What Tactics Should a Surgeon Choose to Treat a Black Extracerebral Tumor? A Case Report of Psammomatous Melanotic Schwannoma of the Meckel Cave and Literature Review.

BACKGROUND: Neoplasms located in the Meckel cave account for 0.2%-0.5% of all intracranial tumors. This area is the site of many types of pathologic lesions, most often trigeminal nerve schwannomas and meningiomas. Melanin-containing tumors are rare in this area. These tumor types can be suspected if the magnetic resonance characteristics of a tumor has some differences in comparison with other types of central nervous system neoplasms. In fact, differential diagnosis of melanotic tumors is based mainly on the histopathologic criteria and immunohistochemical profile. This article presents a case report of melanotic schwannoma of the Meckel cave and a literature review of the problem. CASE DESCRIPTION: A 23-year-old man underwent a 2-stage surgery for a dumbbell pigmented mass lesion located in the Meckel cave. No signs of recurrence were seen on follow-up magnetic resonance imaging (MRI) 3.5 years after the operation. CONCLUSIONS: Melanin-containing tumor can be suspected in the presence of radiologic characteristics, such as a hyperintense MRI signal on T1-weighted images and a hypointense signal on T2-weighted images. If a black extracerebral tumor is detected, the main course of surgical treatment is maximal excision despite it possibly being a malignant melanoma and the temptation to perform partial resection because of an unfavorable prognosis. Chemotherapy can be justified in the presence of an aggressive melanotic schwannoma.

Myxopapillary Ependymoma of Lumbar Soft Tissue: A Case Report With Gene Expression Evaluation.

Primary extraspinal myxopapillary ependymoma (MPE) is an exceptionally rare lesion that is mainly located in the subcutaneous sacrococcygeal region. We describe the first case of MPE that presented as an intramuscular tumor mass located in the lumbar area. Absence of the visible connection with the spinal cord and lack of any other tumors in the reported case argue for the primary ectopic origin of the MPE. The differential diagnosis of MPE is discussed. Additionally, we evaluated the expression level of molecular biomarkers that have a prognostic value in central nervous system tumors.

Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers.

Breast carcinomas caused by inheritance of cancer-predisposing germ-line mutations have specific bioclinical features. This study aimed to analyze the efficacy of conventional cytotoxic treatment in BRCA1 and CHEK2 mutation carriers and non-carriers. The study included 415 Russian breast cancer patients aged 50 years or younger, who were subjected to various standard schemes of neoadjuvant therapy. The choice of therapy was done without the knowledge of the mutations status, because DNA testing was performed retrospectively using the archival tissue samples. 19 BRCA1 (4.6%) and 8 CHEK2 (1.9%) heterozygous genotypes were identified. BRCA1 mutation carriers achieved pathological complete response more frequently than non-carriers [6/19 (31.6%) vs. 46/388 (11.9%), p = 0.024]; this effect was limited to women treated by anthracycline-based therapy without taxanes [5/9 (55.6%) vs. 28/247 (11.3%), p = 0.002] and was not observed in any of 7 BRCA1 carriers receiving taxane-containing regimens. CHEK2 heterozygotes did not experience pathological complete response and showed lower frequency of objective clinical responses as compared to mutation non-carriers [4/8 (50%) vs. 333/388 (85.5%), p = 0.020]; the efficacy of neoadjuvant therapy was particularly poor in CHEK2 carriers receiving anthracyclines without taxanes. This study provides evidence for distinct sensitivity of BRCA1 and CHEK2 mutation-driven breast carcinomas to standard chemotherapeutic schemes.

Detection of EGFR mutations and EML4-ALK rearrangements in lung adenocarcinomas using archived cytological slides.

