy specimens for cancer and 12 NSIP cases identified on surgical lung biopsies. We determined the characteristics of cystic structures (i.e. abnormal airspace), degree of inflammation and severity of pneumocyte injury semi‐quantitatively. In AEF, the wall thickness of the cystic lesions (0.8 mm) was thinner than in UIP (2.1 mm) and thicker than in CLE (0.07 mm). The degree of inflammation and granulation tissue were milder in AEF than in UIP and NSIP and CLE showed milder inflammatory cells than AEF. As for pneumocyte injury, AEF had fewer erosions (0.1/case) and fewer ubiquitin‐positive pneumocytes than UIP (4.8 cells/slide) and NSIP (9.8 cells/slide). Our data suggested that the histological characteristics of AEF differed significantly from UIP, NSIP and CLE.

Anti-N-methyl-D-aspartate receptor encephalitis associated with carcinosarcoma with neuroendocrine differentiation of the uterus.

Dear Sirs, A 65-year-old woman was admitted to the neurology ward of our hospital with a suspected diagnosis of acute meningo-encephalitis. No antecedent flu-like episode was reported. Past medical history included a pelvic tumor which was initially diagnosed as a leiomyoma of the uterus. It had enlarged to a diameter of 10 cm in her pelvic space. On admission, her temperature was 37.6°C; her eyes were open but she was disoriented. The Glasgow Coma Scale score was 14 (E4 V4 M5) points. Signs of meningeal irritation were present. Other neurologic findings were normal. No involuntary movements were evident at admission. CSF analysis on admission showed leukocytes 51/mm3 with 134 monocular cells and 18 polymorphonuclear leukocytes, total protein concentration 23 mg/100 ml, and glucose 67 mg/100 ml (plasma glucose 119 mg/100 ml). HSV and HHV-6 DNA were not detected in CSF using the polymerase chain reaction method. CSF culture and cytology were negative. She was initially treated with acyclovir, panipemem–betamipron (a carbapenem-like antibiotic), vancomycin, and corticosteroids. However, on the 2nd hospital day, she became comatose, and her electroencephalogram demonstrated marked generalized slowing consisting of δ and θ waves. On the 8th hospital day, she exhibited tonic–clonic seizures and oral dyskinesia, which were treated with intravenous anticonvulsants. Her respiration was controlled with an endotracheal tube without the assistance of mechanical ventilation. Cranial MRI revealed abnormalities of high intensity in both, predominantly in the left, limbic area, mainly hippocampus and amygdala, on FLAIR and diffusion images, whereas gadolinium-enhanced T1-weighted image revealed no abnormality in these areas (Fig. 1). Her neurological condition did not improve despite the above treatments, and her comatose state persisted. The anti-NMDA-R antibody was detected in both serum and cerebrospinal fluid. On the 40th hospital day, she underwent surgical removal of the uterus and bilateral accessory organs. The pathological diagnosis was carcinosarcoma with neuroendocrine differentiation of the uterus. Microscopic findings of the tumor were as follows: on HE staining, solid nests of viable atypical cells were observed in the uterine tumor, though this tumor exhibited extensive necrosis. The majority of the atypical cells had scant cytoplasm and spheroid nuclei with granular chromatin, exhibiting frequent mitoses and marked venous/lymphatic infiltration. On immunohistochemical examination, most of this tumor was frequently positive for synaptophysin, neuron-specific enolase (NSE), and CD56. Chromogranin immunoreactivity was also noted. Immunoreactivity for keratin, myogenin, and desmin was detected in only a few neoplastic cells. We also examined whether the tumor exhibited NR1/NR2 subunits ectopically by immunohistochemical staining using a monoclonal antibody to NR1. The tumor was found to exhibit membranous NR1 staining (Fig. 1). She died from complications of multiple organ failure. No autopsy was performed. Fig. 1 Cranial MRI (a–c). Abnormalities of high intensity in both, predominantly in the left, limbic area, mainly hippocampus and amygdala, were revealed on FLAIR (a) and diffusion images (b), whereas gadolinium-enhanced T1-weighted image (c) shown no ... Anti-NMDA-R encephalitis is characterized by prominent psychiatric symptoms, dyskinesias, seizures, autonomic instability, and central hypoventilation [1, 2, 4]. The clinical manifestations in our patient were typical of this disorder. Dalmau and colleagues reported that about 55% of women with anti-NMDA-R encephalitis older than 18 years had an underlying tumor, usually mature or immature ovarian teratomas [2]. They confirmed that components of ovarian teratomas that contained nervous tissue exhibited NR1/NR2 subunits of NMDAR ectopically [1, 3]. Other tumors previously found in association with anti-NMDAR encephalitis did not exhibit subunits of NMDAR. The tumor in our patient was composed mostly of poorly differentiated neuroendocrine carcinoma, a histopathologically rare tumor of the uterus. There are no previous cases of carcinosarcoma with neuroendocrine differentiation reported in association with any paraneoplastic neurological syndromes. This is the first report of tumor cells with neuroendocrine differentiation associated with a paraneoplastic neurological syndrome and exhibiting NR1/NR2 subunits of NMDAR.

