Mislocalization of SMN from the I-band and M-band in human skeletal myofibers in spinal muscular atrophy associates with primary structural alterations of the sarcomere.

Spinal muscular atrophy (SMA) is caused by a deletion or mutation of the survival motor neuron 1 (SMN1) gene. Reduced SMN levels lead to motor neuron degeneration and muscular atrophy. SMN protein localizes to the cytoplasm and Cajal bodies. Moreover, in myofibrils from Drosophila and mice, SMN is a sarcomeric protein localized to the Z-disc. Although SMN participates in multiple functions, including the biogenesis of spliceosomal small nuclear ribonucleoproteins, its role in the sarcomere is unclear. Here, we analyzed the sarcomeric organization of SMN in human control and type I SMA skeletal myofibers. In control sarcomeres, we demonstrate that human SMN is localized to the titin-positive M-band and actin-positive I-band, and to SMN-positive granules that flanked the Z-discs. Co-immunoprecipitation assays revealed that SMN interacts with the sarcomeric protein actin, α-actinin, titin, and profilin2. In the type I SMA muscle, SMN levels were reduced, and atrophic (denervated) and hypertrophic (nondenervated) myofibers coexisted. The hypertrophied myofibers, which are potential primary targets of SMN deficiency, exhibited sites of focal or segmental alterations of the actin cytoskeleton, where the SMN immunostaining pattern was altered. Moreover, SMN was relocalized to the Z-disc in overcontracted minisarcomeres from hypertrophic myofibers. We propose that SMN could have an integrating role in the molecular components of the sarcomere. Consequently, low SMN levels might impact the normal sarcomeric architecture, resulting in the disruption of myofibrils found in SMA muscle. This primary effect might be independent of the neurogenic myopathy produced by denervation and contribute to pathophysiology of the SMA myopathy.

Reorganization of the nuclear compartments involved in transcription and RNA processing in myonuclei of type I spinal muscular atrophy.

Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by the loss or mutation of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to the degeneration of motor neurons and muscular atrophy. In this study, we analyzed the nuclear reorganization in human skeletal myofibers from a type I SMA patient carrying a deletion of exons 7 and 8 in the SMN1 gene and two SMN2 gene copies and showing reduced SMN protein levels in the muscle compared with those in control samples. The morphometric analysis of myofiber size revealed the coexistence of atrophic and hypertrophic myofibers in SMA samples. Compared with controls, both nuclear size and the nuclear shape factor were significantly reduced in SMA myonuclei. Nuclear reorganization in SMA myonuclei was characterized by extensive heterochromatinization, the aggregation of splicing factors in large interchromatin granule clusters, and nucleolar alterations with the accumulation of the granular component and a loss of fibrillar center/dense fibrillar component units. These nuclear alterations reflect a severe perturbation of global pre-mRNA transcription and splicing, as well as nucleolar dysfunction, in SMA myofibers. Moreover, the finding of similar nuclear reorganization in both atrophic and hypetrophic myofibers provides additional support that the SMN deficiency in SMA patients may primarily affect the skeletal myofibers.

Incidental, low-fat variant of spindle cell lipoma: a novel tumour of the small intestine.

A woman underwent surgical intervention for a carcinoma of the ovary. In the intervention, a submucosal nodule of the ileum was found. Pathological study revealed a spindle cell lipoma (SCL). This case revealed the presence of CD34-positive spindle and stellate cells with dendritic cytoplasmic prolongations, a feature shared with dendritic fibromyxolipoma. Fluorescence in in situ hybridisation analysis showed 13q14 heterozygous deletion. Spindle cell lipoma of the small intestine has not been previously reported. Spindle cell lipoma, although rare, should be included among the benign mesenchymal lesions of the small intestine. This report extends the range of locations in which this tumour is found to arise.

Incidental Melanocytic Nevi in Hemorrhoidectomy Specimens.