BACKGROUND: Although the molecular analysis of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in archived lung cancer tissues is relatively well established, the genetic testing of cytological material has not yet become a routine. METHODS: The current study used cell samples that were obtained by bronchial brushing, transthoracic needle aspiration, or biopsy imprint preparation between 1993 and 2008. Islets of malignant cells were visually located on the archived cytological slides, lysed in situ by a drop of sodium dodecyl sulfate-containing buffer, and subjected to the standard DNA and RNA extraction. Examination of paraffin-embedded tissue blocks (resection specimens or biopsy material) from the same patients was performed in parallel. RESULTS: A total of 75 cytological/histological lung adenocarcinoma sample pairs underwent polymerase chain reaction analysis for the EGFR mutation. Two cytological samples and 1 morphological sample failed to produce DNA. Concordance for the wild-type and mutation status was observed in 54 of 72 and 14 of 72 informative pairs, respectively; 3 pairs and 1 pair, respectively, had mutation only in the cytological or histological material. The discrepancies could be explained by the failure to ensure a high percentage of lung cancer cells in the analyzed samples or, alternatively, by the genuine intratumoral molecular heterogeneity of some neoplasms. RNA extraction followed by reverse transcriptase-polymerase chain reaction analysis for the EML4-ALK translocation was performed for 44 EGFR mutation-negative sample pairs; failures were observed for 2 cytological and 6 histological specimens. All informative pairs were concordant either for the norm (32 of 36 pairs) or for the presence of EML4-ALK gene fusion (4 of 36 pairs). CONCLUSIONS: Archived cytological slides appear to be well suited both for EGFR and ALK analysis.

High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia.

The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cancer (BC) predisposition. Sequencing of its entire coding region in 95 genetically enriched Russian BC patients identified two heterozygous carriers of the c.1642 C>T (Q548X) mutation. The extended study revealed this allele in 17/1,498 (1.1%) BC cases vs. 2/1,093 (0.2%) healthy women (p = 0.004). There was a suggestion that BLM mutations were more common in patients reporting first-degree family history of BC (6/251 (2.4%) vs. 11/1,247 (0.9%), p = 0.05), early-onset cases (12/762 (1.6%) vs. 5/736 (0.7%), p = 0.14) and women with bilateral appearance of the disease (2/122 (1.6%) vs. 15/1376 (1.1%), p = 0.64). None of the BLM-associated BC exhibited somatic loss of heterozygosity at the BLM gene locus. This study demonstrates that BLM Q548X allele is recurrent in Slavic subjects and may be associated with BC risk.

KIT mutations in Russian patients with mucosal melanoma.

A single institution series of 48 mucosal melanomas (MMs) has been analyzed for the presence of KIT mutations using high-resolution melting and sequencing of abnormally melted DNA fragments. The analysis of exons 9, 11, 13, and 17 has revealed eight of 48 (17%) nonsynonymous alterations, including zero of seven head and neck, six of 24 anorectal, one of 15 genitourinary, one of one gastric, and zero of one mediastinal MMs. Seven of these mutations were potentially associated with the tumor sensitivity to KIT tyrosine kinase inhibitors. One tumor harbored somatically acquired silent nucleotide substitution c.1383A>G (T461T). This study adds to the evidence that a substantial portion of MMs carry a therapeutically relevant mutation in the KIT oncogene.

Mixed epithelial/mesenchymal metaplastic carcinoma (carcinosarcoma) of the breast in BRCA1 carrier.

This case report describes a 35-year-old woman who was diagnosed with mixed epithelial/mesenchymal metaplastic carcinoma (carcinosarcoma) of the breast. Genetic analysis of blood DNA revealed a common founder mutation, BRCA1 5382insC. Examination of microdissected tumor samples determined that both epithelial and mesenchymal components contained deletion of the wild-type BRCA1 allele. This report exemplifies that even very uncommon breast tumor types may develop through biallelic inactivation of BRCA1 gene, that has to be considered in the genetic testing settings.

High efficacy of first-line gefitinib in non-Asian patients with EGFR-mutated lung adenocarcinoma.

