Tokiko Nakai

A retrospective study of patients with follicular lymphoma (FL): identification of in situ FL or FL-like B cells of uncertain significance in lymph nodes resected at the time of previous surgery for carcinomas

Background and aims In situ follicular lymphoma (iFL)/intrafollicular neoplasia and follicular lymphoma (FL)-like B cells of uncertain significance represent proliferation of Bcl-2/t(14;18)-positive B cells solely in the germinal centres. The condition is interpreted as an early event in the multi-step lymphomagenesis of FL. The aim of this study is to examine the issue more specifically. Methods We reviewed medical history of FL patients in whom thoracoabdominal surgery with lymphadenectomy had been performed for management of carcinomas. These previously resected lymph nodes as well as the current FL nodes were analysed by immunohistochemistry, fluorescent in situ hybridisation, and PCR amplification with direct sequencing. Results We studied four such FL patients from a total of 150 patients with FL; all had iFL in the previously resected lymph nodes. Clonal relation was verified and suggested in one case each. The time from lymphadenectomy to the diagnosis of FL was 23–120 months. There appeared to be a reverse correlation between the rate of Bcl-2-positive follicle proliferation and the time from surgery to diagnosis of FL. Conclusions Although the rate for development of FL in individuals having iFL has been reported to be low from prospective studies, the present data indicate that follow-up studies for a longer period is necessary; the rate of Bcl-2-positive follicle proliferation could be a factor to predict development of FL in prospective studies. Such a retrospective study may contribute to elucidate mechanism(s) involved in lymphomagenesis of FL.

Comparison of genomic abnormality in malignant mesothelioma by the site of origin

Aims Malignant mesothelioma (MM) results from the accumulation of a number of acquired genetic events at the onset. In MM, the most frequent changes are losses in 9p21, 1p36, 22q12 and 14q32, and gains in 5p, 7p and 8q24 by comparative genomic hybridisation analysis. We have examined various genomic losses and gains in MM and benign mesothelial proliferation by fluorescence in situ hybridisation (FISH) analysis. 9p21 deletion was reported to be less frequent in peritoneal than in pleural MMs. This study analysed various genomic losses and gains in MM by the site of origin using FISH analysis. Materials and methods We performed FISH analysis using paraffin-embedded tissues from 54 cases (40 pleural and 14 peritoneal) of MMs and compared the frequency of genomic abnormality by the site of origin. Results 9p21 deletion was shown in 34 of 40 cases (85%) of pleural MMs, and was less frequent in five of 14 cases (36%) of peritoneal MMs (p<0.001) by FISH analysis. By contrast, 5p15 and 7p12 amplification was more significantly frequent in peritoneal than in pleural MMs. No difference between the two sites of MM in other genes was found. Conclusions 9p21 homozygous deletion assessed by FISH has been reported to be useful for differentiating MM from reactive mesothelial proliferation, but it should be noted that 9p21 deletion was less frequent in peritoneal MM. Our study suggests that the pathway of the genetic abnormality might vary between pleural and peritoneal MM.