BACKGROUND: Benign melanocytic nevi (MN) of the anal canal are exceptional and require adequate differential diagnosis. There are no data on incidence of these lesions. Only a single case report of hemorrhoid with an MN has been reported. The necessity of routine pathologic evaluation of hemorrhoidectomy specimens has been questioned. MATERIAL AND METHODS: The authors undertook a retrospective histologic study of the hemorrhoidal tissue obtained in a series of 1918 consecutive hemorrhoidectomies performed between January 2004 and November 2012. RESULTS: Incidental hemorrhoidal MN were detected in 4 (0.21%) patients. The ratio observed was 1 nevus in 480 specimens. Lesions were intradermal or purely junctional in nature. There were no mitoses or architectural disorder. An intradermal nevus showed localized pagetoid melanocytes. The mean age of the patients was 56.5 years (range 47-73 years). The mean size of nevi was 5.86 mm (range 1.89-13.86 mm). All cases were present in external hemorrhoids. CONCLUSIONS: Although uncommonly, incidental MN can be observed in hemorrhoidal tissue. They may show features of flexural nevi and pagetoid melanocytes. Routine histopathological study of hemorrhoidectomy specimens would help to detect benign or malignant melanocytic tumors of the anal canal as these neoplasms can be easily missed clinically. Furthermore, this practice would allow early diagnosis of significant associated processes.

Mucin-secreting clear cell renal cell carcinoma. A rare variant of conventional renal cell carcinoma.

We report herein one case of conventional renal cell carcinoma (RCC) producing extensive extracellular mucinous secretion in a 71-year-old man. To the best of our knowledge, the presence of mucinous secretion in this tumor has not been documented. Mucin production, despite its low frequency, can be considered an additional feature of conventional RCC. Therefore, clear cell RCC should be added to the list of parenchymal renal tumors that can show significant mucin secretion; and it should be included in the inventory of morphologic variations of this tumor, which may cause diagnostic difficulties. It is of primary importance to distinguish mucin-secreting clear cell RCC from the metastasis of a mucin-secreting tumor to conventional RCC. Presence of mucin in a clear cell carcinoma does not exclude a renal origin.

Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy.

Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis is is revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coil in, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.

Concurrent xanthogranulomatous orchiepididymitis and seminoma in the same testis.

Xanthogranulomatous orchiepididymitis (XGO) is a rare inflammatory and destructive disease of the testis that may simulate testicular malignancy. To the authors' knowledge only 19 cases of XGO have been previously reported. Herein is reported the case of a 52-year-old man with XGO who presented with a left testicular mass and pyogenic discharge from the scrotum. Ultrasound examination indicated heterogeneous testicular areas suggestive of neoplasia. Testicular tumor markers were normal. Orchidectomy was performed and histopathology showed XGO and a concurrent, occult typical seminoma. As far as the authors know the coincidence of these two lesions has not been documented previously. XGO may mimic testicular malignancy and may coexist with it. Pathologists should be aware of this concurrence of lesions to avoid potential misdiagnosis. Wide sampling of the orchidectomy specimens with XGO is mandatory to exclude an occult seminoma.

Cutaneous plasmacytosis limited to the extremities in a white patient: an unusual clinical picture.

Cutaneous plasmacytosis is an uncommon disease characterized by a cutaneous polyclonal plasma cell infiltrate usually associated with polyclonal hypergammaglobulinemia. It has predominantly been found in Japanese patients and it is rare in white patients. Clinically, this condition manifests as multiple red to dark brown skin lesions that mainly are located on the trunk. We report the case of a 66-year-old white woman who presented with reddish brown to violaceous macules and plaques restricted to the extremities. The histopathologic findings, laboratory data, and systemic studies led us to the diagnosis of cutaneous plasmacytosis.

Cellular Myxoma of the Vocal Cord: A Case Report and Review of the Literature.

Myxomas are rare in the vocal cords. A 69-year-old man was admitted with one-year history of progressive dysphonia. Laryngoscopy revealed a polypoid mass on the right vocal cord. The diagnosis was cellular myxoma. A review of the literature including the present case revealed eleven reported cases of myxoma. Ten cases were classic myxoma. To the best of our knowledge, cellular myxoma has not been previously reported in the vocal cord. Hypercellularity does not affect the behavior of cellular myxoma. However, its recognition is important to prevent confusion with the group of low-grade myxoid sarcomas. Cellular myxoma should be considered in the differential diagnosis of any vocal cord mass.

Clinically unapparent melanocytic nevi on the prepuce.

