Donald Ming-Tak Ho

Primary intracranial germ cell tumor. Pathologic study of 51 patients

Fifty‐one primary intracranial germ cell tumors (GCT), including germinoma, teratoma, endodermal sinus tumor, choriocarcinoma and mixed GCT, were studied. The incidence of GCT in the surgically removed intracranial neoplasms was 11.1% for pediatric patients and 0.6% for adult patients. The age/sex of the patients and the location of the tumors were analyzed. Morphologic findings of these tumors were identical to that of their gonadal counterparts. Immunohistochemical studies showed that alpha‐fetoprotein (a‐AFP), human chorionic gonadotropin (HCG), and placental alkaline phosphatase (PLAP) were helpful, whereas carcinoembryonic antigen (CEA) and cytokeratin (CKER) were of little help in determining the diagnosis. Serum tumor markers, a‐AFP and HCG, were helpful in recognizing GCT producing them. However, they could not be used for specific diagnosis because different tumors could have similar serum levels. Histopathologic study was handicapped by the small size of most specimens (which usually could not include all of the components if the tumor was a mixed GCT), but it was the only means for specific diagnosis.

Gamma knife surgery for vestibular schwannoma: 10-year experience of 195 cases

OBJECT The authors conducted a study to determine the optimal radiation dose for vestibular schwannoma (VS) and to examine the histopathology in cases of treatment failure for better understanding of the effects of irradiation. METHODS A retrospective study was performed of 195 patients with VS; there were 113 female and 82 male patients whose mean age was 51 years (range 11-82 years). Seventy-two patients (37%) had undergone partial or total excision of their tumor prior to gamma knife surgery (GKS). The mean tumor volume was 4.1 cm3 (range 0.04-23.1 cm3). Multiisocenter dose planning placed a prescription dose of 11 to 18.2 Gy on the 50 to 94% isodose located at the tumor margin. Clinical and magnetic resonance (MR) imaging follow-up evaluations were performed every 6 months. A loss of central enhancement was demonstrated on MR imaging in 69.5% of the patients. At the latest MR imaging assessment decreased or stable tumor volume was demonstrated in 93.6% of the patients. During a median follow-up period of 31 months resection was avoided in 96.8% of cases. Uncontrolled tumor swelling was noted in five patients at 3.5, 17, 24, 33, and 62 months after GKS, respectively. Twelve of 20 patients retained serviceable hearing. Two patients experienced a temporary facial palsy. Two patients developed a new trigeminal neuralgia. There was no treatment-related death. Histopathological examination of specimens in three cases (one at 62 months after GKS) revealed a long-lasting radiation effect on vessels inside the tumor. CONCLUSIONS Radiosurgery had a long-term radiation effect on VSs for up to 5 years. A margin 12-Gy dose with homogeneous distribution is effective in preventing tumor progression, while posing no serious threat to normal cranial nerve function.

Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma†

Perivascular epithelioid cell tumours (PEComas) are a family of tumours including classic angiomyolipoma, lymphangioleiomyomatosis, and clear epithelioid cell tumours reported under a variety of names such as epithelioid angiomyolipoma, pulmonary and extrapulmonary clear cell sugar tumour, and PEComa. Our previous comparative genomic hybridization study of PEComas demonstrated recurrent chromosomal aberrations including deletions on chromosome 16p, where the TSC2 gene is located. In this study, we focused on the alteration of chromosome 16p, including TSC2. We collected ten sporadic and two tuberous sclerosis complex‐associated PEComas, as well as 14 sporadic classic hepatic and renal angiomyolipomas (AMLs) as controls. We used 16 microsatellite markers distributed along chromosome 16p to test for allelic imbalances on chromosome 16p and at TSC2, and two markers for TSC1. Furthermore, we carried out immunohistochemical staining for phospho‐p706K, phospho‐AKT, and phospho‐S6 to evaluate the effect of TSC2 alterations on the mTOR signalling pathway. Loss of heterozygosity (LOH) was found in 11 PEComas and involved the region of the TSC2 locus in seven. Six classic angiomyolipomas had allelic changes at chromosome 16p. Microsatellite instability was detected in two PEComas. The incidence of genetic aberrations was significantly higher in the PEComa group. Only one PEComa showed LOH at the TSC1 locus. Eleven PEComas and 13 AMLs revealed elevated phospho‐p70S6K accompanied by reduced phospho‐AKT. Five PEComas and eight classic angiomyolipomas were positive for phospho‐S6. The phosphorylation profile indicates functional activation of the mTOR pathway through a disrupted TSC1/2 complex. Our observations of frequent deletion of TSC2 and the mTOR signalling pathway provide evidence that the oncogenetic lineage of PEComa, as a distinct TSC2‐linked neoplasm, is similar to that of angiomyolipoma. Copyright

Prognostic significance of the 2004 WHO/ISUP classification for prediction of recurrence, progression, and cancer-specific mortality of non-muscle-invasive urothelial tumors of the urinary bladder: a clinicopathologic study of 1,515 cases.

