As-needed intranasal corticosteroid spray for allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: As-needed intranasal corticosteroid spray (INCS) is commonly used by patients with allergic rhinitis (AR) who have suboptimal symptom control. This systematic review aimed to assess the effectiveness of as-needed INCS for treating AR. METHODOLOGY: Systematic searches for randomized controlled trials studying the effects of as-needed INCS compared to regular INCS, as-needed antihistamine, or placebo were performed. Primary outcomes were total nasal symptom score (TNSS) and disease-specific quality of life (DSQoL). RESULTS: Eight studies (882 participants) met the criteria. Regular use of INCS showed greater improvements than as-needed INCS in TNSS, DSQoL, nasal peak inspiratory flow, sneezing, and nasal congestion scores with small effect sizes. There were no differences between regular and as-needed INCS usage for ocular symptoms, symptom-free days, nasal itching, and rhinorrhea scores. As-needed INCS was superior to as-needed antihistamine and placebo with medium effect sizes. There were no differences in risk of adverse events between the groups in all three comparisons. CONCLUSIONS: Regular use of INCS improved total nasal symptoms score and DSQoL better than as-needed INCS. However, as-needed INCS improved TNSS better than as-needed antihistamine and placebo. The effects of as-needed INCS were closer to regular INCS usage than to placebo or as-needed AH usage.

Allergen-specific immunotherapy for local allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: Local allergic rhinitis (LAR) is a phenotype of chronic rhinitis exhibiting a local Th2-driven inflammation without positive clinical markers of atopy. Immunomodulatory effects of allergen-specific immunotherapy (AIT) induce allergen-specific tolerance. However, AIT is not well-recognized as a treatment for LAR. METHODOLOGY: Systematic search on six electronic databases and registries was performed. Experimental and observational studies of AIT for LAR patients were retrieved. The primary outcomes were symptom score, medication score, combined symptom medication score, and disease-specific quality of life. Secondary outcomes were serum specific(s) IgG4, sIgE, and adverse events. RESULTS: Four double-blind randomized controlled trials (156 patients) from two research units assessed the effects of subcutaneous immunotherapy (SCIT). Compared with placebo, SCIT showed significant reductions in symptom score, medication score, combined symptom medication score, disease-specific quality of life, and an increase in serum sIgG4. There was no significant change in serum sIgE. Likewise, two observational studies (one using SCIT and one using sublingual immunotherapy) improved post-therapeutic symptom score. No studies assessed the effects after discontinuation of treatment. AIT was safe without serious adverse events. CONCLUSION: AIT has beneficial effects and safe for LAR. Its effects are restricted to studies with short-term follow-up. AIT may be considered in LAR patients.

Prolonged breastfeeding and protective effects against the development of allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: There is insufficient evidence to confirm the protective effects of prolonged breastfeeding against the development of allergic rhinitis (AR). METHODOLOGY: A systematic review and meta-analysis was performed to assess the associations between prolonged breastfeeding and AR symptoms later in life. Comparisons were conducted between breastfeeding durations less than 6 months and 6 months or more and between less than 12 months and 12 months or more. Exclusive breastfeeding and nonexclusive breastfeeding were analysed separately. Outcomes were risks of AR development later in life. RESULTS: Twenty-three observational studies (161,611 children, age 2-18 years, 51.50% male) were included. Two studies (9%) were with high quality. Both exclusive and nonexclusive prolonged breastfeeding (6 months or more) decreased the risk of AR. The long-term (12 months or more) nonexclusive breastfeeding lowered the likelihood of AR compared to the 12 months or fewer. The long-term exclusive breastfeeding did not show the same protective effect; however, this result was restricted to only one study. CONCLUSIONS: Exclusive breastfeeding and nonexclusive breastfeeding for 6 months or more may have protective effects against the development of AR up to 18 years of age. The findings should be interpreted with caution given the limitation of low-quality observational studies.

Intralymphatic immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis.

