DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.

The association of fibrillary glomerulonephritis (FGN) with monoclonal gammopathy has been controversial, although monotypic FGN is currently classified as a monoclonal gammopathy of renal significance (MGRS) lesion. To define this lesion, we correlated findings by immunofluorescence on frozen and paraffin tissue, IgG subtype staining and serum protein electrophoresis with immunofixation in patients with monotypic FGN. Immunofluorescence was performed on paraffin sections from 35 cases of DNAJB9-associated FGN that showed apparent light chain restriction of glomerular IgG deposits by standard immunofluorescence on frozen tissue. On paraffin immunofluorescence, 15 cases (14 lambda and one kappa restricted cases on frozen tissue immunofluorescence) showed no light chain restriction, 19 showed similar light chain restriction, and one was negative for both light chains. Seven of the 15 cases with masked polyclonal deposits also had IgG subclass restriction and these cases would have been diagnosed as a form of monoclonal protein-associated glomerulonephritis if paraffin immunofluorescence was not performed. Monotypic FGN (confirmed by paraffin immunofluorescence and IgG subclass restriction) accounted for only one of 151 (0.7%) patients with FGN encountered during the last two years. Only one of 11 of cases had a detectable circulating monoclonal protein on serum protein electrophoresis with immunofixation. We propose that paraffin immunofluorescence is required to make the diagnosis of lambda-restricted monotypic FGN as it unmasked polytypic deposits in over half of patients. When confirmed by paraffin immunofluorescence and IgG subclass staining, DNAJB9-positive monotypic FGN is very rare and is not associated with monoclonal gammopathy in the vast majority of patients. Thus, there is a question whether this lesion should be included in MGRS-related diseases.

Clear cell-papillary renal cell carcinoma of the kidney not associated with end-stage renal disease: clinicopathologic correlation with expanded immunophenotypic and molecular characterization of a large cohort with emphasis on relationship with renal angiomyoadenomatous tumor.

Clear cell-papillary renal cell carcinoma (CC-Pap RCC) is a recently described renal tumor initially reported in the setting of end-stage renal disease (ESRD). It has unique morphologic and immunohistochemical features that differentiate it from the more common clear cell RCC and papillary RCC. Recently, these tumors have also been described in a sporadic setting. We studied 64 cases of CC-Pap RCC not associated with ESRD (57 CC-Pap RCCs and 7 cases with features of renal angiomyoadenomatous tumors [RAT] including 5 initially diagnosed as such). The morphologic features of all cases and the immunohistochemical profile of 59 cases were studied along with the clinical and molecular features of 30 and 12 cases, respectively. All the tumors were well circumscribed with a mean tumor size of 2.6 cm and showed a wide array of architectural patterns, usually mixed, including tubular (77%), papillary (62%), tubulocystic (52%), and compact nested (21%). Seventy-three percent of the cases showed areas in which the tumor nuclei had a distinct orientation away from the basement membrane. Ninety-two percent of the cases had a low Fuhrman nuclear grade (nuclear grade 2%-86%, and nuclear grade 1%-6%); however, 8% cases showed foci of Fuhrman nuclear grade 3. In 4 cases, epithelial tumor comprised <5% of the tumor; >95% of the tumor was cystic or hyalinized. The stroma varied from being minimal to occasionally prominent myxoid to hyalinized and rarely with organized amianthoid fibers or well-defined smooth muscle bundles. Pathologic stage was reliably assigned in 60 cases, of which 93.3% (56 cases) were pT1, 3.3% (2 cases) were pT2, and 3.3% (2 cases) were pT3a with extension into the perinephric fat. One case had coagulative necrosis; sarcomatoid change and vascular invasion was not identified. The tumors showed a fairly typical immunoprofile characterized by positivity for CK7 (100%), HMCK (96%), CAIX (94%), and vimentin (100%) with negativity for AMACR, RCC, and TFE3; CD10 was positive in 24%. None of the cases tested showed recurrent chromosomal imbalances by virtual karyotyping, fluorescence in situ hybridization, or 3p loss of heterozygosity analysis. VHL gene mutations were, however, noted in 3 cases (2 in exon 1 and 1 in exon 3). Clinical follow-up information was available in 47% of the patients, with a mean and median follow-up of 47 and 37 months, respectively (range, 18 to 108 mo). One case occurred in the setting of VHL syndrome and multiple benign cysts. None of the cases showed local recurrence, metastasis, or death due to disease. Morphology, immunophenotype, and molecular studies did not vary between typical cases, those with prominent smooth muscle (so-called RAT), and historically published data on cases occurring in ESRD. Our analysis confirms that CC-Pap RCC is a unique subtype of adult renal epithelial neoplasia in which tumors are frequently small, are of low nuclear grade and pathologic stage, and have extremely favorable short to intermediate range prognosis. Tumors occurring sporadically, with prominent smooth muscle stroma (so-called RAT), and occurring in ESRD are in the spectrum of the same category of tumors.