Characterization of microglia/macrophages in gliomas developed in S-100β-v-erbB transgenic rats

Glioma‐infiltrating microglia/macrophages are referred to as tumor‐associated macrophages (TAMs). Transgenic (TG) rats expressing v‐erbB, which is a viral form of the epidermal growth factor receptor, under transcriptional regulation by the S100‐β promoter, develop brain tumors. This study was designed to clarify the pathological characteristics of TAMs in these experimental tumors. We carried out immunohistochemical and morphometrical analyses of microglia/macrophages in brain tumors (5 malignant glioma, 4 anaplastic oligodendroglioma, 4 astrocytoma) that developed in TG rats. TAMs with ionized calcium‐binding adaptor molecule 1 (Iba1) positivity and morphology of activated, non‐phagocytic microglia increased within and around the tumors in malignant gliomas and anaplastic astrocytomas. The Iba1‐positive TAMs of the tumor core were significantly more activated than Iba1‐positive microglia of non‐neoplastic brain tissue in intraparenchymal anaplastic oligodendrogliomas. Iba1 expression showed a significant positive correlation to Ki‐67 expression in all the gliomas. Most TAMs showed no or little expression against CD68, CD163 or CD204, although CD204‐positive TAMs were observed in necrosis as well as in the proliferating vascular wall. In conclusion, S‐100β‐v‐erbB TG rats may serve as a useful animal model for further analysis of TAMs in terms of tumor cell proliferation, microvascular proliferation and phagocytosis, and as a tool for therapeutic use in malignant gliomas, although it should be noted that the polarization of TAMs toward the M2 phenotype remains unclear.

Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia.

Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disease, which is characterized clinically by parkinsonism, cerebellar ataxia and/or autonomic dysfunction, and pathologically by alpha‐synuclein‐related multisystem neurodegeneration, so‐called alpha‐synucleinopathy, which particularly involves the striatonigral and olivopontocerebellar systems, with glial cytoplasmic inclusions and neuronal cytoplasmic/nuclear inclusions (NCIs/NNIs). In the recent consensus criteria for the diagnosis of MSA, dementia is described as one of the features not supporting a diagnosis of MSA. However, MSA with dementia has been reported, although the location of the lesion responsible for the dementia remains unclear. In the present study, we aimed to investigate where this lesion may be found, by analyzing 12 autopsy‐proven MSA cases, with a particular focus on the medial temporal region. Three of 12 cases with MSA had dementia (MSA‐D). Compared with MSA cases without dementia, MSA‐D cases had frequent globular NCIs (G‐NCIs) in the medial temporal region, especially in their subiculum. In addition, MSA‐D cases could be divided into two types; MSA‐D with distinct fronto‐temporal lobar degeneration (FTLD type) and without distinct fronto‐temporal lobar degeneration (non‐FTLD type). There was no association between dementia and Alzheimer pathologies, such as neurofibrillary tangles and senile plaques. We suggest that frequent G‐NCIs in the medial temporal region, and particularly the subiculum, is one of the important pathological findings of MSA‐D, even when a case with MSA‐D reveals no significant cerebral atrophy.

Medial temporal regional argyrophilic grain as a possible important factor affecting dementia in Parkinson's disease