BACKGROUND: Melanocytic nevi from the genitalia are uncommon. Nevi on the vulva are much better described than nevi on male genitalia. To our knowledge, a systematic study of preputial melanocytic nevi has not been reported. OBJECTIVE: To investigate the frequency of clinically unapparent melanocytic nevi on a series of preputial excisions. MATERIALS AND METHODS: We undertook a prospective histologic study of the prepuce obtained in a series of 372 consecutive circumcisions for phimosis performed during the period between January 2000 and December 2002. RESULTS: Incidental preputial melanocytic nevi were detected in four (1.1%) patients. Lesions were dermal in nature, most of them showed pigment in superficial dermal nests and had pseudovascular spaces. There were no cytologic atypia, mitotic figures, architectural disorder or inflammatory infiltrate. The mean (standard deviation, SD) of the maximum diameter was 1.08 (0.85) mm (range 0.34-1.79 mm). The mean age (SD) of the patients was 41.5 (4.95) years (range 29-58). CONCLUSIONS: Incidental melanocytic nevi, although uncommonly, can be observed in the prepuce. They are detected in adults and may pose a diagnostic challenge when they are detected in the setting of concurrent malignant melanoma.

Pagetoid dyskeratosis of the nipple epidermis: an incidental finding mimicking Paget's disease of the nipple.

Pagetoid dyskeratosis (PD) is considered a selective keratinocytic response in which a small part of the normal population of pale keratinocytes is induced to proliferate. PD has been found incidentally in the squamous epithelium of the skin and mucosas in various locations, but not in the nipple. In cases in which PD cells are conspicuous, there is the danger of overdiagnosis. In a retrospective study, we describe the location and incidence of PD and other pale cells in the nipple epidermis, in 288 mastectomy specimens from women operated on for breast carcinoma, in situ or infiltrating, selected consecutively from our histopathologic files. In addition to the conventional histologic methods an immunohistochemical study was performed in selected cases. PD was found in 184 (63.9%) cases and was a prominent finding in 37 (12.8%) cases. Toker cells (TCs) were identified by standard light microscopy in 24 (8.3%) nipples. Paget carcinoma cells (PCCs) were found in 12 (4.2%) cases, and in 9 (3.1%) they were an incidental finding. The immunohistochemical profile of each type of pale cells was as follows: PD cells, EMA-,LMWCK-,CK7-,HMWCK+, CEA-, HER2/neu protein-, HMB45-, HPV-; TCs, EMA+, LMWCK+, CK7+, HMWCK-, CEA-, HER2/neu protein-, HMB45-, HPV-; PCCs, EMA+, LMWCK+, CK7+, HMWCK-, CEA+, HER2/neu protein+, HMB45-, HPV-. In conclusion, friction may be the stimulus for the appearance of PD cells. PD cells must be distinguished from TCs, PCCs, clear cells of Bowen's disease, pagetoid melanoma cells, cells of clear cell papulosis, koilocytes, artifactual clear cells, and glycogen-rich squamous cells. A combination of immunohistochemical markers is useful for this distinction; however, routine histologic study is usually adequate for recognizing PD. Pathologists should be familiar with the histologic features of PD in the nipple epidermis to avoid misdiagnosis.

Extragenital subcutaneous cellular angiofibroma. Case report.

Cellular angiofibroma (CAF) is a rare distinctive mesenchymal neoplasm that occurs almost exclusively in the genital area. We report the case of a 38-year-old woman who presented with an asymptomatic subcutaneous mass, 3.5 cm in diameter, located in the left hypochondrium, which had progressively enlarged during the previous 6 months. The lesion was completely excised. No recurrence was observed 3 months after the excision. A review of the literature--and including the present report--revealed five cases (three men and two women) with location outside the urogenital tract. Mean age was 57 (range 38-78) years; mean 41 years for women and 68 years for men. Average tumor size was 9 (range 3.5-25) cm; mean 5 cm for women and 12 cm for men. Tumors were located in the superficial soft tissue of the trunk, except for one case in the retroperitoneum. Mean follow-up was 29 (range 3-102) months, and no patient developed recurrence or metastasis. Extragenital CAF, except for location, shows similar clinicopathological features to genital CAF. Simple tumorectomy appears to be adequate treatment. Morphologically, CAF is closely related to spindle cell lipoma.