To verify prognostic significance of the 2004 World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading systems, we retrospectively studied the tumors of 1,515 patients who underwent transurethral resection of primary non-muscle-invasive urothelial tumors (pTa, 1,006 patients; pT1, 509 patients) confined to the bladder. Cases were classified according to the 2004 WHO/ISUP systems as 212 cases of papillary urothelial neoplasm of low malignant potential (PUNLMP), 706 low-grade papillary urothelial carcinomas (LPUCs), and 597 high-grade papillary urothelial carcinomas (HPUCs). PUNLMP showed the statistically significantly lowest recurrence cumulative incidence compared with the other tumor types. There were significant differences and trends for higher progression and cancer-specific mortality cumulative incidence in the following order: PUNLMP, LPUC, pTa HPUC, and pT1 HPUC. No differences of progression and cancer-specific mortality cumulative incidence were found between pTa and pT1 LPUC. Our study validates the usefulness of the 2004 WHO/ISUP system to classify urothelial tumors into prognostically distinct categories that would contribute to the design of therapeutic and monitoring strategies for patients with non-muscle-invasive bladder urothelial tumors.

Treatment of spinal cord ependymomas by surgery with or without postoperative radiotherapy.

AbstractPurpose: To evaluate the effectiveness of complete resection and postoperative radiotherapy in spinal cord ependymomas. Methods and materials: We conducted a retrospective study over 20 patients (13 males and 7 females) with histologically confirmed spinal cord ependymomas between July 1985 and April 2001. Among them, 13 patients had ependymomas, 6 had myxopapillary ependymomas, and 1 had anaplastic ependymoma. All patients received radical surgery for tumor removal with 13 patients achieving complete resection and 7 incomplete resection due to technical difficulty. Among those with incomplete resection, 6 patients received postoperative radiotherapy to tumor bed and only one patient with anaplastic ependymoma received surgery alone. The total tumor dose ranged from 50 to 60 Gy. Results: Among the 20 patients, 19 patients were alive and showed local control. The median survival time of all patients was 109 months, with 104 months in the complete resection alone group and 135 months in the incomplete resection with postoperative radiotherapy group. One patient with anaplastic ependymoma and no postoperative radiotherapy developed leptomeningeal seeding 9 months after surgery. Salvage therapy of radiotherapy and chemotherapy maintained normal neurological functions. The patient expired 34 months from the initial diagnosis due to progression of leptomeningeal seeding. Conclusion: Complete resection alone in spinal cord ependymoma can achieve excellent local control and survival. Patients should receive complete resection if technically possible. Postoperative radiotherapy is not recommended for complete resection. For incomplete resection, postoperative local radiotherapy is recommended and it can also achieve excellent local control and survival. Local radiotherapy with 50-60 Gy is effective and safe. Salvage radiotherapy improves quality of life for local recurrence or leptomeningeal seeding patients.

A clinicopathologic study of 81 patients with ependymomas and proposal of diagnostic criteria for anaplastic ependymoma.

Optimal histologic criteria for the classification of and grading of ependymomas, including their anaplastic forms, remain elusive. This is especially true because of the poor correlation of these criteria with clinical outcome. The aim of this study was to identify the histopathologic parameters that could distinguish different prognostic groups of patients with ependymomas. Eighty-one patients with ependymal tumors, including those originally diagnosed ependymomas, anaplastic ependymomas and myxopapillary ependymomas, were enrolled in this study. Thirteen histologic parameters, including hypercellularity, nuclear pleomorphism, mitoses, endothelial proliferation, necrosis, clear cell, thrombi, dystrophic calcification, psammoma bodies, bone, cartilage, Rosenthal fibers and MIB-1 labeling index (LI), were evaluated in each patient and correlated with clinical outcome. We assigned one score for each histopathologic parameter evaluated and used a stepwise selection method with entry model based on the significance of the log-rank statistic to formulate a scoring model. Four parameters were chosen in this process, including mitoses ≥ 4/10 hpf (1.7/mm2), hypercellularity, endothelial proliferation and necrosis. The sum of these four parameters (scores) was the histopathologic score of the tumor. The progression-free survival (PFS) and overall survival (OS) of patients with histopathologic scores 0 and 1 were significantly better than those with histopathologic scores 2, 3 and 4 (p < 0.001 and p = 0.005, respectively). Because of the latter finding, we proposed that anaplastic ependymoma could be diagnosed by the presence of any two of the aforementioned four parameters. Multivariate analyses including clinical and histopathologic variables showed that histopathologic score ≥ 2 and subtotal resection were the factors related to increased risk of recurrence, while histopathologic score ≥ 2 was the only factor related to overall survival. Based on the above findings, we concluded that histopathology is an important prognostic indicator for patients with ependymomas.