Metastasizing pleomorphic adenoma in cavernous sinus: letter to the editor

Dear Editor, Pleomorphic adenoma (PA) is the most common benign tumor of the lacrimal and salivary glands.While recurrence after resection of PA is a well-known phenomenon, PA without malignant transformation has also been reported to metastasize [1, 5]. We present herein a case of metastasizing PA (MPA) in the cavernous sinus (CS) 24 years after resection of PA as an oral tumor originating from the parotid gland. To the best of our knowledge, this represents the first report of MPA in the CS. A 45-year-old man presented with a 2-month history of progressive diplopia due to incomplete right oculomotor palsy. In addition to hypertension, he had a history of surgical treatment for a large oral PA 24 years earlier. That PA had been located in the right para-pharyngeal space, measured 8 × 5× 4 cm, originated from the parotid gland, and was removed en bloc. With the present visit, CT and MRI of the head showed the 3.8-cm tumor located in the right CS, with no evidence of continuity between the middle fossa of the skull base and the infra-temporal fossa space (Fig. 1a and b). The patient underwent surgical intervention for tumor removal via an orbitozygomatic approach. The tumor was whitish in color, fragile, easily aspirated, and not particularly hemorrhagic. As much of the tumor mass as possible was gently removed, taking care to avoid injury to the ICA. Microscopic examination of the permanent preparation showed two elements: epithelial cells, and a mesenchymal component. The epithelial cells were dispersed throughout the stromal background in small strands or sheets. Smaller polygonal myoepithelial cells were also observed, along with apparent cartilaginous differentiation. Despite numerous foci of squamous metaplasia, no evidence of malignant transformation was observed (Fig. 1c). The specimen retrieved from the previous oral tumor demonstrated the same histopathological pattern seen for the present tumor in the CS (Fig. 1d). As of 1 year after surgery, the patient remains free of recurrence, but follow-up MRI will be continued to check for recurrences in the future. At this time, the tumor in the CS did not extend extracranially. That is, there was no evidence of tumor invasion from the extracranial parapharyngeal space, where the initial tumor had been supposed to be located, into the CS inside the cranium where the present tumor had been located. This tumor was thus considered to represent metastasis rather than a recurrence. The most common site of MPA is bone (36.6 %), followed by the lungs (33.8 %) [4]. MPA to the CS has not previously been reported, even though it rarelymetastasizes intracranially [7, 8]. MPA has been reported to display aggressive behavior, contrasting with its benign histological features [4]. According to the histological classification of the World Health Organization, MPA is included among three different types of malignant change from PA, along with carcinoma ex pleomorphic adenoma and carcinosarcoma. The CS is the site of origin for various kinds of primary tumor, including meningioma, schwannoma, and cavernous angioma. Pituitary adenoma and other types of malignant tumor can invade the CS. However, metastasis forming a localized CS tumor is very rare, although head and neck cancers and other exceptional types of cancer have been reported [2, 3, 6]. * Yasushi Motoyama myasushi@naramed-u.ac.jp

Angiosarcoma arising in schwannoma of cerebellopontine angle and later associating with meningioma in a patient with neurofibromatosis type 2.

Here, we describe an extremely rare case of angiosarcoma arising in schwannoma of the cerebellopontine angle and later associating with meningioma in a patient with neurofibromatosis type 2. A 33-year-old disabled Japanese man with right drop foot after surgery for an unspecified tumor demonstrated multiple tumors, suspected to be schwannoma, in the bilateral cerebellopontine angles, the cervical and lumbar spinal cord, and on the right nuchal skin. Also present were several tumors in the medulla and thoracic spinal cord suspected to be ependymoma or astrocytoma. The patient was diagnosed with neurofibromatosis type 2 according to the diagnostic criteria by the U.S. National Institutes of Health. The bilateral tumors in the cerebellopontine angle were resected to reduce symptoms and brain stem compression. Histopathological analysis revealed angiosarcoma arising in schwannoma of the bilateral tumors, and angiosarcoma was proportionally larger in the right tumor than in the left. At age 36, the patient underwent a second resection of the regrown tumor in the left cerebellopontine angle, and histopathology demonstrated mixed angiosarcoma and meningioma. That angiosarcoma arises in schwannoma is a pathogenesis within the realm of conjecture, especially that the phenomenon of mixed meningioma and angiosarcoma has not been reported to date.

MicroRNAs in Smoking-Related Carcinogenesis: Biomarkers, Functions, and Therapy

Long-term heavy cigarette smoking is a well-known high-risk factor for carcinogenesis in various organs such as the head and neck, lungs, and urinary bladder. Furthermore, cigarette smoking can systemically accelerate aging, and as the result, promoting carcinogenesis via changing the host microenvironment. Various inflammatory factors, hormones, and chemical mediators induced by smoking mediate carcinoma-related molecules and induce carcinogenesis. MicroRNAs (miRNAs) are a family of short noncoding RNA molecules that bind to mRNAs and inhibit their expression. Cigarette smoke induces the expression of various miRNAs, many of which are known to function in the post-transcriptional silencing of anticancer molecules, thereby leading to smoking-induced carcinogenesis. Analysis of expression profiles of smoking-induced miRNAs can help identify biomarkers for the diagnosis and prognosis of smoking-related cancers and prediction of therapeutic responses, as well as revealing promising therapeutic targets. Here, we introduce the most recent and useful findings of miRNA analyses focused on lung cancer and urinary bladder cancer, which are strongly associated with cigarette smoking, and discuss the utility of miRNAs as clinical biomarkers.