BACKGROUND: Intralymphatic immunotherapy (ILIT) is a new route of allergen-specific immunotherapy. Data confirming its effect is restricted to a small number of studies. METHODOLOGY: A systematic review with meta-analysis was conducted. The short-term (less than 24 weeks), medium-term (24-52 weeks), and long-term (more than 52 weeks) effects of ILIT in patients with allergic rhinoconjunctivitis (ARC) were assessed. The outcomes were combined symptom and medication scores (CSMS), symptoms visual analog scale (VAS), disease-specific quality of life (QOL), specific IgG4 level, specific IgE level, and adverse events. RESULTS: Eleven randomized controlled trials and 2 cohorts (483 participants) were included. Compared with placebo, short term benefits of ILIT for seasonal ARC improved CSMS, improved VAS and increased specific IgG4 level but did not change QOL or specific IgE level. Medium-term effect improved VAS. Data on the long-term benefit of ILIT remain unavailable and require longer term follow-up studies. There were no clinical benefits of ILIT for perennial ARC. ILIT was safe and well-tolerated. CONCLUSION: ILIT showed short-term benefits for seasonal ARC. The sustained effects of ILIT were inconclusive. It was well tolerated.

KIT mutations and CD117 overexpression are markers of better progression-free survival in vulvar melanomas.

BACKGROUND: Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas. OBJECTIVES: To evaluate the clinicopathological features of 95 cases of vulvar melanoma. METHODS: p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials. RESULTS: Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing. CONCLUSIONS: KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches.

Stem cell markers (cytokeratin 15, CD34 and nestin) in primary scarring and nonscarring alopecia.

BACKGROUND: Although the pathogenesis of most primary scarring alopecias is poorly understood, recent studies implicate the bulge region as a possible target. OBJECTIVES: To corroborate these results, we ascertained involvement of follicular bulge stem cells using a panel of antibodies that putatively targeted the same. METHODS: Antibodies used included anticytokeratin (CK) 15, CD34 and nestin on vertical and horizontal tissue sections of 50 cases of scarring and 34 cases of nonscarring alopecia. RESULTS: Comparing expression of these markers in scarring vs. nonscarring alopecia, CK15 was noted in the follicular bulge region in 23 of 43 (53%) vs. 27 of 27 (100%) cases and in the peripheral layer of the outer root sheath (ORS) (upper two-thirds of the follicle) in 50 of 50 (100%) vs. 34 of 34 (100%) cases; CD34 was noted in the peripheral layer of the ORS (below pilar muscle attachment) in 24 of 35 (69%) vs. 18 of 18 (100%) cases; and nestin was noted in the infundibular region in 18 of 46 (39%) vs. seven of 32 (22%) cases and in the inner aspect of the ORS (below pilar muscle attachment) in eight of 31 (26%) vs. 23 of 23 (100%) cases. CONCLUSIONS: Our findings of differential follicular localization of stem cells underscore follicular progenitor cell heterogeneity and suggest the target in scarring alopecia is not merely follicular bulge stem cells but involves stem cells in the inner and outer aspect of the ORS. Enhanced expression of nestin in the infundibular region in scarring alopecia indicates availability of an accessible, in vivo niche of potential utility as an autologous source of stem cells for therapeutic application.

CD34 expression in desmoplastic melanoma.

