Histopathology of radiation necrosis with severe peritumoral edema after gamma knife radiosurgery for parasagittal meningioma. A report of two cases.

BACKGROUND: Gamma knife radiosurgery (GKS) has been an effective treatment for meningiomas. Nevertheless, it still has certain risks. We present 2 cases of parasagittal meningioma after GKS complicated with radiation necrosis and peritumoral edema. The results of histologic examination are discussed. CASE DESCRIPTION: Two cases of parasagittal meningioma received GKS. Symptomatic peritumoral edema developed 3-4 months after GKS. Both of them underwent surgical resection of their tumor afterwards. Histologic examination showed necrotic change inside the tumor and infiltration of inflammatory cells in both cases. Hyalinization of blood vessels was seen in the 2nd case. The patients had improvement of neurologic function after surgical resection. Imaging performed 3 months after surgical resection showed alleviation of brain edema. CONCLUSION: After radiosurgery peritumoral edema tends to occur in meningiomas with a parasagittal position. Radiation necrosis, infiltration of inflammatory cells, and radiation injury to the vasculature causing hyalinization of blood vessels are suggested as the underlying histopathology.

Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer.

PURPOSE: Lung cancer cells frequently exhibit marked chromosome instability. We postulated that alterations of the double-strand break repair genes (BRCA1, BRCA2, and XRCC5) might be involved in lung cancer. PATIENTS AND METHODS: We examined the loss of protein and mRNA expression and the 5'CpG hypermethylation and allelic imbalance of the BRCA1, BRCA2, and XRCC5 genes in 98 non-small cell lung cancer (NSCLC) samples. Anchorage-dependent growth after reexpression of these genes was examined in a lung cancer cell line that originally lacked BRCA1 and BRCA2 expression. RESULTS: The data indicated that low protein expression of BRCA1 and BRCA2 was frequent in lung adenocarcinomas (42-44%), whereas low XRCC5 protein expression was more prevalent among squamous cell carcinoma (32%). In addition, low BRCA1 expression was significantly associated with low RB expression, especially in lung adenocarcinoma. Concurrent alterations in XRCC5 and p53 were the most frequent profiles in smoking patients. Importantly, low mRNA and protein expressions of BRCA1, BRCA2, and XRCC5 were significantly associated with their promoter hypermethylation. 5-Aza-2'-deoxycytidine treatment of NSCLC cells showed demethylation and reexpression of the BRCA1 and BRCA2 genes and reduced anchorage-independent growth. CONCLUSIONS: Our retrospective study provides compelling evidence that low mRNA and protein expression in the BRCA1/BRCA2 and XRCC5 genes occur in lung adenocarcinoma and squamous cell carcinoma, respectively, and that promoter hypermethylation is the predominant mechanism in deregulation of these genes. Alteration of the double-strand break repair pathway, perhaps by interacting with p53 and RB deregulation, is important in the pathogenesis of a subset of NSCLC.

Colorectal mesenchymal tumor: a clinicopathologic study of 25 cases.

BACKGROUND: It is important to distinguish gastrointestinal stromal tumors (GISTs) from other gastrointestinal mesenchymal tumors (GIMTs), because of the malignant potential of GISTs and the availability of molecular targeted therapy. GISTs represent the most common subgroup of GIMTs, and rarely occur in the colon and rectum. The first objective of our retrospective study was to reclassify colorectal mesenchymal tumors, from files collected over 20 years, to determine if, based on immunohistologic features, the lesions were truly GISTs. The second objective was to identify the relationship between clinicopathologic features and prognostic factors of GISTs in the colon and rectum. METHODS: We evaluated all cases of colorectal mesenchymal tumor identified from the database of the Department of Surgical Pathology at Taichung Veterans General Hospital for the period 1983-2001. For 25 patients, clinical data, and information about tumor characteristics, surgical procedures, and survival outcomes, were obtained and analyzed. Histopathologic evaluations, and appropriate immunohistochemical markers, were used to distinguish between various GIMT subtypes. The relationship between KIT expression and clinicopathologic features was investigated. RESULTS: The following variables were significantly associated with different CD117 results: symptomatic presentation, location, gross features, tumor size, mitotic count, cellularity, and type of surgery. Only 18 tumors were identified as GISTs. For these, the following variables were significantly associated (by univariate analysis) with increased lethality: tumor size (p = 0.049); mitotic count (p = 0.019); nuclear atypia (p = 0.019); and tumor necrosis (p = 0.045). However, only mitotic activity showed a significant difference in the survival analysis (p = 0.0304; log-rank test). CONCLUSION: Two clinicopathologically different categories were identified from our colorectal mesenchymal tumors: intramural GISTs and polypoid submucosal leiomyomas. Our study suggests that GIST is a better categorization than smooth muscle tumor because of the malignant potential. Prognosis is strictly related to the number of mitoses. However, tumor size, nuclear atypia and tumor necrosis are probably also significant predictive factors of lethality. Future studies with DNA analysis and larger patient numbers are essential to evaluate the prognostic significance of our findings.