Differences in chronic intragraft inflammation between positive crossmatch and ABO-incompatible kidney transplantation.

BACKGROUND: ABO-incompatible kidney transplantations (ABOiKTxs) seem to have better long-term outcomes than positive crossmatch kidney transplantations (+XMKTxs). METHODS: This study aimed to assess the differences in chronic injury on histologic findings on 1- and 5-year surveillance biopsies and the clinical outcomes in living-donor kidney transplantations performed between May 1999 and November 2006 including 102 +XMKTxs, 73 ABOiKTxs, and 652 conventional KTxs. RESULTS: Although 5-year patient survival was similar between groups, graft loss between 1 and 5 years was similar in ABOiKTx (2.6% per year) and conventional KTx (1.7% per yr), and both were lower than that of +XMKTx (5.8% per year). At 5 years, renal function was similar in ABOiKTx and conventional KTx, and both were higher than that of +XMKTx, which had higher rates of inflammation and chronic glomerulopathy on both 1- and 5-year biopsies. Despite having evidence of less chronic injury, ABOiKTx showed a higher rate of intragraft complement activation (C4d deposition) at 5 years compared with +XMKTx (77.8% vs. 18.9%, P<0.001). CONCLUSION: These data suggest that +XMKTxs have high rates of chronic inflammation at 1 and 5 years after transplantation, which may explain the higher rates of graft loss and lower renal function compared with other factors such as anti-donor antibody or intragraft complement deposition.

CD10+ and CK7/RON- immunophenotype distinguishes renal cell carcinoma, conventional type with eosinophilic morphology from its mimickers.

BACKGROUND: The distinction between renal cell carcinoma conventional (clear cell) type with eosinophilic morphology (ccRCC), chromophobe renal cell carcinoma eosinophilic variant (chRCC), and renal oncocytoma (RO) is a common diagnostic dilemma. We aimed to identify an immunohistochemical panel to discriminate ccRCC from its morphologic mimics. MATERIALS AND METHODS: Fifty-three renal neoplasms (19 ccRCC, 18 chRCC, and 16 RO) were selected. Immunohistochemical stains for CD10, cytokeratin 7 (CK7), c-Kit, E-cadherin, N-cadherin, kidney-specific cadherin (Ksp-cadherin), and Recepteur d'origine nantais (RON) were performed. RESULTS: Ten (53%) of 19 ccRCC were positive for CD10, 11 (58%) for E-cadherin, 8 (42%) for N-cadherin, 5 (26%) for Ksp-cadherin, 9 (47%) for RON, 6 (32%) for CK7, and 5 (26%) for c-Kit. In chRCC/RO group, 5 of 34 (15%) were positive for CD10, 32 (94%) for E-cadherin, 2 (6%) for N-cadherin, 1 (3%) for Ksp-cadherin, 22 (65%) for RON, 14 (41%) for CK7, and 25 (25/32, 76%) for c-kit. Univariately, negative c-Kit [odds ratio (OR)=8.75, P=0.001, area under the receiver operating characteristic curve (AUC)=0.747], negative E-cadherin (OR=11.64, P=0.005, AUC=0.681), positive N-cadherin (OR=11.64, P=0.005, AUC=0.681), positive Ksp-cadherin (OR=11.79, P=0.031, AUC=0.617), and positive CD10 (OR=6.44, P=0.005, AUC=0.690) detects ccRCC versus chRCC/RO. Multivariate analysis showed significant association between CD10 positivity and ccRCC (OR=16.90, P=0.007) and between RON negativity and ccRCC (OR=7.17, P=0.047) when CK7 is negative. CONCLUSIONS: The best single predictors for ccRCC are negative c-Kit, negative E-cadherin, positive N-cadherin, positive Ksp-cadherin, and positive CD10. However, considering the studied markers, a combination of positive CD10 and negative CK7 and RON is considered the best immunohistochemical panel in distinguishing ccRCC from chRCC/RO.

Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma.

Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable-type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component classically identified as sarcomatoid change.

Intrathyroidal parathyroid carcinoma in a pediatric patient.

Parathyroid carcinoma is unusual and its intrathyroidal variant is extremely rare. Therefore, few cases have been reported to describe a case of parathyroid carcinoma located inside the thyroid gland. The case corresponds to a 14-year-old girl who came to the office with a severe osteoarticular disease, depression, calcemia of 14.3 mg/dl and parathyroid hormone of 2,792 pg/ml. Right neck exploration was conducted and a parathyroid carcinoma was found located intrathyroidally. A right thyroid lobectomy was performed. A 20-month follow-up period revealed no recurrence of clinical or biochemical signs. In patients with severe hypercalcemia and significant elevation of parathyroid hormone, the diagnosis of parathyroid carcinoma has to be considered. It is worth highlighting the early age of presentation in this case. Treatment has allowed the effective control of the disease and its recommended long-term follow-up.

Cystic lesions of the pancreas: clinical and pathologic review of cases in a five year period.

CONTEXT: Cystic lesions of the pancreas represent an important subgroup of pancreatic tumors. The characterization of these lesions has evolved in recent years, and will continue to change according to the increasing number of biopsies and resections performed. DESIGN: Pancreatectomy specimens containing cystic lesions collected over a five-year period were reviewed. MAIN OUTCOME MEASURES: Demographic and pathologic features were recorded. SETTING: Cases were subclassified in diagnostic categories and were grouped according to the nature of the lesion (non-neoplastic vs. neoplastic). RESULTS: Of 361 pancreatic lesions, 97 cysts corresponding to 95 patients were studied. The patients' mean age was 60 years. Sixty two cysts (63.9%) occurred in women. Among the 97 cysts, five (5.2%) were non-neoplastic and 92 (94.8%) were neoplastic (59.8% benign, 17.5% borderline, 17.5% malignant). Intraductal papillary mucinous neoplasm was the most common diagnosis (n=51; 52.6%) followed by serous cystic neoplasm (n=20; 20.6%) and mucinous cystic neoplasm (n=13; 13.4%). Frequency of female gender was higher and age was lower in the borderline lesions (P=0.001 and P=0.002, respectively). Tumor size was significantly lower in benign neoplastic lesions (P=0.045). Incidental identification was more frequent in benign lesions (P=0.028), whereas malignant lesions were more frequently symptomatic (P=0.001). CONCLUSION: Cystic lesions are found in 20.6% of all pancreatectomy specimens. Among this heterogeneous group, benign neoplasms predominate, particularly those with mucinous lining. Age at presentation, gender, location and tumor size are highly variable, with the exception of solid pseudopapillary tumor. Clinical presentation, diagnostic imaging and laboratory data should be consistently reported to improve the therapeutic approach.

[Evaluation of fine needle aspiration cytology in the diagnosis of cancer of the parotid gland]. / Evaluación de la citología por punción-aspiración con aguja fina en el diagnóstico de cáncer de la glándula parótida.

BACKGROUND: Fine needle aspiration (FNA) is commonly used in the study of neoplastic lesions of the parotid gland, however controversy exists regarding its diagnostic accuracy. OBJECTIVE: To evaluate the performance of FNA biopsy as compared to open surgical biopsy in the diagnosis of carcinoma of the parotid gland. MATERIAL AND METHOD: Forty-six patients with parotid masses from 7 health centres in Bucaramanga, Colombia were identified and included in the study. All patients underwent FNA and open surgical biopsy, with the latter considered the diagnostic gold standard. The FNA and final surgical histopathology were interpreted as either positive or negative for malignancy by pathologists blinded to the FNA outcome. Only standard histological stains were used. The data were compared in a contingency table and analyzed statistically to determine the accuracy of FNA to predict the surgical pathology according to standard measures. RESULTS: The mean age of patients was 52 +/- 16 years old and 59 % were female. Using FNA, 18 % of the initial diagnoses were found to be erroneous at final pathology. FNA had a sensitivity of 0.54, a specificity of 0.90, a PPV of 0.70, an NPV of 0.83, an LR+ of 5.92, an LR of 0.5, and kappa of 0.48 in the identification of parotid gland carcinoma from referral population with a disease prevalence of 28.3 %. CONCLUSIONS: In line with other previous studies, FNA biopsy alone was unreliable to diagnose parotid gland carcinoma. Its low sensitivity and LR indicates its limitations as a screening test; in addition its low kappa shows a modest correlation to the eventual diagnosis. Therefore, further critical examination of techniques and interpretation of parotid FNA are recommended. The development of new methods allowing a valid and precise diagnosis of this pathology and that, like the FNA, have low cost and ease of application is recommended.