BACKGROUND: Primary and metastatic malignant melanoma can simulate various soft tissue tumors, including dermatofibrosarcoma protuberans (DFSP). Expression of CD34, a marker characteristic of DFSP, as well as other spindle cell tumors, has not been previously documented in malignant melanoma. METHODS: We present here an unusual case of metastatic malignant melanoma with a strong histologic resemblance to DFSP and also CD34 expression. RESULTS: The patient, a 72-year-old man with a history of an invasive malignant melanoma of the skin of the right lower abdomen, presented with a right axillary mass. Histologic sections revealed intersecting fascicles of spindle cells with nuclear pleomorphism and numerous mitotic figures, diffusely infiltrating the adipose tissue in a pattern closely simulating that seen in DFSP. In other foci, epithelioid neoplastic cells with abundant cytoplasm, prominent nucleoli, nuclear pseudoinclusions, and focal cytoplasmic melanin pigment were seen. The neoplastic spindle cells were strongly labeled by two anti-CD34 monoclonal antibodies. Some of the spindle cells and the majority of the epithelioid neoplastic cells expressed S-100 protein and focally tyrosinase. The tumor cells were negative for HMB-45 and MART-1. Melanosomes were not identified by electron microscopy. CONCLUSION: This case demonstrates the potential of melanoma to simulate DFSP closely, on both morphologic and immunohistochemical grounds, and confirms the utility of employing a broad panel of immunohistochemical reagents in problematic cases.

Clear cell carcinoid tumor of the gallbladder: another distinctive manifestation of von Hippel-Lindau disease.

We describe a morphologically distinctive carcinoid tumor of the gallbladder that occurred in a 38-year-old man with von Hippel-Lindau (VHL) disease. The carcinoid tumor was composed predominantly of lipid-containing clear cells arranged in nests and tubules with pagetoid spread into the biliary epithelium and was interpreted as metastatic renal cell carcinoma. The neoplastic cells showed diffuse immunoreactivity for chromogranin, synaptophysin, cytokeratins (cytokeratin 7 and AE1/AE3) and, unexpectedly, for inhibin, but were negative for monoclonal carcinoembryonic antigen, serotonin and a variety of peptide hormones. This clear cell carcinoid tumor of the gallbladder was histologically similar to the recently described clear cell endocrine pancreatic tumor associated with VHL. Four cases of the latter tumor, which were also inhibin positive showed, in addition, focal and variable reactivity for the pancreatic hormones. Two classical carcinoid tumors of the gallbladder, two renal cell carcinomas associated with VHL and 11 of 13 sporadic endocrine pancreatic tumors (not associated with VHL) did not show immunoreactivity for inhibin. Inhibin appears to be an immunohistochemical marker for gallbladder clear cell carcinoid and clear cell endocrine pancreatic tumors associated with VHL and is a useful tool to distinguish these tumors from metastatic renal cell carcinoma. However, the basis for the inhibin positivity in these endocrine tumors is unknown.

Metaplastic lesions of the extrahepatic bile ducts: a morphologic and immunohistochemical study.

Although metaplastic changes can occur in the extrahepatic bile ducts, a detailed morphologic study of these lesions has not been done. We examined the bile duct mucosa in 42 pancreaticoduodenectomy specimens, 32 with neoplastic lesions and ten with inflammatory lesions of the extrahepatic bile ducts, to assess the prevalence and type of metaplastic lesions. For comparison, the common bile ducts from 10 autopsy cases were reviewed. Twenty of the 42 total cases (48%), 13 of the 32 neoplastic cases (40%), and 7 of the 10 inflammatory cases (70%) had metaplastic changes. Pyloric gland metaplasia was the most common type (16/20 cases; 80%), whereas intestinal metaplasia was seen in 1/20 cases (5%). A combination of pyloric gland and intestinal metaplasia occurred in 2/20 cases (10%), and squamous metaplasia plus the above-mentioned two types of metaplasia was seen in 1/20 cases (5%). None of the normal common bile ducts obtained from ten autopsies had metaplastic changes. Endocrine cells were identified in nine (56%) of 17 metaplastic lesions. In contrast, endocrine cells within the intramural glands were seen in only 2 of the 10 normal common bile ducts. Although a significant proportion of carcinomas (6/13 cases) was in close proximity to areas of metaplasia, we were unable to find dysplastic foci within the metaplastic glands or the metaplastic surface epithelium. Reactive atypical cells involved the surface biliary epithelium and intramural glands and were associated with inflammation and metaplastic changes. The presence of goblet, mucinous, squamous, and reactive atypical cells in association with hyperplasia of intramural glands in frozen sections or small biopsy specimens may be mistaken for malignancy; hence, recognition of these lesions is of diagnostic importance.