Ovarian serous cystadenoma with mural nodules of genital rhabdomyoma.

We present an extremely rare case of ovarian serous cystadenoma with mural nodules of rhabdomyoma. The patient, a 48-year-old woman, was admitted to our hospital with left lower abdominal pain and vaginal bleeding. A unilocular cystic tumor, measuring 13 x 10 x 10 cm, was found in her left ovary and was removed. The tumor contained clear serous fluid, approximately 600 mL, and 2 mural nodules, up to 7.5 x 5.5 x 4.5 cm. The internal cystic wall was thin for the most part and lined with ciliated cuboidal epithelium without any malignant feature. The mural part was composed of mainly more mature muscle fibers with easily discernible cross-striations, set in abundant myxoid to fibromyxoid stroma, similar to clinical and microscopic manifestations of genital rhabdomyomas reported in other sites. Because extracardiac rhabdomyoma has never been described occurring in the ovary, especially arising in serous cystadenoma, to our knowledge, this is the first case reported in the English literature.

Molecular cytogenetics of ovarian granulosa cell tumors by comparative genomic hybridization.

OBJECTIVE: Patients with stage I granulosa cell tumors (GCTs) may occasionally develop metastasis, which is hard to predict using pathologic criteria. It is interesting to elucidate whether certain chromosomal imbalances (CIs), detected by comparative genomic hybridization (CGH), could be useful prognostic markers. METHODS: CGH was used to identify CI(s) in 37 adult-type GCTs from 36 women. Nonrandom CIs were compared with clinical and pathological features to evaluate their significance as a prognostic marker. RESULTS: Twenty-two (61%) of the 36 primary tumors had CIs. One woman's tumor showed identical CIs to another tumor that occurred in contralateral ovary 2 years later, supporting a metastatic nature. The nonrandom CIs included losses of 22q (31%), 1p33-p36 (6%), 16p13.1 (6%), and 16q (6%) and gains of 14 (25%), 12 (14%), and 7p15-p21 (6%). No tumor exhibited high-level amplification. The associations between each CI and pathological features, including the growth pattern, tumor size, and mitotic activity, were not evident. The only CI repeatedly detected in tumors with metastasis was monosomy 22, which presented in 2 of the 4 cases with metastasis but also in 2 of the 5 cases without recurrence for more than 5 years. CONCLUSIONS: Monosomy 22 was the most common CI in GCTs, which often coexisted with trisomy 14 (in 55% cases). Deletion of 22q seems to be, albeit not very specific, associated with the risk of early metastases of stage I disease. The role of loss-of-function mutation(s) of certain putative tumor suppressor gene(s) on 22q is worthy of further investigations.

Treatments of multi-invasive giant prolactinoma.

We present a 68-year-old male patient with an exceptionally aggressive tumour which invaded to the skull base, cavernous sinus, nasopharynx, sphenoid sinus, pituitary fossa, bilateral parasellar regions, premedullary cistern, and left infratemporal fossa. Headache was the only symptom. The serum prolactin level was 95,973 ng/ml. The patient was treated by right subfrontal craniotomy with removal of the tumour. Because it did not respond well to surgical treatment and the electron micrograph showed abundant secretory granules in some parts of the specimen, post-operative radiotherapy and bromocriptine therapy were instituted. After combined therapies and a long-term follow-up, only little residual pituitary tumour was seen with serum prolactin progressively dropped to 717 ng/ml with no obvious symptoms. The histological findings, the ideal treatments and the clinical course of multi-invasive giant prolactinoma will be discussed.

Association of aryl hydrocarbon receptor and cytochrome P4501B1 expressions in human non-small cell lung cancers.

It has been shown that cytochrome P4501B1 (CYP1B1) is over-expressed in variety of tumors. The objective of this study was to examine the expression and localization of CYP1B1 in normal lungs and tumor tissues of non-small cell lung cancers (NSCLC). CYP1B1 was detectable in the microsomes of normal lungs and lung tumors with Western immunoblotting. Utilizing immunohistochemical staining, we found that CYP1B1 was constitutively expressed in the cytoplasm of smooth muscle cells, but not in pneumocytes. Bronchiolar epithelia from three out of 19 normal lungs expressed CYP1B1. Among 89 NSCLC tumor tissues, more than 50% expressed CYP1B1. In addition, CYP1B1 expression was more common in adenocarcinomas than in squamous cell carcinomas. Recently, we reported over-expression of aryl hydrocarbon receptors (AhR) in lung adenocarcinomas. In the present study, we observed an association between CYP1B1 and AhR expression in 89 NSCLC tumor tissues. These results suggest that CYP1B1 overexpression in NSCLC is accompanied by up-regulation of AhR expression.