A Hypopharyngeal Lipoma Resulting in Obstructive Sleep Apnea

A 64-year-old man presented with snoring and daytime sleepiness. Polysomnography revealed that the mean apneahypopnea index (AHI) was 88.2 events per hour, and the patient was diagnosed with severe obstructive sleep apnea syndrome (OSAS). A screening with magnetic resonance (MR) imaging showed a large, wedge-shaped, space-occupying lesion in the hypopharynx. The intensity of the signal within the lesion in MR images was homogeneous and high (Picture 1A: T1-weighted image, Picture 1B: T2-weighted image). The tumor caused severe stenosis of the hypopharynx which was a contributing factor to OSAS. The tumor was resected, and the AHI was remarkably improved (AHI: 12.3 events/hour). The 30×47×77 mm tumor had a smooth surface (Picture 2A) and was histologically diagnosed as a lipoma because it was composed of mature adipocytes closely resembling normal adipose tissue (Picture 2B). Each patient with OSAS should therefore be examined carefully for the potential presence of an upper aero-digestive tract lesion (1, 2). The authors state that they have no Conflict of Interest (COI).

Histological Grade: Analysis of Prognosis of Non-small Cell Lung Cancer After Complete Resection

Background/Aim: Although the 2015 World Health Organization Classification reported that histological grading may be helpful in lung cancer management, a widely accepted histological grading system with clearly defined criteria and demonstrable clinical significance has not been developed. We investigated the prognoses of patients with resected non-small cell lung cancer (NSCLC) to identify prognostic factors, especially histological grade. Materials and Methods: The medical records of 531 patients between 2010 and 2015 were retrospectively reviewed. Overall survival (OS) curve was plotted using the Kaplan–Meier method. Cox regression analyses were used to evaluate the hazard ratio (HR) with endpoint of OS. Results: The 5-year OS rate in groups with histological grade 1, grade 2, and grade 3+4 groups was 95.8%, 85.7%, and 72.1%, respectively (p<0.001). Multivariate analysis identified histological grade and vascular invasion as independent predictors of OS [histological grade: HR=1.533, p=0.002]. Conclusion: Histological grade was an independent prognostic factor of patients resected for all stages of NSCLC.

Clinical and pathological characteristics of surgically resected intrapulmonary lymph nodes: Can they be differentiated from other malignant nodules?

BACKGROUND Intrapulmonary lymph nodes (IPLNs) are often recognized as sub-centimeter solid pulmonary nodules (SCPNs). The present study investigated their clinical and pathological characteristics to allow clinicians to distinguish them from malignant nodules. METHODS Among 194 SCPNs surgically resected between 2006 and 2016, 26 IPLNs were investigated histopathologically. In addition, 145 resected malignant SCPNs were compared radiographically with the 26 IPLNs. RESULTS Radiographically, most IPLNs were in a middle or lower lobe, and all lesions were within 20 mm of the visceral pleura. Enlargement was seen in one lesion. Three lesions demonstrated linear density contiguous to pleura (LD), and 13 lesions were adjacent to the peripheral pulmonary vein (APV). Microscopically, all IPLNs showed adjacency to pulmonary veins, 23 showed interlobular septa extending from the IPLN, and 18 were surrounded by a dilatated lymphoid channel. Radiographical findings of LD and APV were also seen in malignant SCPNs (LD, 12/145; APV, 25/145). Comparative analysis revealed that enlargement and APV were significant predictors differentiating IPLNs from malignant SCPNs. The sensitivity/specificity of enlargement and APV were 92%/92% and 17%/50%, respectively. CONCLUSIONS IPLNs show typical high-resolution computed tomography findings that reflect their histopathological characteristics. Such findings help identify IPLNs prior to surgery. Specifically, enlargement and APV may differentiate IPLNs from malignant SCPNs. However, atypical cases are also possible, and radiological findings are not specific for differentiating IPLNs from malignant lesions. Thus, clinicians should consider surgical exploration when diagnosing SCPNs.