Expression of protein gene product 9.5 in epithelioid and conventional malignant peripheral nerve sheath tumors.

CONTEXT: Due to the frequent lack of S100 protein expression in malignant peripheral nerve sheath tumors (MPNSTs), especially the epithelioid variant, these tumors are difficult to diagnose without the aid of electron microscopy or a clinical history of neurofibromatosis. METHODS: Protein gene product 9.5 (PGP9.5), a broad neural marker, is expressed in nerve fibers and neurons of both the peripheral and central nervous systems. We compared its expression to that of S100 protein in 16 cases of MPNST. As controls, 6 monophasic synovial sarcomas, 9 leiomyosarcomas, and 5 dermatofibrosarcoma protuberans were included. RESULTS: Expression of PGP9.5 was seen in 15 MPNSTs, with 3 to 4+ positivity in the majority of the cases. Ten cases, 2 epithelioid and 8 conventional MPNSTs, were reactive with PGP9.5, but were negative for S100 protein. Five cases were immunoreactive for both S100 protein and PGP9.5. One case was negative for PGP9.5 but demonstrated focal S100 protein positivity. Expression of PGP9.5 was seen in 4 of 6 synovial sarcomas, 3 of 9 leiomyosarcomas, and none of 5 dermatofibrosarcoma protuberans. CONCLUSION: Although PGP9.5 is not a specific marker for MPNST, it is a more sensitive marker than S100 protein (94% vs 38%). When there is a lack of S100 protein expression and a broad panel of immunostains, such as cytokeratin, epithelial membrane antigen, and smooth muscle actin, yields only focal or equivocal staining, PGP9.5 is a useful diagnostic adjunct in confirming the neural origin of a spindle cell sarcoma.

Molecular and biomarker analyses of salivary duct carcinomas: comparison with mammary duct carcinoma.

Salivary duct carcinoma (SDC) is a rare high-grade aggressive neoplasm that manifests close histologic features with invasive ductal carcinoma of the breast (IDC). In contrast to SDC, extensive molecular studies have been performed on IDC and led to the identification of certain biological markers. To investigate the underlying molecular and biologic characteristics of SDC, we performed molecular analyses using microsatellite markers on chromosomal arms 6q, 16q, 17p, and 17q, DNA flow cytometry and immunohistochemical staining for androgen receptor (AR) and p53 expression on 28 examples of these tumors in comparison to 24 IDC cases. Our results show that generally similar allelic alterations, elevated p53 and androgen receptor expressions, and high frequency of DNA aneuploidy are manifested in both SDCs and IDCs. Differences at certain markers on 6q, 17p and 17q chromosomal loci, however, were observed between the two entities. Certain loci on 6q were more frequently altered in SDC than IDC which loci on chromosomes 17p and q arms were more seen in IDCs than SDCs. The majority of SDCs had high AR expression while most of IDCs were AR negative. Our study indicates that: i) SDC may share some genetic alterations with IDC, ii) high AR expression in SDC may play a role in tumor progression, and iii) p53 overexpression and DNA aneuploidy in both entities reflect their aggressive behavior.

Primary mammary small-cell carcinoma: a molecular analysis of 2 cases.