Prichard's structures of the fossa ovalis are age-related phenomena composed of nonreplicating endothelial cells: the cardiac equivalent of cutaneous senile angioma.

Prichard's structures or minute endocardial deformities with lacunas of capillary size lined by plump endothelial cells located in the fossa ovalis are an age-related alteration of unknown origin. In this report the histogenesis, the proliferative potential and the incidence in the aged of these structures are investigated. We have undertaken a prospective histological study of the fossa ovalis in a series of 111 consecutive hearts of patients aged >/=70 years obtained at autopsy. Included in this study was immunohistochemical staining for vimentin, CD31, CD34, thrombomodulin, c-kit (CD117), Ki67 (MIB1) and vascular endothelial growth factor receptor 2 in six cases showing these structures. Prichard's structures were observed in 50 hearts (45%), and were more frequent in males. We confirmed that these structures are age-related phenomena. Subendothelial structures were more common than intracavitary structures. Most individuals had Prichard's structures located on the right side; however, the structures were more numerous on the left side of the fossa ovalis. The immunohistochemical study revealed that Prichard's structures consisted of adult, fully differentiated, postmitotic-type endothelial cells. We suggest that Prichard's structures are formed by infolding of the endothelial lining of the endocardium of the fossa ovalis as an irritational response to altered blood flow, eddies or turbulence. A parallel can be established between Prichard's structures and senile angiomas as both structures increase with age; they are not genuine neoplasms; and they are overgrowths made up of endothelial cells with terminal differentiation. We propose that Prichard's structures are the cardiac equivalent of cutaneous senile angioma.

[Clear and pale cells of the nipple epidermis: a critical study of their varieties]. / Las células claras y pálidas de la epidermis del pezón: estudio crítico de sus variedades.

The stratified squamous epithelium of the nipple-areola complex may contain pale cells including: Paget's disease cells (PDCs), Toker cells (TCs), and so-called clear cells (CCs). PDCs are atypical, commonly concentrated along the basal layer. They stain for EMA, CAM5.2, cytokeratin 7, and HER2/neu oncoprotein. TCs are bland cells with roundish and scant-chromatin nuclei. TCs are reactive for EMA, CAM5.2, and cytokeratin 7, but show negativity for HER2/ neu oncoprotein. The majority of cells that have been called epidermal CCs fit the features of pagetoid dyskeratosis, reactive for high molecular weight cytokeratin. Other CCs showing signet-ring morphology correspond to a fixation artefact.

Histiocytoid cardiomyopathy and ventricular noncompaction presenting as sudden death in an adult male.

Histiocytoid/oncocytic cardiomyopathy (HCM) is a rare, distinctive arrhythmogenic disorder that presents as arrhythmia or sudden death in infants and children. Ventricular noncompaction (VNC) is a rare cardiomyopathy characterized by a thickened endocardial layer of noncompacted myocardium and a thin epicardial layer of compacted myocardium. Only six cases of the association of both cardiomyopathies have been reported previously in the literature. All these cases were in children. To the best of our knowledge, a case of HCM has not been described in the adult. We report the case of a 45-year-old man with an increased heart weight and involvement of both ventricles by HCM and VNC cardiomyopathy. Besides, multiple foci of myocardial disorganization were detected. He died suddenly while hiking. The association of both processes HCM and VNC was an unexpected finding at autopsy. The death was linked to functional abnormalities of the cardiac histiocytoid cells, and it was favored by a state of abnormal development of the heart.

Lymphocyte-rich capillary-cavernous hemangioma of the mitral valve: a case report and review of the literature.

Valvular hemangioma incidence is extremely low. In this report, we describe a 62-year-old man who presented with mild edema of the lower limbs. An echocardiogram revealed an incidental 1.3-cm diameter mass on the anterior mitral valve leaflet for which he underwent surgical resection and mitral valve replacement. Histopathological examination showed a lymphocyte-rich capillary-cavernous hemangioma. The exuberant lymphoid stroma is unusual for hemangioma and represents an undescribed pattern of cardiac hemangioma. Including the present report, only 13 cases of mitral valve hemangioma have been reported to date. Most patients are adult. Mitral hemangioma originates in the atrial aspect of the valve and involves more commonly the anterior leaflet. The average maximum diameter of the lesion is 1.7 (S.D.=0.75) cm. Pure cavernous hemangioma is the predominant type of mitral hemangioma. Most of them are described as pedunculated or polypoid. Surgical excision appears to be curative. Recurrences have not been reported. Lymphocyte-rich cardiac hemangioma represents a peculiar type of hemangioma which should be included in the differential diagnosis of other vascular lesions.