BACKGROUND: Several Asian studies demonstrated feasibility of front-line administration of gefitinib for the treatment of non-small cell lung carcinomas (NSCLCs) harboring intragenic epidermal growth factor receptor (EGFR) mutations. The experience of the use of this EGFR tyrosine kinase inhibitor (TKI) in non-Asian subjects remains limited. PATIENTS AND METHODS: The study included lung adenocarcinoma (AC) patients treated at the N.N. Petrov Institute of Oncology (Russia). RESULTS: DNA analysis of 192 consecutive AC revealed 38 (20%) TKI-sensitizing mutations. Presence of the exon 19 deletion (del19) or L858R was strongly correlated with nonsmoking status (smokers: 8/98 (8%); non-smokers: 30/94 (32%); p = 0.00004). The efficacy of first-line gefitinib therapy was evaluated in 25 patients with EGFR-mutated advanced AC. Twelve (48%) cases demonstrated tumor response (1 (4%) complete response, 11 (44%) partial responses; 10/17 (59%) patients with del19 mutation vs. 2/8 (25%) cases with L858R substitution, p = 0.11). The remaining 13 (52%) patients experienced disease stabilization. Median progression-free survival was 8.0 months. Grade 3 toxicity was the maximal adverse event, being observed only in 4 (16%) cases. CONCLUSION: Gefitinib may be considered as an upfront treatment option for EGFR-mutated NSCLC.

Down-staging of EGFR mutation-positive advanced lung carcinoma with gefitinib followed by surgical intervention: follow-up of two cases.

BACKGROUND: Non-small cell lung carcinomas (NSCLC) carrying a mutation in the epidermal growth factor receptor (EGFR) gene show unprecedented sensitivity to gefitinib or erlotinib. CASE REPORTS: We present the follow-up data of 2 EGFR mutation-positive stage IV NSCLC patients who received upfront 250 mg gefitinib daily, then underwent potentially curative surgery, and resumed gefitinib therapy in the adjuvant setting. Patient 1 was diagnosed with a rightsided adenocarcinoma of the upper lobe with multiple metastases to the middle lobe. After 2 months of gefitinib treatment, only a small primary lesion was seen, and a bilobectomy with lymph node dissection was performed. The patient remained disease-free during a scheduled 12-month adjuvant therapy but relapsed 9 weeks after cessation of this treatment. Patient 2 presented with adenocarcinoma of the lower lobe of the right lung and a single metastasis to the left adrenal. After 3 months of receiving gefitinib, the metastasis was no longer detectable, and the primary tumor was significantly reduced. Surgery included lobectomy and adrenalectomy. This patient relapsed with metastasis in the remaining adrenal 4 months after the start of adjuvant therapy. CONCLUSION: Gefitinib can be used preoperatively for the management of advanced EGFR mutation-positive NSCLC. It remains to be established whether surgical intervention indeed renders survival advantage for this category of patients.

High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients.

BACKGROUND: A significant portion of ovarian cancer (OC) cases is caused by germ-line mutations in BRCA1 or BRCA2 genes. BRCA testing is cheap in populations with founder effect and therefore recommended for all patients with OC diagnosis. Recurrent mutations constitute the vast majority of BRCA defects in Russia, however their impact in OC morbidity has not been yet systematically studied. Furthermore, Russian population is characterized by a relatively high frequency of CHEK2 and NBS1 (NBN) heterozygotes, but it remains unclear whether these two genes contribute to the OC risk. METHODS: The study included 354 OC patients from 2 distinct, geographically remote regions (290 from North-Western Russia (St.-Petersburg) and 64 from the south of the country (Krasnodar)). DNA samples were tested by allele-specific PCR for the presence of 8 founder mutations (BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT, CHEK2 1100delC, CHEK2 IVS2+1G>A, NBS1 657del5). In addition, literature data on the occurrence of BRCA1, BRCA2, CHEK2 and NBS1 mutations in non-selected ovarian cancer patients were reviewed. RESULTS: BRCA1 5382insC allele was detected in 28/290 (9.7%) OC cases from the North-West and 11/64 (17.2%) OC patients from the South of Russia. In addition, 4 BRCA1 185delAG, 2 BRCA1 4153delA, 1 BRCA2 6174delT, 2 CHEK2 1100delC and 1 NBS1 657del5 mutation were detected. 1 patient from Krasnodar was heterozygous for both BRCA1 5382insC and NBS1 657del5 variants. CONCLUSION: Founder BRCA1 mutations, especially BRCA1 5382insC variant, are responsible for substantial share of OC morbidity in Russia, therefore DNA testing has to be considered for every OC patient of Russian origin. Taken together with literature data, this study does not support the contribution of CHEK2 in OC risk, while the role of NBS1 heterozygosity may require further clarification.

