Histological characteristics of lung adenocarcinoma with uncommon actionable alterations: special emphasis on MET exon 14 skipping alterations.

AIMS: In the evolving era of precision medicine, increasing emphasis is placed on detecting molecular alterations driving the development of specific cancers and targeting them with matched therapies that can yield the best outcomes for patients. Lung adenocarcinomas with uncommon actionable alterations, including MET exon 14 skipping (METex14), ERBB2 and BRAF mutations, are rare and poorly characterised cancers. METHODS AND RESULTS: To more clearly understand the histopathological features of lung adenocarcinoma with uncommon actionable alterations, we compared the histological features of 678 cases with mitogenic driver alterations from 996 surgically resected lung adenocarcinomas. Genomic data from our cohort revealed METex14, ERBB2 and BRAF mutations in 13, 16 and 15 cases, respectively. Patients who had lung adenocarcinoma with METex14 were often elderly females. Histological features such as clear cell features (23%), hyaline globules (31%) and nuclear pleomorphism (39%) were the most frequently identified in METex14-positive cases; among those, three cases (23%) had tumour cells with bizarre giant or multilobulated nuclei. Additionally, the micropapillary pattern was the most frequently identified in ERBB2-mutated lung adenocarcinoma (31%). Lung adenocarcinoma with BRAF mutations tended to be less invasive, and the BRAF V600E mutation was identified in only one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2 and BRAF-positive tumours, except for invasive mucinous adenocarcinoma, were positive for thyroid transcription factor 1 (TTF-1). CONCLUSIONS: Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumour cells with marked nuclear pleomorphism, hyaline globules and expression of TTF-1 in elderly women who never or lightly smoked.

A large series of hyalinizing trabecular tumors: Cytomorphology and ancillary techniques on fine needle aspiration.

BACKGROUND: Hyalinizing trabecular tumors (HTTs) are rare, essentially benign, follicular cell-derived thyroid neoplasms characterized by a trabecular growth pattern and nuclear pseudoinclusions. Their cytological findings are misleading, because these tumors are often misinterpreted on fine needle aspirate cytology as malignant lesions, such as papillary thyroid cancer and/or medullary thyroid cancer, leading to unnecessary total thyroidectomy. The aim of this study was to analyze the cytomorphological features and application of ancillary techniques in a series of HTTs. METHODS: Of 26 histological cases of HTT collected from September 2001 to December 2018, 18 cases had concomitant cytopathology. Cytological cases were processed with liquid-based cytology (LBC). Immunocytochemistry for HBME-1 and galectine-3 as well as molecular testing for BRAFV600E mutation were performed on both LBC and histological specimens. RESULTS: The 18 lesions with fine needle aspirate cytology ranged in size from 5 to 45 mm. Cytological diagnoses included: 1 benign lesion favoring goiter (5.5%), 4 atypia of undetermined significance (22.2%), 6 follicular neoplasms (33.3%), 5 suspicious for malignancy favoring papillary thyroid cancer (28%), and 2 malignant (11%). Hence, 89% HTT had a negative concordant immunopanel, and they were 100% wild-type BRAFV600E . CONCLUSION: The majority of our HTTs (83.3%) were diagnosed in the indeterminate Bethesda categories, suggesting that their cytomorphological features pose issues for reaching a conclusive cytological diagnosis. The ancillary test results in our series support the fact that HTT is a benign neoplasm.

Clinicopathological analysis of 232 radicular cysts of the jawbone in a population of southern Taiwanese patients.

This retrospective study aimed to evaluate the clinicopathological features of 232 cases of radicular cyst (January 2001-December 2016) submitted for histopathological examination to Department of Oral Pathology by endodontists in our institution. Demographic data including age, gender, affected site, involved tooth, and histopathological features, were reviewed. The study population comprised 133 females (57.3%) and 99 males (42.7%), with a mean age of 40.5 years and an age range of 13-78 years. Two-hundred and one cysts occurred in the maxilla (86.7%) and 31 in the mandible (13.3%). Most cases involved the anterior teeth of the maxilla (67.2%). The most frequently-involved tooth was the maxillary lateral incisor (50.5%). In most cases (228 cases; 98.3%), the cyst was lined with nonkeratinized stratified squamous epithelium, with two cases containing epithelial lining of the mucoepidermoid epithelium (0.9%) and respiratory epithelium (0.9%), respectively. One case (0.4%) revealed epithelial dysplasia of the epithelial lining. Hyaline body was seen in two cases (0.9%), and Rushton body was noted in seven cases (3.0%). Odontogenic epithelial rest was noted in one case (0.4%). Cholesterol clefts (54 cases; 23.3%), foamy histiocytes (72 cases; 31.0%), hemosiderins (57 cases; 24.6%), dystrophic calcifications (94 cases; 40.5%), foreign bodies (44 cases; 19.0%), and bacterial colonies (22 cases; 9.5%) were also observed. Fifty-three cases (22.8%) showed a mixed acute and chronic inflammatory infiltrate, whereas chronic inflammatory infiltrate only was noted in 179 cases (77.2%). In summary, the current findings provide a valuable source for clinicopathological reference concerning radicular cysts of the jawbone.