Immunohistochemical and molecular genetic profiling of acquired cystic disease-associated renal cell carcinoma.

Aims:  Acquired cystic disease‐associated renal cell carcinoma (ACD‐associated RCC) is a unique neoplasm that specifically develops in the background of acquired cystic disease of the kidney. The aim was to analyse nine ACD‐associated RCCs from three patients to determine their immunohistochemical and molecular characteristics using immunohistochemistry, comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH).

Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer

Purpose: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer. Experimental Design: Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients. Results: Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P < 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues. Conclusions: Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.

1-11C-Acetate Versus 18F-FDG PET in Detection of Meningioma and Monitoring the Effect of γ-Knife Radiosurgery

This study aimed to define the potential of 1-11C-acetate PET, compared with 18F-FDG, in detecting meningiomas and monitoring the effect of γ-knife radiosurgery. Methods: Twenty-two patients with the neuroradiologic diagnosis of meningioma were examined by 1-11C-acetate and 18F-FDG PET on the same day. There were 12 cases of histopathologically proven meningioma (8 grade I, 2 grade II, and 2 grade III), 1 of tuberculous granuloma, and 1 of degenerative tissue. 1-11C-acetate PET scans of fasting patients were obtained 10 min after intravenous administration of 740 MBq of 1-11C-acetate. 18F-FDG PET was performed at 2 h after 1-11C-acetate scanning. The PET images were evaluated by a qualitative method and semiquantitative analysis using standardized uptake value and tumor-to-cortex ratio. Results: The 18F-FDG PET study revealed a hypometabolic focus in 17 meningiomas (8 grade I, 1 grade II, and 8 unknown grade) and hypermetabolism in 1 grade II and 2 grade III meningiomas. High uptake of 1-11C-acetate was observed in all 20 meningiomas, in contrast to the low uptake in surrounding normal brain tissue, allowing a clearer demarcation of the tumor boundary than that provided by 18F-FDG. Dissociation of regional accumulation of 1-11C-acetate and 18F-FDG within the tumor was also noted on the coregistered images. The standardized uptake value for 1-11C-acetate was not different from that for 18F-FDG (mean ± SD, 3.16 ± 1.75 vs. 3.22 ± 1.50, P = 0.601), but the tumor-to-cortex ratio for 1-11C-acetate was higher than that for 18F-FDG (3.46 ± 1.38 vs. 0.93 ± 1.08, P < 0.005). 18F-FDG was able to differentiate grade I from grade II–III meningiomas, whereas 1-11C-acetate was unable to do so. Tuberculous granuloma had a high 1-11C-acetate and 18F-FDG uptake similar to that of grade II/III meningioma. Five patients received 1-11C-acetate and 18F-FDG PET before and after γ-knife surgery. 1-11C-acetate performed better than did 18F-FDG in monitoring the response of tumor metabolism to radiosurgery. Conclusion: 1-11C-acetate was found to be useful for detecting meningiomas and evaluating the extent of meningiomas and potentially useful for monitoring tumor response to radiosurgery. However, 1-11C-acetate was not useful for evaluating the tumor grade. 18F-FDG was found to be less useful than 1-11C-acetate for evaluating the extent of meningiomas and the response to radiosurgical treatment but may be useful for differentiating benign from malignant meningiomas. 18F-FDG and 1-11C-acetate are complementary for assessing diverse cell metabolism of meningioma.

Correlation of magnetic resonance images with neuropathology in acute Wernicke's encephalopathy

We correlated serial brain MRIs with neuropathological findings in a 16-year-old female whose autopsy was consistent with Wernickes encephalopathy (WE). Diffusion-weighted imaging, diffusion coefficients mapping and neuropathology findings were suggested vasogenic edema in the periaqueductal and peri-the-fourth ventricular areas. This is the first documented case report to make this direct comparison. The characteristic WE changes in the mammillary body was also correlated with the findings of MRI with contrast enhancement. Bilateral cortical lesions revealed by MRI were atypical and rare in WE and were not evidenced by pathological changes.