Evaluación de la citología por punción-aspiración con aguja fina en el diagnóstico de cáncer de la glándula parótida / Evaluation of fine needle aspiration cytology in the diagnosis of cancer of the parotid gland

Contexto: La punción-aspiración con aguja fina (PAAF) se utiliza con frecuencia en el estudio de las lesiones neoplásicas de la glándula parótida, a pesar de que se mantiene la controversia respecto a su precisión diagnóstica. Objetivo: Evaluación del rendimiento de la PAAF en comparación con la biopsia quirúrgica abierta para el diagnóstico del carcinoma de la glándula parótida. Material y método: En el estudio participaron 47 pacientes con lesiones ocupantes de espacio en la glándula parótida y que fueron atendidos en 7 centros sanitarios de Bucaramanga, Colombia. Todos los pacientes fueron evaluados mediante PAAF y biopsia quirúrgica abierta, considerada esta última como la prueba diagnóstica de referencia. La PAAF y el estudio anatomopatológico final efectuado sobre la biopsia quirúrgica abierta fueron interpretados como positivos o negativos para lesión maligna por anatomopatólogos que desconocían el resultado obtenido en la PAAF. Sólo se utilizaron técnicas de tinción histológicas convencionales. Los datos fueron comparados mediante una tabla de contingencia y analizados estadísticamente para determinar la precisión de la PAAF en la predicción del resultado diagnóstico anatomopatológico obtenido en la biopsia quirúrgica abierta mediante muestreo y análisis transversal. Resultados: La media ± desviación estándar de edad de los pacientes fue 52 ± 16 años; el 59 % eran mujeres. El 18 % de los diagnósticos establecidos mediante la PAAF fue erróneo en comparación con el diagnóstico anatomopatológico final. La PAAF presentó una sensibilidad y una especificidad de 0,54 y 0,90, respectivamente; unos valores predictivo positivo y predictivo negativo de 0,90 y 0,70, respectivamente; unos cocientes de probabilidad positivo y negativo de 5,92 y 0,5, respectivamente, y un estadístico kappa de 0,48, respecto a la identificación del carcinoma de la glándula parótida en la población evaluada, en la que la prevalencia de la enfermedad fue del 28,3 %. Conclusiones: La PAAF, utilizada como método diagnóstico aislado, careció de fiabilidad para el diagnóstico del carcinoma de la glándula parótida, en concordancia con los resultados obtenidos en otros estudios previos. Sus bajos valores de sensibilidad y de cociente de probabilidad negativo indican sus limitaciones como prueba de detección o cribado; además, el escaso valor del estadístico kappa demuestra que esta técnica posee una correlación modesta con el diagnóstico final. Por tanto, se recomienda el análisis crítico adicional con otras técnicas de análisis adicionales que mejoren la interpretación de la PAAF sobre la glándula parótida. También se considera importante el desarrollo de nuevos métodos que permitan establecer un diagnóstico válido y preciso de este problema y que, de la misma manera que la PAAF, tengan un coste económico bajo y sean fáciles de utilizar

Background: Fine needle aspiration (FNA) is commonly used in the study of neoplastic lesions of the parotid gland, however controversy exists regarding its diagnostic accuracy. Objective: To evaluate the performance of FNA biopsy as compared to open surgical biopsy in the diagnosis of carcinoma of the parotid gland. Material and method: Forty-six patients with parotid masses from 7 health centres in Bucaramanga, Colombia were identified and included in the study. All patients underwent FNA and open surgical biopsy, with the latter considered the diagnostic gold standard. The FNA and final surgical histopathology were interpreted as either positive or negative for malignancy by pathologists blinded to the FNA outcome. Only standard histological stains were used. The data were compared in a contingency table and analyzed statistically to determine the accuracy of FNA to predict the surgical pathology according to standard measures. Results: The mean age of patients was 52 ± 16 years old and 59 % were female. Using FNA, 18 % of the initial diagnoses were found to be erroneous at final pathology. FNA had a sensitivity of 0.54, a specificity of 0.90, a PPV of 0.70, an NPV of 0.83, an LR+ of 5.92, an LR– of 0.5, and kappa of 0.48 in the identification of parotid gland carcinoma from referral population with a disease prevalence of 28.3 %. Conclusions: In line with other previous studies, FNA biopsy alone was unreliable to diagnose parotid gland carcinoma. Its low sensitivity and LR– indicates its limitations as a screening test; in addition its low kappa shows a modest correlation to the eventual diagnosis. Therefore, further critical examination of techniques and interpretation of parotid FNA are recommended. The development of new methods allowing a valid and precise diagnosis of this pathology and that, like the FNA, have low cost and ease of application is recommended