Argyrophilic grain (ArG) is the main pathological feature of argyrophilic grain disease (AGD) and is clinically characterized by cognitive impairment, behavioral abnormalities, personality changes, and emotional imbalances. However, ArG can not only be found in AGD but also in various other neurological disorders, including Parkinsons disease (PD). The association of ArG with psychosis and/or dementia in various neurological disorders remains unknown; in this study, we have investigated this in PD. The distribution and degree of ArG deposition, spongiform change in the transentorhinal cortex (TER SpC), and phosphorylated alpha‐synuclein‐positive neurites in CA2/3 were assessed, and we used formalin‐fixed, paraffin‐embedded specimens obtained from the anterior/posterior medial temporal region of 20 autopsy cases diagnosed as PD. These cases were clinically divided into two groups: PD without dementia (PDND) and PD with dementia (PDD). Most PDD cases revealed scattered to numerous ArG or moderate to severe TER SpC, both of which were rarely observed in the PDND group. Furthermore, by the degree of ArG density and TER SpC, the PDD group was further divided into three subtypes: PDD with ArG, with TER SpC and without ArG/TER SpC. Scattered‐to‐numerous ArG and/or moderate‐to‐severe TER SpC were observed only in PDD, which suggested that both ArG and TER SpC could be important factors affecting dementia in PD and that their distribution and degree are equally important.

Neuropathological features of Japanese familial amyotrophic lateral sclerosis with p.N352S mutation in TARDBP

In this case report, for the first time, we provide descriptive cliniconeuropathological features of a case of familial amyotrophic lateral sclerosis (familial ALS, FALS) with p.N352S mutation in TARDBP. The present Japanese patient (Figure 1, II-4, the proband) was born in Wakayama Prefecture. At 74 years, he experienced weakness in the muscles of both hand. He visited our neurology department with complaints of impaired fine motor skills of both hands at 76 years, and his neurological examination showed muscle weakness and muscular atrophy of both hands. At 77 years, his muscle weakness descended to both thighs, leading to difficulty in walking by himself. While his tongue revealed slight atrophy and fasciculation, there were no detectable upper motor neurone (UMN) signs, cognitive impairment, dysphagia, dysarthria, sensory disturbances, or gait disturbances. Electromyography disclosed active denervation of muscle potentials in both the upper and lower extremities, and he was diagnosed with ALS. His respiratory function gradually worsened, and he died of respiratory failure at 78 years, 4 years after onset. In the patient’s pedigree, his niece (III-2), who is now 60 years old, was also affected by ALS. She had complaints of muscle weakness of the lower extremities at 45 years and is currently on ventilatory support. She can still communicate using lip movements. Informed consent for the gene study was obtained from the patient and his family. Genomic DNA was extracted from peripheral blood leucocytes using standard methods. All exons and exon–intron boundaries of copper/zinc superoxide dismutase (SOD1) and TARDBP were analysed by polymerase chain reaction and direct sequencing, as previously reported [1,2]. TARDBP analysis identified a c.1055A>G heterozygous missense mutation at codon 352 (p.N352S) and no mutation of SOD1. The present study was approved by the ethics committees of all participating institutions. Neuropathologically, brain weight after fixation was 1295 g. Macroscopically, both the cerebrum and cerebellum were preserved. In the brainstem, medullary pyramid volumes were slightly decreased. The spinal cord was relatively preserved, except for slightly decreased volumes of both the cervical and lumbar enlargements and slightly atrophic spinal anterior roots. Major neuropathological features of the present case are summarized in Table 1. Microscopically, even though the shape of the spinal cord was preserved (Figure 2a), the spinal anterior horn was mildly affected by neuronal loss and gliosis (Figure 2b). A large number of axonal spheroids were noted in the spinal anterior horn (Figure 2c). In the residual anterior horn neurones, Bunina bodies were obvious (Figure 2d). The posterior funiculus, lateral and posterior horns and Clarke’s columns were well preserved. In the brainstem, slight neuronal atrophy and loss of both neurones and fibres with gliosis were observed in the hypoglossal, facial and motor nuclei of the trigeminal nerve. In addition, a Bunina body was observed in the hypoglossal nuclei and left motor nucleus of the trigeminal nerve. Other brainstem nuclei revealed no significant features. In the pyramidal tract, slight fibre loss with macrophage reaction was observed in both the lateral and anterior corticospinal tracts and in the medullary pyramids. In the precentral gyrus, slight atrophy and loss of Betz cells were observed, although no neuronophagia was detected. Other cerebral regions, including the frontal and temporal cortices, cerebral limbic system, striatonigral system, and cerebellum were preserved. The distribution of neurofibrillary tangles and senile plaques corresponded to Braak’s stage I and C, respectively [3,4]. The degree of neurogenic muscular atrophy was mild to moderate in the diaphragm, mild in the intercostal and iliopsoas muscles, and slight in the sternocleidomastoid muscle. Immunohistochemically, a few phosphorylated TAR DNA-binding protein of 43 kDa (pTDP-43)-positive rough dot-shaped neuronal cytoplasmic inclusions (NCIs) were observed in the spinal anterior horn neurones (Figure 2e). Moreover, a few glial cells with pTDP-43-positive crescentshaped glial intracytoplasmic inclusions (GCIs) were observed at the thoracic cord level (Figure 2f). Neurones with pTDP-43-positive NCIs were also detected in the dentate gyrus of the hippocampus, subiculum and cornu ammonis 2 area, but only a single affected neurone was

Differential diagnosis of trichosporonosis using conventional histopathological stains and electron microscopy.