The correlation between aberrant connexin 43 mRNA expression induced by promoter methylation and nodal micrometastasis in non-small cell lung cancer.

Reduced connexin (Cx) 43 gene expression has been shown in most of lung tumors and cancer cell lines. Although aberrant Cx43 gene expression was linked with lung tumorigenesis, our understanding to the mechanism was still limited. We hypothesized that the evidence of aberrant Cx43 gene expression was gradually intensified from adjacent normal lung tissues surrounding tumors toward tumor tissues. In this study, 90 lung tumors and adjacent normal tissues were collected to examine Cx43 mRNA expression by reverse transcription-PCR (RT-PCR). Our data showed that Cx43 mRNA expression in adjacent normal lung tissue was significantly correlated with nodal involvement (P = 0.03), but the similar trend was not observed in tumor tissues. To verify whether lack of Cx43 mRNA expression resulted from promoter methylation, PCR-based methylation assay was performed for Cx43 promoter methylation analysis. A higher frequency of promoter methylation was observed in Cx43 mRNA-negative patients (21 of 33, 63.7%) compared with Cx43 mRNA-positive patients (3 of 57, 5.3%, P < 0.0001). To elucidate whether aberrant Cx43 gene expression originated from adjacent normal lung tissues, 25 lung tumors and each of five adjacent normal tissues at various distances from tumor tissues were collected to examine Cx43 mRNA and protein expression by RT-PCR and Western blot, respectively. The results show that Cx43 mRNA and protein expressions gradually decreased from adjacent normal lung tissues to tumor tissues with a positive correlation to the distance from the tumor tissues. Gel-shift assay data also revealed that shifted band binding with AP1 was only observed in adjacent normal tissues, which were far from the tumor tissues. These results indicate that promoter methylation may interfere with AP1 binding to the promoter to cause aberrant Cx43 gene expression. Thus, Cx43 mRNA in adjacent normal tissue surrounding lung tumor simply detected by RT-PCR may act as a molecular marker of nodal micrometastasis in non-small cell lung cancer.

Src phosphorylates Grb2-associated binder 1 upon hepatocyte growth factor stimulation.

Grb2-associated binder 1 (Gab1) is known to play an important role in hepatocyte growth factor (HGF) signaling, which rapidly becomes tyrosine-phosphorylated upon HGF stimulation. In this study, we found that the tyrosine phosphorylation of Gab1 in the cells derived from Src/Yes/Fyn null mouse embryos was approximately 40% lower than that in their wild type counterparts upon HGF stimulation. Increased expression of wild-type Src enhanced HGF-induced phosphorylation of Gab1, and, in contrast, expression of the Src kinase-deficient mutant or treatment of the specific Src inhibitor PP1 suppressed it. Expression of a constitutively active Src mutant (Y527F) or oncogenic v-Src led to a prominent increase in Gab1 phosphorylation independent of HGF stimulation. Moreover, Src interacted with Gab1 via both its Src homology 2 and 3 domains and was capable of phosphorylating purified Gab1 in vitro. Finally, the increased phosphorylation of Gab1 by Src selectively potentiated HGF-induced activation of ERK and AKT. Taken together, our results establish a new role for Src in HGF-induced Gab1 phosphorylation.

Mitomycin C-induced renal insufficiency: a case report.

A 58-year-old normotensive male with normal renal function and gastric cancer underwent total gastrectomy and received adjuvant chemotherapy with mitomycin C (MMC) for 10 months. He developed anemia, hypertension, and renal function impairment 9 months after initiation of chemotherapy. Kidney biopsy showed thrombotic microangiopathy with marked mesangiolysis and expansion of the subendothelial space resulting in cystic dilation of the glomerular capillaries, and cellular atypia in the tubular cells. His renal function deteriorated gradually then stabilized after treatment with plasma exchange, antihypertensive agents, and antiplatelet agents. He had no sign of tumor recurrence after 3 years of follow-up. We suggest that patients receiving MMC should have their blood pressure and renal function closely monitored for the possibility of development of drug-induced renal insufficiency.

Amyloidosis of medium-sized arteries presenting as perioral mass: a case report.