Ultrastructural study of the primary olfactory pathway in Macaca fascicularis.

Olfactory ensheathing glial cells (OEGs) interact with a wide repertoire of cell types and support extension of olfactory axons (OAs) within the olfactory pathway. OEGs are thought to exclude OAs from contact with all other cells between the olfactory epithelium and the glomerulus of the olfactory bulb. These properties have lead to testing to determine whether OEGs support axonal growth following transplantation. The cellular interactions of transplanted OEGs will probably resemble those that occur within the normal pathway where interactions between OEGs and fibroblasts are prominent. No previous primate studies have focused on these interactions, knowledge of which is important if clinical application is envisioned. We describe the detailed intercellular interactions of OAs with supporting cells throughout the olfactory epithelium, the lamina propria, the fila olfactoria, and the olfactory nerve layer by using transmission electron microscopy in adult Macaca fascicularis. Patterns of OEG ensheathment and variations of the endo- and perineurium formed by olfactory nerve fibroblasts are described. OAs mainly interacted with horizontal basal cells, OEGs, and astrocytes. At both transitional ends of the pathway seamless intercellular interactions were observed, and fibroblast processes were absent. Perineurial cells produced surface basal lamina; however, endoneurial, epineurial, and meningeal fibroblasts did not. Perineurial cells contained intermediate filaments and were distinct from other fibroblasts and meningeal cells. OAs had direct contacts with astrocytes near the glia limitans. The properties of OEGs differed depending on whether astrocytic or fibroblastic processes were present. This indicates the importance of the cellular milieu in the structure and function of OEGs in primates.

Effects of epidural hypothermic saline infusion on locomotor outcome and tissue preservation after moderate thoracic spinal cord contusion in rats.

OBJECT: Regionally delivered hypothermia has advantages over systemic hypothermia for clinical application following spinal cord injury (SCI). The effects of local hypothermia on tissue sparing, neuronal preservation, and locomotor outcome were studied in a moderate thoracic spinal cord contusion model. METHODS: Rats were randomized to four treatment groups and data were collected and analyzed in a blinded fashion. Chilled saline was perfused into the epidural space 30 minutes postcontusion to achieve the following epidural temperatures: 24 +/- 2.3 degrees C (16 rats), 30 +/- 2.4 degrees C (13 rats), and 35 +/- 0.9 degrees C (13 rats). Hypothermia was continued for 3 hours when a 45-minute period of rewarming was instituted. In a fourth group a moderate contusion only was induced in 14 animals. Rectal (core) and T9-10 (epidural) temperatures were measured continuously. Locomotor testing, using the Basso-Beattie-Bresnahan (Ba-Be-Br) scale, was performed for 6 weeks, and rats were videotaped for subsequent analysis. The lesion/preserved tissue ratio was calculated throughout the entire lesion cavity and the total lesion, spinal cord, and spared tissue volumes were determined. The rostral and caudal extent of gray matter loss was also measured. At 6 weeks locomotor recovery was similar in all groups (mean Ba-Be-Br Scale scores 14.88 +/- 3.71, 14.83 +/- 2.81, 14.50 +/- 2.24, and 14.07 +/- 2.39 [p = 0.77] for all four groups, respectively). No significant differences in spared tissue volumes were found when control and treatment groups were compared, but gray matter preservation was reduced in the infusion-treated groups. CONCLUSIONS: Regional cooling applied 30 minutes after a moderate contusive SCI was not beneficial in terms of tissue sparing, neuronal preservation, or locomotor outcome. This method of cooling may reduce blood flow in the injured spinal cord and exacerbate secondary injury.