Hyaline globules and papillary fragments in cytologic smears from two intra-abdominal tumors (ovarian and hepatic) in female patients: A diagnostic pitfall with histologic correlation.

Hyaline globules and papillary fragments in cytologic samples from two intra-abdominal tumors in young females are presented including the cytological features and the correlation with the histopathologic and immunohistochemical findings. In the first case a cytologic study from an ovarian mass showed papillary structures and isolated tumor cells with epithelioid morphology, irregular reniform-like nuclear contour, pale or vacuolated cytoplasm, abundant hyaline globules and occasional glomeruloid structures resembling Schiller-Duval bodies. Yolk sac tumor (YST) was the diagnosis on the histological slides. Tumor cells showed positivity for cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), alpha-fetoprotein (AFP) and Sal-like protein 4 (SALL4). In case number two the cytologic study from a liver metastasis displayed papillary and rosette-like clusters composed of uniform and bland cells showing occasional long cytoplasmic tails, hyaline globules and nuclear grooves. A diagnosis of hepatic metastasis from solid pseudopapillary neoplasm of the pancreas (SPNP) was rendered from the histology. Tumor cells revealed immunoreactivity for cytokeratin (AE1/AE3), Vimentin, Galectin-1 (GAL-1), Neuron specific-enolase, CD10, progesterone and ß-catenin (nuclear stain). Regarding differential diagnosis, in the patient with the ovarian mass an ovarian clear cell carcinoma was considered, as well as other germ cell tumors or metastatic carcinoma, while in the patient with a liver metastasis a neuroendocrine carcinoma was taken into account. YST and SPNP share some cytological findings, including hyaline globules, papillary structures, clear cells and intercellular eosinophilic basement membrane deposits. Thus, a detailed study and careful interpretation of the cytological, histological and immunohistochemical findings may be worthwhile to avoid a potential misdiagnosis, particularly in the cytologic specimens of the ovarian and/or intra-abdominal mass, when involving young females. Diagn. Cytopathol. 2016;44:935-943. © 2016 Wiley Periodicals, Inc.

Fine-needle aspiration cytology of type A thymoma with adenoid cystic pattern: a case report with emphasis on peculiar hyaline globules in cytologic smear.

Here we report a case of type A thymoma with adenoid cystic pattern, which extended to the lower anterior neck and clinically mimicked a nontoxic thyroid goiter. The cytologic smears of fine-needle aspiration showed cohesive fragments of short spindle cells with finely granular chromatin and inconspicuous nucleoli. Scant interspersed lymphocytes were present. On air-dried Liu stained preparation, there were many magenta-colored hyaline globules wrapped by spindle tumor cells. The cytomorphologic findings correlated with the adenoid cystic pattern in histology. The cytologic differential diagnosis and the prognostic aspects of type A thymoma were briefly discussed.

Hyaline matrix in hyalinizing trabecular tumor: Findings in fine-needle aspiration smears.

Hyalinizing trabecular tumor (HTT) is a rare neoplasm which usually follows an indolent clinical course. The cytologic diagnosis of HTT can be challenging as these neoplasms share cytomorphological features with other thyroid neoplasms and paraganglioma. In fine-needle aspiration (FNA) smears a diagnosis of papillary thyroid carcinoma (PTC) or suspicion of PTC is often made. Herein we report cytologic findings in two patients with HTT examined by FNA. The key to a correct diagnosis is the recognition of a hyaline and colloid/amyloid-like material in the background of the smears. Immunocytochemical examination showing aberrant membranous and peripheral cytoplasmic staining for MIB-1 can help in rendering a correct diagnosis.

The biomechanical behaviour of the hyalinized periodontal ligament in dogs during experimental orthodontic tooth movement.

During orthodontic tooth movement, the mechanical behaviour of the extracellular matrix of the periodontal ligament (PDL) determines the cellular processes involved in turnover of the PDL and alveolar bone. This mechanical behaviour is the basis for finite element (FE) models and FE analyses. Five young adult male beagle dogs were used to test the null hypothesis that the mechanical behaviour of the PDL is identical in normal and hyalinized PDL. Therefore, tooth transposition was measured after standardized force application by super-elastic nickel titanium (NiTi) coil springs, exerting a constant force of 100 cN for 5 hours in both conditions. A rapid transposition during the first few seconds was found. However, it was significantly less for hyalinized than for non-hyalinized PDL. Subsequently, a short-lived creep movement was found for hyalinized PDL, while creep persisted at the non-hyalinized sides (analysis of variance and Tukey's multiple comparisons post hoc tests). The results showed substantial biomechanical differences between hyalinized and non-hyalinized PDL at different time points (Mann-Whitney). This indicates that FE models in the study of long-term orthodontic tooth movement, which are based solely on the characteristics of normal PDL should be reconsidered.