Primary small-cell carcinoma of the breast is an exceedingly rare variant of breast carcinoma whose genetic profile has not been previously investigated. We report the molecular features of 2 cases of small-cell carcinoma of the breast: 1 with an adjacent intraductal carcinoma, and 1 with prior pleomorphic lobular carcinoma in situ. Laser capture microdissection followed by loss of heterozygosity (LOH) analysis revealed identical molecular alterations at multiple chromosomal regions, including BRCA-1, BRCA-2, p53, and retinoblastoma gene loci, in 1 case of small-cell carcinoma and its adjacent intraductal component. Additionally, LOH in 1 or both small-cell carcinomas was detected at 3p, 4q31.2-qter, 8p21-24, 11q13 (MEN-1 locus), 11q23.3, 11q24.1-25, 16q24.1 (H-cadherin locus), and 17q25. The results of our molecular analysis suggest that genetic changes in mammary small-cell carcinoma resembled those seen in both invasive ductal carcinomas and pulmonary small-cell carcinoma. Second, mammary small-cell carcinoma is clonally related to ductal carcinoma in situ and might represent an example of divergent differentiation occurring in a multipotential neoplastic stem cell.

Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation.

BACKGROUND: Recurrent melanocytic lesions may histologically resemble malignant melanoma. METHODS: We evaluated the original nevi (ON) and recurrent nevi (RN) of 15 patients by routine histology and immunohistochemistry (IHC), examining expression of S-100 protein, gp100 (with HMB-45), MART-1, tyrosinase, and the Ki-67 proliferation marker. RESULTS: Compared with ON, RN had a dermal scar, a significantly greater number of melanophages, and a greater extent of cellular atypia including prominent nucleoli and larger cell size. Architecturally, RN showed significantly less symmetry than ON; however, the percentage of junctional cohesive nests, the presence of suprabasal spread, and the degree of confluence were similar between ON and RN. Both ON and RN showed a decrease in expression of gp100 and tyrosinase with increasing depth ("maturation gradient") and low proliferative activity in both the junctional (4.6% for ON vs. 4.13% for RN) and the dermal components (0.93% for ON vs. 1.45% for RN). CONCLUSIONS: RN exhibit a dermal scar, a greater number of melanophages, cytologic atypia, and asymmetry than ON, features that may raise concern about the possibility of malignant melanoma. However, the area with the irregular architectural pattern is restricted to the epidermis and dermis immediately above the scar. In addition, IHC helps to distinguish RN from malignant melanoma; specifically, RN demonstrate an immunohistochemical "maturation pattern" (with HMB-45 and anti-tyrosinase) and a low proliferative index (with Ki-67).

Atypical bile duct adenoma, clear cell type: a previously undescribed tumor of the liver.

A variable proportion of bile duct adenomas of the liver are still confused with metastatic well-differentiated adenocarcinoma by surgeons and pathologists. We present here three examples of previously undescribed primary hepatic bile duct tumors that were composed almost entirely of clear cells that closely mimicked metastatic renal cell carcinoma. They were interpreted as atypical bile duct adenomas and occurred in two males and one female whose ages ranged from 25 to 64 years. All three tumors were incidental findings and measured from 0.8 to 1.1 cm. The clear neoplastic cells showed mild nuclear atypia and no mitotic activity. They were arranged in tubules and nests that focally infiltrated the hepatic parenchyma. For comparison, a case of clear cell cholangiocarcinoma and 13 conventional bile duct adenomas were examined. The clear cell cholangiocarcinoma was larger (6.0 cm) and had the tubular pattern of conventional cholangiocarcinoma and an abundant desmoplastic stroma. The clear cells of this tumor exhibited greater nuclear atypia and increased mitotic activity. All three atypical bile duct adenomas expressed cytokeratin (CK) 7, p53 protein, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA); they were negative for CK20, vimentin, Hep Par 1, chromogranin, and prostatic specific antigen (PSA) and exhibited less than 10% of Ki-67-positive nuclei. One atypical bile duct adenoma displayed luminal immunoreactivity for villin. With the exception of Ki-67 reactivity, the 13 conventional bile duct adenomas and the clear cell cholangiocarcinoma had essentially a similar immunohistochemical profile as that of the atypical clear cell bile duct adenomas. The absence of an extrahepatic primary tumor, the histologic features, the immunohistochemical profile, and the fact that all patients are symptom-free 2 months to 18 years after wedge liver biopsy support the interpretation of atypical clear cell bile duct adenoma. The differential diagnosis with clear cell hepatocellular carcinoma and metastatic clear cell carcinomas is discussed.

Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel-Lindau disease.

The dominantly inherited von Hippel-Lindau disease is characterized by clear cell neoplasms in various organs including the kidney and pancreas. Determination of primary versus metastatic lesion in this setting can be a diagnostic dilemma. The authors present five cases of clear cell endocrine pancreatic tumor (EPT) closely mimicking renal cell carcinomas in five patients with a family history or histologic evidence of von Hippel-Lindau disease. In fact, two of these tumors were confused with metastatic renal cell carcinoma by fine-needle aspiration. All five tumors had a component of clear cells arranged in nests, cords, and tubules with central hemorrhage separated by thin-wall vessels resembling renal cell carcinoma. However, these tumors also exhibited cords and festoons and a gyriform pattern suggestive of an endocrine neoplasm, and expressed chromogranin and synaptophysin. Vascular invasion was identified in four tumors, one of which metastasized. The concurrent primary renal cell carcinomas and the multicentric microcystic adenomas found in three patients did not show reactivity for the neuroendocrine markers. Focal clear cell change was noted in only one of 29 endocrine pancreatic tumors arising in patients without von Hippel-Lindau disease. Eleven metastatic renal cell carcinomas in the pancreas did not show immunoreactivity with the endocrine markers. Clear cell EPTs closely mimicking renal cell carcinoma are distinctive neoplasms of von Hippel-Lindau disease. In contrast to clear cell EPT, metastatic renal cell carcinoma does not express neuroendocrine markers and lacks neurosecretory granules by electron microscopy. Von Hippel-Lindau disease should be strongly suspected in patients with renal cell carcinoma, clear cell EPT, and multifocal microcystic serous adenomas.

HER-2/neu gene amplification compared with HER-2/neu protein overexpression and interobserver reproducibility in invasive breast carcinoma.

We compared the detection of HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) with detection of HER-2/neu protein overexpression by immunohistochemistry using 2 antibodies on 100 archival invasive breast carcinomas. Protein overexpression for each marker was scored independently by 4 pathologists using standardized criteria, and consensus was compared with results obtained from gene amplification. The concordance rate between FISH and immunohistochemistry was 76% for e2-4001 and 91% for the HercepTest. Of the 37 cases positive by e2-4001, 21 demonstrated no gene amplification; 7 of 24 cases positive by the HercepTest demonstrated no gene amplification. However, 1 of 61 cases negative by e2-4001 showed gene amplification; none of the cases negative by the HercepTest showed amplification. The predictive values of gene amplification based on 0-1+, 2+, and 3+ immunohistochemical staining were best for cases scored as 3+ (75% for e2-4001 and 89% for the HercepTest). Complete agreement among observers for immunohistochemical scoring of e2-4001 and the HercepTest was achieved in 75 and 85 cases, respectively. The pairwise kappa agreement values were substantial for e2-4001 and substantial to almost perfect for the HercepTest. Immunohistochemical staining may be considered a useful screening test. While negative staining almost always correlated with a lack of gene amplification, positive membranous staining, especially 2+, did not predict gene amplification. The low interobserver reproducibility in separating 2+ from 3+ cases necessitates further confirmation by FISH before treatment decisions are made.

Bisalbuminuria in an adult with bisalbuminemia and nephrotic syndrome.

Bisalbuminemia (or alloalbuminemia) is a relatively rare hereditary or acquired condition characterized by the presence of two distinct albumin bands, or, less commonly, a single widened albumin band, after agarose gel electrophoresis of serum. Bisalbumins are caused by point- or chain-mutations that occur with a population frequency of 1:10,000 to 1:1000. Although no adverse clinical effects have been attributed to bisalbumins, some albumin variants have altered affinity for steroid hormones, thyroxine, or drugs. We report a case of bisalbuminuria in a 25-year-old man with bisalbuminemia and nephrotic syndrome.