Naoki Oishi

High prevalence of the MYD88 mutation in testicular lymphoma: Immunohistochemical and genetic analyses

The activating mutation of MYD88 has been identified in diffuse large B‐cell lymphoma (DLBCL). We investigated the mutational status and both the gene amplification and protein expression of MYD88 in 23 cases of testicular DLBCL. To detect the MYD88 mutations, we employed the allele‐specific PCR and Sanger sequencing. MYD88 gene amplification and protein expression were analyzed by quantitative PCR and by immunohistochemistry, respectively. There were 17 cases of primary testicular DLBCL: 94% (16/17) exhibited a non‐Germinal center B‐cell (non‐GCB) subtype, 82% (14/17) showed the MYD88 L265P, and 65% (11/17) had intense expression of MYD88. When compared with normal lymph nodes, the MYD88 is significantly amplified in primary testicular DLBCL. However, the amplification status showed no correlation with its mutational status or protein expression. Moreover, neither the MYD88 mutational status nor the expression pattern affected overall survival. Six cases were secondary testicular DLBCL with an 83% (5/6) and an 80% (4/5) incidence of the non‐GCB subtype and of the MYD88 L265P, respectively. In conclusion, we demonstrated a high prevalence of the non‐GCB subtype and the common MYD88 L265P in both primary and secondary testicular DLBCL. Our data suggest that the MYD88 mutation is a fairly consistent genetic feature in testicular DLBCL.

High prevalence of neuroendocrine carcinoma in breast lesions detected by the clinical symptom of bloody nipple discharge.

AIM Bloody nipple discharge (BND) is an important clinical symptom in breast disorders, especially cancers. However, the association between this symptom and breast neuroendocrine carcinomas (NECs) has not been sufficiently investigated or well understood. METHODS We clinicopathologically studied 89 cases using biopsy and/or resection in 144 patients who came to the hospital for a thorough examination of symptomatic BND. RESULTS Of these 89 cases examined histologically, 24 (27%) were neuroendocrine carcinomas (NECs) in which >50% of cells immuno-expressed chromogranin A and/or synaptophysin. Moreover, NECs made up 44% (24/55) of the mammary cancers found because of the BND. The frequency of diagnosing malignancy preoperatively in 24 NECs was 4% by nipple discharge cytology, 40% by fine needle aspiration cytology, 62% by core needle biopsy and 67% by mammotome biopsy. There were neither postoperative recurrences nor metastases in the NEC cases during a mean follow-up of 83.7 months. The 24 NECs were subclassified into neuroendocrine ductal carcinoma in situ (NE-DCIS) (9 cases) and microinvasive (7 cases) and invasive (8 cases) NECs with extensive NE-DCIS components. Most NECs had early-stage and low-grade pathological parameters: pTis or pT1 (96%), pN0 (96%), low nuclear grade (83%), absence of necrosis (88%), immuno-positivity of estrogen and progesterone receptors (100%) and absence of HER2 protein overexpression (100%). CONCLUSIONS NECs predominantly with NE-DCIS lesions, often under-diagnosed preoperatively, accounted for an important share of breast conditions associated with BND. It is, therefore, worth keeping this type of breast cancer in mind when performing medical examinations on patients with BND.

Neuroendocrine cells associated with neuroendocrine carcinoma of the breast: nature and significance

Background The developmental mechanisms of breast neuroendocrine carcinoma (B-NEC) have not been sufficiently analysed and are not well understood. Aims To investigate NE cells in the background tissues surrounding B-NECs. Methods Three cases (four breasts) having many NE cells in the background tissues of multifocal B-NECs were identified at the University of Yamanashi Hospital and St Lukes International Hospital, Japan. These patients were, respectively, 28-, 31- and 38-year-old women with no familial history of NE tumour. The totally-resected breasts were serially studied by immunohistochemistry for specific NE markers (chromogranin A/synaptophysin) and the morphologies and/or localisation of NE cells were investigated. Results Immunohistochemical examination showed extensively-distributed NE cells in the background mammary ducts/lobules of the NECs in all breasts. These NE cells were classifiable into three emerging patterns: isolated/scattered, clustered and circumferential. Their distributions were intermingled and were not clearly related to B-NEC foci. NE cells were morphologically polygonal, oval or columnar with sometimes eosinophilic and/or fine-granular cytoplasm and round-to-ovoid nuclei lacking atypia. Some cells were located between epithelial and myoepithelial cells. Apical snouts were occasionally observed in NE cells forming luminal structures. Conclusions Benign-appearing NE cells in the parenchyma of a breast with NEC could be regarded as hyperplastic from their emerging patterns and distribution; this NE cell hyperplasia may be associated with the histogenesis of B-NEC as a precancerous condition. These observations might raise questions about the treatment for B-NEC.