K-ras mutation analysis of residual liquid-based cytology specimens from endoscopic ultrasound-guided fine needle aspiration improves cell block diagnosis of pancreatic ductal adenocarcinoma

Background Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) technology is widely used for the diagnosis of pancreatic masses. However, in some cases, inadequate tissue volume or difficulty of morphological diagnosis are constraining factors for adequate cytopathological evaluation. K-ras mutation is the most frequently acquired genetic abnormality, occurring in approximately 90% of all patients with pancreatic ductal adenocarcinoma (PDAC). In the present study, the clinical utility of residual liquid-based cytology (LBC) specimens obtained using EUS-FNA for K-ras mutation analysis was evaluated. Methods In this study, 81 patients with pancreatic lesions were examined. The cell block (CB) specimens separated from EUS-FNA samples were morphologically evaluated by hematoxylin–eosin (HE) staining. Final diagnoses were confirmed by CB specimens, surgical resection specimens, diagnostic imaging, and clinical follow-up. Genomic DNA of residual LBC specimens stored at 4°C for several months were extracted and assessed for K-ras mutations using a fluorescence resonance energy transfer-based preferential homoduplex formation assay. Results K-ras mutation analysis using residual LBC samples was successful in all cases. The sensitivity, specificity, and accuracy of CB examination alone were 77.4%, 100%, and 81.3%, respectively, and those of the combination of CB examination and K-ras mutation analysis were 90.3%, 92.3%, and 90.7%, respectively. Furthermore, K-ras mutations were detected in 8 (57.1%) of 14 PDAC samples for which the CB results were inconclusive. Conclusion These findings suggest that K-ras mutation analysis using residual LBC specimens improves the diagnostic accuracy of EUS-FNA.

Cytological characteristics of meningeal solitary fibrous tumor metastatic to the lung: A case report with immunocytochemical analysis

Solitary fibrous tumor (SFT) is a relatively uncommon mesenchymal tumor, and its occurrence in the meninges is rare. We herein report what is, to the best of our knowledge, the first cytological case of meningeal SFT metastatic to the lung with immunocytochemical analysis for signal transducer and activator of transcription 6 (STAT6), and compare the cytological characteristics to those of pleuropulmonary SFT. A 58-year-old Japanese male patient was found to have multiple nodules in the bilateral lungs after surgery for meningeal SFT. Partial resection of the nodules was performed, and touch smears were obtained. The Papanicolaou smear revealed cohesive hypercellular clusters of polygonal to elongated neoplastic cells with scant cytoplasm and oval to short spindle-shaped nuclei with nucleoli containing coarse chromatin. Mild-to-moderate nuclear pleomorphism was observed. No collagenous stroma was noted. Immunocytochemical analysis revealed that the neoplastic cells diffusely expressed STAT6. Histopathological and immunohistochemical studies confirmed the diagnosis of meningeal SFT metastatic to the lung. Moreover, reverse transcription-polymerase chain reaction analysis revealed that the lung tumor harbored NAB2ex6-STAT6ex16 fusion. Recent studies demonstrated that there is a clinicopathological difference among NAB2-STAT6 fusion variants in SFT. As reflected in fusion variants, meningeal SFT occasionally lacks collagenous stroma, as in the present case, although the most characteristic cytological feature of SFT is the presence of spindle-shaped neoplastic cells embedded in dense collagenous stroma. Thus, immunocytochemical analysis for STAT6 is very useful for diagnosing SFT.