Measurement of DPD and TS transcripts aimed to predict clinical benefit from fluoropyrimidines: confirmation of the trend in Russian colorectal cancer series and caution regarding the gene referees.

BACKGROUND: Measurement of intratumoral expression of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) may have some value in predicting the response to fluoropyrimidine-containing therapy. PATIENTS AND METHODS: We attempted to validate this association in a series of Russian metastatic colorectal cancer cases. While replicating already published protocols, we unexpectedly found that the use of commonly utilized gene referees, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin, may lead to artifacts due to pseudogene-driven amplification from the genomic DNA template. We have developed a real-time PCR protocol which amplifies short PCR fragments, thus allowing efficient analysis of archival formalin-fixed paraffin-embedded tumor samples, and relies on succinate dehydrogenase (SDHA) as a gene referee, therefore avoiding amplification from genomic DNA. RESULTS: Low content of DPD transcripts was observed in 13/20 (65%) patients with disease control (tumor response or disease stabilization) as compared to only 3/9 (33%) subjects with progressive disease (p = 0.11). Despite the low number of patients, this association reached the level of statistical significance when similar analysis was done for TS expression (11/20 (55%) vs. 1/9 (11%); p = 0.03). CONCLUSIONS: Our data confirm that low DPD and TS expressors have higher chances of success of fluoropyrimidine-containing regimens.

Nonrandom distribution of oncogene amplifications in bilateral breast carcinomas: Possible role of host factors and survival bias.

Amplification of HER2, C-MYC and CCND1 oncogenes is a hallmark of breast cancer (BC); however, its involvement in the bilateral form of this disease has not been investigated yet. In this study, 50 bilateral BC (biBC) pairs (100 tumors) and 72 control unilateral BC were examined using real-time PCR analysis of microdissected archival tissues. In biBC, the frequency of >3-fold oncogene amplification was 6/100 (6%) for HER2, 6/100 (6%) for C-MYC and 7/100 (7%) for CCND1. Altogether, 18/100 (18%) biBC tumors had increased gene dosage of at least one oncogene. Tumors forming synchronous biBC pairs had amplification in 11/46 cases (24%). In 3 of 8 patients with amplification-positive carcinomas, the amplification was detected in both neoplasms: 2 biBC had concordant activation of the same oncogene (HER2 and CCND1, respectively), and in the remaining case distinct oncogenes were affected (HER2 and C-MYC). In contrast, amplifications in metachronous biBC were strongly discordant: none of 27 first carcinomas carried this abnormality, while the frequency of amplification in second tumors (7/27; 26%) was similar to the one observed in unilateral BC (20/72; 28%). The trend toward concordance of oncogene amplification status in synchronous but not in metachronous biBC pairs can be explained by the nearly identical natural history of the disease in simultaneously arising tumors. The skewed pattern of amplifications in metachronous biBC might be attributed to their association with adverse BC prognosis; it appears that only patients with amplification-negative first BC have sufficient chances to survive until the development of the contralateral carcinoma.

Benign schwannoma with perineurioma-like areas: A clinicopathologic study of 11 cases.