The changing characteristics and molecular profiles of papillary thyroid carcinoma over time: a systematic review

Background The genetic alterations of papillary thyroid carcinoma (PTC) have been reported to change over the past few decades. We performed this systematic review to further examine the trends and modifications of patient demographic, clinicopathological features and molecular profiles of PTC over time. Methods A literature search was performed within six electronic databases to identify relevant articles. The inclusion criteria were published studies investigating BRAF mutations, RET/PTC rearrangements or RAS mutations in PTCs or classical PTCs. Two teams of reviewers independently screened titles and abstracts of all articles. Full texts of potential articles were read and extracted data were listed and stratified into an excel file according to country, city, institution, and surgical time period. Student t test and Pearson Chi-square were used to analyze the trends of demographic and clinicopathological features of PTC patients and the prevalence of each genetic alteration in individual institutions. Results From 3139 articles, we included 16 articles for final analysis. Our results showed an increasing trend of BRAF and a decreasing trend of RET/PTC prevalence over time in PTCs and classical PTCs, accompanied by an older age of PTC patients, an increase in proportion of PTMC and less aggressive behaviours of tumours. Conclusions The demographic and clinicopathological characteristics and molecular profile of PTCs have been changing over the past few decades. These modifications suggest changes in etiologies and risk factors of thyroid cancer that influence the tumorigenesis of PTCs.

Spindle cell oncocytoma of adenohypophysis: Report of a case and immunohistochemical review of literature

We present a case of spindle cell oncocytoma (SCO) of the adenohypophysis in a 70-year-old Vietnamese male. The patient was admitted to Cho Ray Hospital after suffering from headache and visual disturbance for 6 months. Clinicians detected a 60×55×45 mm(3) mass located in the suprasellar-sellar region. Histopathologically, the resected tumor was composed of spindle cells with oncocytic appearance. Immunohistochemical examination revealed expression of anti-mitochondria antibody (AMA), vimentin, thyroid transcription factor 1 (TTF-1), epithelial membrane antigen (EMA) and galectin-3. These histologic and immunohistochemical findings are suggestive of SCO.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma: Case report and literature review

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare neoplasm characterized by morphological analogy to papillary thyroid carcinoma and abnormal expression of thyroid transcription factor-1 (TTF-1). Here we report a novel case of TL-LGNPPA with literature review. The patient was a 43-year-old woman complaining of nasal obstruction. Laryngoscopic study and computed tomography identified a pedunculated mass located on the posterior edge of the left nasal septum. Histologically, the tumor consisted of papillary growth of cuboidal or columnar epithelium. Tubular architecture and a spindle cell component were also observed focally. Some tumor cells exhibited intra-nuclear cytoplasmic inclusions. Immunohistochemically, the neoplastic cells were positive for pancytokeratin (AE1/AE3), CK7, CK19, TTF-1, vimentin and HBME1, but negative for thyroglobulin, Pax8 and CK5/6. Ki67-labeling index reached 5% in the most concentrated spot. Despite the morphological and immunohistochemical similarity to papillary thyroid carcinoma, no BRAF V600E mutation was detected by mutation-specific immunohistochemistry. The patient had neither local recurrence nor distant metastasis 19 months after removal of the tumor.

Associations among q-space MRI, diffusion-weighted MRI and histopathological parameters in meningiomas

AbstractObjectivesThe purposes of this MR-based study were to calculate q-space imaging (QSI)–derived mean displacement (MDP) in meningiomas, to evaluate the correlation of MDP values with apparent diffusion coefficient (ADC) and to investigate the relationships among these diffusion parameters, tumour cell count (TCC) and MIB-1 labelling index (LI).MethodsMRI, including QSI and conventional diffusion-weighted imaging (DWI), was performed in 44 meningioma patients (52 lesions). ADC and MDP maps were acquired from post-processing of the data. Quantitative analyses of these maps were performed by applying regions of interest. Pearson correlation coefficients were calculated for ADC and MDP in all lesions and for ADC and TCC, MDP and TCC, ADC and MIB-1 LI, and MDP and MIB-1 LI in 17 patients who underwent subsequent surgery.ResultsADC and MDP values were found to have a strong correlation: r = 0.78 (P = <0.0001). Both ADC and MDP values had a significant negative association with TCC: r = –0.53 (p = 0.02) and –0.48 (P = 0.04), respectively. MIB-1 LI was not, however, found to have a significant association with these diffusion parameters.ConclusionIn meningiomas, both ADC and MDP may be representative of cell density.Key Points• Diffusion-weighted MRI offers possibilities to assess the aggressiveness of meningiomas. • The q-space imaging-derived mean displacement correlates strongly with apparent diffusion coefficients. • Both diffusion parameters showed a strong negative association with tumour cell counts. • Derived mean displacement may help assess the aggressiveness of meningiomas preoperatively.

Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

BRAF V600E mutation, RET rearrangements, and RAS mutations are the common genetic alterations in differentiated thyroid carcinomas derived from follicular thyroid cells. However, the relationship between these alterations and iodine intake is still controversial. To clarify the influence of iodine intake on the occurrence of differentiated thyroid carcinomas, we performed molecular analyses for two differentiated carcinomas, papillary thyroid carcinomas (PTCs) and follicular thyroid carcinomas (FTCs), from an iodine‐rich country (Japan) and an iodine‐deficient country (Vietnam). We examined 120 PTCs (67 Japanese and 53 Vietnamese) and 74 FTCs (51 Japanese and 23 Vietnamese). We carried out allele‐specific polymerase chain reaction (AS‐PCR) for BRAF V600E, PCR and direct sequencing for RAS mutations (codon 12, 13, and 61 in NRAS, HRAS, and KRAS), and RT‐PCR for RET/PTC1 and RET/PTC3. BRAF V600E was present in 55/67 (82.1%) Japanese PTCs and 44/53 (83%) Vietnamese PTCs. RET/PTC1 was identified in only one PTC from each country, and no samples had RET/PTC3. NRAS mutation was found in 17/51 (33.3%) Japanese FTCs and 4/23 (17.4%) Vietnamese FTCs. NRAS mutation was cited in codon 61 (20 cases) and codon 12 (one case). None of FTCs had KRAS or HRAS mutations. There were no significant differences in the prevalence of BRAF V600E, RET/PTC, or RAS mutations between the two countries. Our study showed no differences in genetic alterations of thyroid cancers from iodine‐rich and iodine‐deficient countries, possibly suggesting that iodine intake might not affect the genetic alterations of differentiated thyroid cancer.

Immunohistochemical detection of NRASQ61R protein in follicular-patterned thyroid tumors

The NRAS(A182G) mutation, which results in the NRAS(Q61R) protein, is a major driver mutation in follicular-patterned thyroid neoplasms. Although new immunohistochemistry (IHC) for NRAS(Q61R) is now available, its sensitivity, specificity, and diagnostic utility for thyroid tumors are not yet established. We performed IHC for NRAS(Q61R) and direct sequencing for NRAS codon 61 in 4 thyroid cancer-derived cell lines and 98 follicular-patterned thyroid tumors that included 22 follicular thyroid adenomas (FTAs), 35 follicular thyroid carcinomas (FTCs), and 41 cases of nodular hyperplasia (NH). In the tumors with NRAS(Q61R), the expression of BRAF(V600E) was further evaluated immunohistochemically. Two cell lines with NRAS(A182G) showed selective immunoreactivity for NRAS(Q61R). In tumor tissues, NRAS(Q61R) IHC was positive in 18% (4/22), 29% (10/35), and 2% (1/41) of FTAs, FTCs, and NH samples, respectively. The frequencies of the NRAS(Q61R) in FTAs and FTCs were significantly higher than that in NH (P=.046 and P=.001, respectively). All tumors with NRAS(Q61R) expression exhibited uniform cytoplasmic positivity with or without accumulation in their cell membranes. Of the 15 tumors with NRAS(Q61R) expression, 13 cases showed NRAS(A182G) in direct sequencing, whereas all of the tumors without NRAS(Q61R) expression were negative for the mutation. There were no tumors with overlapping expression of NRAS(Q61R) and BRAF(V600E). In reference to the direct sequencing, sensitivity and specificity of the NRAS(Q61R) IHC were 100% and 98%, respectively. In conclusion, NRAS(Q61R) IHC is a highly sensitive and specific tool that is useful for differentiating follicular-patterned thyroid tumors.

Novel potential of tunicamycin as an activator of the aryl hydrocarbon receptor - dioxin responsive element signaling pathway

Tunicamycin is a well‐known inhibitor of protein glycosylation and used as an inducer of endoplasmic reticulum (ER) stress. We found that tunicamycin induced expression of cytochrome P450 1A1 in a dose‐dependent manner. Like dioxin, the transcriptional induction was associated with dose‐dependent activation of the dioxin responsive element (DRE). This effect was independent of inhibition of protein glycosylation or induction of ER stress. Pharmacological and genetic inhibition of the aryl hydrocarbon receptor (AhR) significantly attenuated activation of DRE by tunicamycin. These results elucidated the novel potential of tunicamycin as an activator of the AhR – DRE signaling pathway.