Obana Y, Sano M, Jike T, Homma T & Nemoto N
(2010) Histopathology56, 372–383

A Japanese patient with familial ALS and a p.K510M mutation in the gene for FUS (FUS) resulting in the totally locked‐in state

We describe a Japanese patient with familial amyotrophic lateral sclerosis (ALS) and a p.K510M mutation in the fused in sarcoma gene (FUS). The patients condition was characterized clinically by an early onset and rapid progression. The patient eventually required mechanical ventilation and progressed to the totally locked‐in state. Neuropathologically, multiple system degeneration with many FUS‐immunoreactive structures was observed. The involvement of the globus pallidus, subthalamic nucleus, substantia nigra, cerebellar efferent system, and both upper and lower motor neurons in the present patient was comparable to that described for ALS patients with different mutations in FUS, all of whom progressed to the totally locked‐in state. However, the patient also exhibited degeneration of the cerebellar afferent system and posterior column. Furthermore, the appearance of non‐compact FUS‐immunoreactive neuronal cytoplasmic inclusions and many FUS‐immunoreactive glial cytoplasmic inclusions were unique to the present patient. These features suggest that the morphological characteristics of the FUS‐immunoreactive structures and distribution of the lesions vary with the diversity of mutations in FUS.

Phosphorylated α-synuclein immunoreactivity in the posterior pituitary lobe.

Parkinsons disease is now recognized as a major form of α‐synucleinopathy involving both the central and peripheral nervous systems. However, no research has focused on the posterior pituitary lobe (PPL), despite the fact that this organ also plays an important role in systemic homeostasis. In the present study, we aimed to distinguish phosphorylated α‐synuclein (pαSyn)‐positive deposits in the PPL, as is observed in Lewy body‐ and non‐Lewy body‐related disorders. PαSyn deposits were immunohistochemically analyzed using formalin‐fixed, paraffin‐embedded PPL specimens obtained from 60 autopsy cases. Among the cases with Lewy body‐related disorders, PPL pαSyn deposits were observed in almost all cases of Parkinsons disease (22/23), and in one case of dementia with Lewy bodies (1/1). On the other hand, only 3/36 cases of non‐Lewy body‐related disorders had pαSyn immunoreactivity in the PPL. The present study confirms the presence of pαSyn‐positive deposits, as demonstrated by high specificity (97.1%) and sensitivity (88.5%), in both Parkinsons disease and dementia with Lewy bodies, suggesting that this finding can be a useful hallmark of Lewy body‐related disorders.

Perirhinal accumulation of neuronal alpha‐synuclein in a multiple system atrophy patient with dementia

We report the case of a 79‐year‐old Japanese woman who developed cerebellar ataxia followed by rigidity, dysautonomia and cognitive disorders, and was thus clinically diagnosed as having possible MSA with dementia. Neuropathological findings demonstrated not only olivopontocerebellar and striatonigral degeneration with frequent glial cytoplasmic inclusions (GCIs), but also degenerative changes in the parahippocampal region, accentuated in the anterior portion of perirhinal cortex, where neuronal cytoplasmic inclusions (NCIs) and NFTs were numerous while GCIs were limited. NCIs were frequent in the deep layer, whereas NFTs were more frequent in superficial cortical layers. Other hippocampal subregions including subiculum, dentate fascia and cornu ammonis were minimally involved. NCIs in the perirhinal cortex showed intense argyrophilia with the Campbell‐Switzer silver impregnation method, but not argyrophilic with the Gallyas method. Most neuronal alpha‐synuclein aggregates in dendrosomatic fraction formed globular/tadpole‐like, and ultrastructurally comprised granular‐coated fine fibrils 12–24 nm in diameter. To the best of our knowledge, alpha‐synuclein‐related neuronal pathology localized in the perirhinal region without hippocampal involvement has not been previously reported in MSA, and may provide clues to elucidate how neuronal pathology evolves in the hippocampal/parahippocampal regions in MSA, particularly in cases with dementia.