Pneumopolycystic endometritis.

Emphysematous inflammations of the abdomen and pelvis are uncommon and potentially life-threatening conditions that require aggressive treatment. Pneumopolycystic endometritis is a rare benign condition of which only 1 case has been described. This report describes the sonographic and histologic appearance of pneumopolycystic endometritis in a 49-year-old woman who presented with irregular menses and hypermenorrhea of 1 year's duration. The entity is characterized by gas-filled cysts in the endometrium stroma, in a pattern similar to pneumatosis of the vagina. The histologic picture is specific and should not be confused with gas gangrene involving the uterus characterized by the presence of tissue necrosis and life-threatening infection. Our patient is the first documented case that occurred spontaneously and at the same time was limited to the endometrium. Recognition of pneumopolycystic endometritis is important because this condition does not represent an aggressive life-threatening infection, and spontaneous resolution is to be expected.

Adenoid squamous cell carcinoma of the larynx: an uncommon histological variant of squamous cell carcinoma.

Adenoid squamous cell carcinoma (ASCC) or acantholytic squamous cell carcinoma is a well-recognized variant of squamous cell carcinoma. ASCC commonly occurs in the sun-exposed areas of the skin and has only rarely been observed in mucosal sites. We report a case of ASCC in the larynx of a 75-year-old man with a history of odynophagia and dysphonia of 3 months' duration that presented as an exophytic lesion on the right vocal cord. Biopsy was performed and the histological diagnosis was squamous cell carcinoma. Treatment consisted of total laryngectomy and radical neck dissection. Microscopically, the tumor showed a prominent alveolar pattern with cystic degeneration of the neoplastic epithelium and formation of pseudoglandular structures. In the lumina there were acantholytic cells. Transition areas from conventional squamous cell carcinoma to adenoid pattern were found. To the best of our knowledge this is only the third case of ASCC reported in the larynx. We reviewed the nine mucosal ASCCs of the upper aerodigestive tract reported. The assertion that these tumors are associated with an aggressive behavior and poor prognosis cannot be estimated in this review as the number of cases is small and the tumors are located in different places.

Myeloid sarcoma of the extrahepatic bile ducts presenting as obstructive jaundice.

We report a rare case of myeloid sarcoma (MS) of the extrahepatic bile ducts presenting as obstructive jaundice in a patient without leukemia at time of diagnosis. A 75-year-old female presented with a one-month history of abdominal pain and jaundice. Computerized tomography scan of the abdomen showed stenosis of the extrahepatic bile ducts. Endoscopic retrograde cholangiography disclosed an irregular narrowing of the common biliary duct, suggestive of a cholangiocarcinoma, and resection was performed. Histologic examination showed diffuse transmural infiltration of malignant cells. These cells exhibited medium-sized round nuclei with central nucleoli and eosinophilic cytoplasm, and were strongly positive for myeloperoxidase, CD68, lysozyme, CD45, CD117 (c-kit protein) and CD43. Eight months following surgery the patient presented with multiple cutaneous nodules and bone marrow trephine biopsy showed acute myelomonocytic leukemia. A literature search identified two previously reported cases of MS of the extrahepatic biliary duct. MS should be taken into consideration in the differential diagnosis of a patient with obstructive jaundice. Immunohistochemistry is essential for a correct diagnosis.

Ectopic epididymal tissue in appendix testis.

Aberrant epididymal tissue is uncommon and may be associated with an undescended testis. To the best of our knowledge, aberrant epididymal tissue has not been described in a testicular appendix. We report the case of a 7-year-old boy with left cryptorchidism who underwent a homolateral orchidopexy. At operation, the surgeon removed a pedunculated appendix testis containing an epididymal heterotopia. This Wolffian-derivative tissue was confirmed by the diffuse strong CD10 reactivity of the luminal border of the epithelial cells. Awareness of this aberrant tissue avoids misinterpretation as a transected functional reproductive structure.