Eleven schwannomas are described. All tumors were well demarcated and surrounded by a true capsule or pseudocapsule and manifested Antoni A and Antoni B areas, Verocay bodies, and hyalinized vessels. In addition to typical schwannoma, there were clear cell areas composed of spindled cells arranged either in parallel sheets or in loops within the myxoid matrix, morphologically identical to retiform (reticular) perineurioma. The Schwann cells in the conventional schwannomatous areas displayed typical ultrastructural features. Those comprising the perineurioma-like areas revealed a primitive morphology. They were slender or polygonal and were devoid of an external lamina, pinocytic vesicles, or junctions. These findings suggest that the perineurioma-like areas consist of primitive or modified Schwann cells, or, alternatively, these perineurioma-like areas represent true, but incomplete perineurial differentiation within otherwise ordinary benign schwannomas. These neoplasms represent a morphologic variant of schwannoma having distinctive perineurial-like areas, a pattern which may elicit diagnostic difficulties.

CHEK2 1100delC mutation is frequent among Russian breast cancer patients.

This study was aimed to assess the role of CHEK2 1100delC mutation in breast cancer (BC) predisposition in Russia. The 1100delC allele was detected in 14/660 (2.1%) unilateral BC cases and in 8/155 (5.2%) patients with the bilateral form of the disease, but only in 1/448 (0.2%) middle-aged control females and in none of 373 elderly tumor-free women. The obtained data point at potentially high clinical relevance of CHEK2 1100delC testing in females of Russian origin and warrant similar case-control studies in ethnically and geographically related regions, especially in Ukraine, Belarus and Baltic countries.

High frequency of BRCA1 5382insC mutation in Russian breast cancer patients.

BRCA1 5382insC variant was repeatedly detected in Jewish breast cancer (BC) families residing in USA and Israel as well as in non-Jewish familial BC patients from Poland, Latvia, Hungary, Russia and some other European countries. However, the distribution of BRCA1 5382insC mutation in unselected BC cases vs. controls has been systematically investigated mainly in Ashkenazi Jews. Here we applied a case-control study design in order to evaluate the impact of BRCA1 5382insC allele on BC incidence in St Petersburg, Russia. High frequency of the BRCA1 5382insC allele was detected in a group of bilateral breast cancer patients (10.4%; 15/144). Randomly selected unilateral BC cases demonstrated noticeable occurrence of BRCA1 5382insC mutation as well (3.7%; 32/857), with evident excess of the carriers in the early-onset (40 years) category (6.1%; 6/99) and in patients reporting breast and/or ovarian tumours in first-degree relatives (11.3%; 11/97). Strikingly, none of 478 middle-aged controls and 344 elderly tumour-free women carried the 5382insC variant. The presented data confirm a noticeable contribution of BRCA1 5382insC mutation in BC development in Russia, that may justify an extended BRCA1 5382insC testing within this population.

NBS1 657del5 mutation may contribute only to a limited fraction of breast cancer cases in Russia.

The gene for Nijmegen chromosomal breakage syndrome (NBS1) plays a role in a variety of processes protecting chromosomal stability. Recently, it was suggested in a Polish case-control study that the founder hypomorphic mutation in NBS1, 657del5, which occurs in approximately 0.5% of Slavic subjects, may be associated with an increased risk of breast cancer (BC). We attempted to validate these findings in Russian subjects, who are also of Slavic descent. Heterozygous carriers for the 657del5 mutation were detected in 2 of 173 (1.16%) bilateral breast cancer cases, 5 of 700 (0.71%) unilateral breast cancer patients, 2 of 348 (0.57%) healthy middle-aged females and in 0 of 344 elderly tumor-free women. The difference between the "extreme" cohorts, i.e., biBC patients vs. elderly controls, approached the formal limit of statistic significance (p=0.046). LOH at NBS1 was detected in only 3 of 5 available breast tumors from NBS1 657del5-carriers. In 2 of these tumors, the loss involved the mutant NBS1-allele. Overall, our data suggest that the NBS1 657del5 allele may contribute only to a limited fraction of breast cancer cases in Russia.