We report a case of amyloidosis localized to the medium-sized arteries of the face and presenting as prominent perioral swelling. The condition was identified as primary AL-type amyloidosis on the basis of immunohistochemical reactivity, predominantly for anti-lambda light chain antibody within amyloid deposits. Subsequent radiographic and laboratory evaluation of the patient disclosed multiple myeloma. Although amyloid deposits were subsequently detected in the temporal arteries, evidence of widespread amyloidosis has not been observed after 1 year of follow-up. To the best of our knowledge, this is the first report of myeloma-associated amyloidosis mainly localized to the medium-sized arteries of the face.

Synergistic effect of focal adhesion kinase overexpression and hepatocyte growth factor stimulation on cell transformation.

Although an elevated level of focal adhesion kinase (FAK) has been observed in a variety of invasive human tumors, forced expression of FAK alone in cultured cells does not cause them to exhibit transformed phenotypes. Therefore, the role of FAK in oncogenic transformation remains unclear. In this study, we have demonstrated that FAK overexpression in Madin-Darby canine kidney epithelial cells rendered them susceptible to transformation by hepatocyte growth factor (HGF). Using various FAK mutants, we found that the simultaneous bindings of Src and p130(cas) were required for FAK to potentiate cell transformation. Expression of FAK-related nonkinase, kinase-deficient Src, or the Src homology 3 domain of p130(cas), which respectively serve as dominant negative versions of FAK, Src, and p130(cas), apparently reversed the transformed phenotypes of FAK-overexpressed cells upon HGF stimulation. Moreover, FAK overexpression was able to enhance HGF-elicited signals, leading to sustained activation of ERK, JNK, and AKT, which could be prevented by the expression of the Src homology 3 domain of p130(cas). Taken together, our results indicate that the synergistic effect of FAK overexpression and HGF stimulation leads to cell transformation and implicate a critical role of p130(cas) in this process.

Synovial sarcoma of the mediastinum.

Synovial sarcomas are exceedingly rare neoplasms of the mediastinum. We herein report a case of synovial sarcoma occurring in the mediastinum of an 11-year-old boy. The patient presented with superior vena cava syndrome, and the tumor was found located in the upper superior mediastinum. Due to the large size of the tumor making complete removal impossible, an incisional biopsy was performed. The biopsy showed the typical biphasic pattern of synovial sarcoma. After surgery, the patient received radiotherapy and chemotherapy, and was still alive 2 years after diagnosis.

Loss of heterozygosity at loci of candidate tumor suppressor genes in microdissected primary non-small cell lung cancer.

To investigate the etiological association of allelic loss at chromosomal regions containing tumor suppressor genes (TSGs) in non-small cell lung cancer (NSCLC) in Taiwan, we examined 48 microdissected NSCLC samples for loss of heterozygosity (LOH) at nine loci where TSGs are localized nearby. The associations of LOH at each locus with clinicoparameters and prognosis were also examined. The frequent LOH was observed using markers, D3S1285 near the FHIT gene (58.3%), D17S938 near the p53 gene (56.7%), D9S925 near the p16 gene (54.5%), and D13S153 near the RB gene (47.6%). The occurrence of LOH at each TSG locus was compared with the patients' clinicoparameters. The incidence of LOH at D17S938 (p53 gene) and D3S4545 (VHL gene) was significantly higher in squamous carcinoma tumors than in adenocarcinoma tumors (P = 0.003 and 0.024, respectively). LOH of these two loci also occurred frequently in tumors from smoker patients compared to that from nonsmoker patients (P = 0.013 and 0.025, respectively). LOH at D13S153 (RB gene) was also associated with smoking (P = 0.008). In addition, the prognostic analyses indicated that the patients with LOH at D18S535 (18q21, near the SMAD2/4 gene) had significantly longer post-operative survival time compared to those without LOH (P = 0.03). Our results suggested that LOH at FHIT, p53, and p16 genes may occur frequently in NSCLC patients in Taiwan. In addition, LOH at p53, RB, and VHL may associate with smoking or squamous carcinoma patients and LOH at SMAD2/4 may be correlated with better prognosis.

Collagenous spherulosis presenting as a mass of the breast.

Collagenous spherulosis (CS) is a rare benign lesion which typically presents as an incidental microscopic finding accompanying other breast lesions. Pathologists who are not familiar with this entity occasionally misdiagnose CS as adenoid cystic carcinoma (ACC), cribriform ductal carcinoma in situ (C-DCIS), or atypical intraductal hyperplasia (AIH), especially when it presents as a mass. It is of utmost importance to differentiate benign CS from its malignant mimics in order to avoid unnecessary treatment. We report an unusual case of CS manifested as a mass in the right breast of a 45-year-old female and discuss the problems of differential diagnosis and histogenesis.