Familial amyotrophic lateral sclerosis with Cys111Tyr mutation in Cu/Zn superoxide dismutase showing widespread Lewy body-like hyaline inclusions.

We described a 43-year-old Japanese man with familial amyotrophic lateral sclerosis (FALS) in whom we identified a missense mutation (Cys111→Tyr) in exon 4 of the Cu/Zn superoxidase dismutase-1 (SOD1) gene in which no pathological data have been reported. The disease duration was 5 years, and he died of respiratory failure. The initial sign was weakness of the right leg. He had no clear upper motor involvement. Neuropathological examinations showed neuronal intracytoplasmic Lewy body-like hyaline inclusions (LBHIs) not only in the anterior horn cells of the spinal cord, but also in many other affected neurons. LBHIs were seen in the anterior horn cells, Onufrowicz nucleus, Clarke's nucleus, intermediolateral nucleus, and posterior gray horn of the spinal cord. In addition, LBHIs were observed in the periaqueductal gray matter, nucleus raphe dorsalis, locus ceruleus, trigeminal motor nucleus, vestibular nucleus, dorsal vagal nucleus, hypoglossal nucleus, and reticular formation of the brain stem. These are very specific findings that neuronal LBHIs in our case are for more widespread reported cases, and similar cases to ours have never reported in FALS.

[Stroma-rich variant of hyaline-vascular Castleman's disease: a clinicopathologic and histogenetic study].

OBJECTIVE: To study the histologic features and immunohistochemical findings of interfollicular stromal cells in hyaline-vascular Castleman's disease (HVCD), and to explore the role of these stromal cells in the pathogenesis of this disease. METHODS: The clinical findings and microscopic features of 23 cases of HVCD cases were reviewed. Immunohistochemical study for CCL21, MSA, CD21, CD35, S-100 and CD34 was carried out. RESULTS: According to the criteria proposed by Danon et al., stroma-rich variant of HVCD contained prominent interfollicular zone which occupied at least 50% of the lymph node area. In the current study, there were 14 cases of stroma-rich HVCD and 9 cases of conventional HVCD. Eleven of the stroma-rich HVCD had paraneoplastic pemphigus and contrastly, no pemphigus lesion obtained in all the 9 cases of conventional HVCD. The association between stromal cell hyperplasia and paraneoplastic pemphigus was statistically significant (P < 0.01).In all the conventional HVCD cases studied, CCL21 and MSA were positive in the stromal cells.The stromal cells in 13 of the 14 cases of the stroma-rich HVCD were also positive for CCL21 and MSA, however, staining for CD21, CD35, S-100 and CD34 was negative in both groups. There was no statistical significance obtained (P > 0.05) between the differences of the staining results. CONCLUSIONS: Stroma-rich HVCD and conventional HVCD represent two distinctive histologic variants and have a different association with paraneoplastic pemphigus. Most of the stromal cells locating in the interfollicular areas are fibroblastic reticular cells in origin, with the immunophenotype as CCL21(+)/MSA(+)/CD34⁻/CD21⁻/S-100⁻. The stromal cells proliferation correlate with the occurrence of paraneoplastic pemphigus, nevertheless, more cases are expected for a further study of the underlying pathogenesis.

Fine-needle aspiration cytology of Castleman disease: case report with review of the literature.

Organs involved by Castleman disease (CD) may be investigated by fine-needle aspiration cytology. No specific cytomorphological criteria are currently described for a definitive diagnosis. The cytological features of three fine-needle aspirations from three different lymph nodes of a patient with histologically confirmed CD of the hyaline-vascular type are herein reported, with a review of the literature. The fine-needle aspirations showed branching capillaries associated with fragments of germinal center. Review of the literature yielded 12 other case reports with over half describing similar findings. Because branching hyalinized small blood vessels penetrating follicular germinal center are characteristic of CD of the hyaline-vascular type on histology, this finding in fine-needle aspirates should raise that diagnostic possibility.

Subpleural pulmonary hyalinizing granuloma presenting as a solitary pulmonary nodule.

We introduce a case of pulmonary hyalinizing granuloma presented as a solitary pulmonary nodule located subpleurally. The patient was a 57-year-old man who had abnormal chest roentgenograms showing a solitary pulmonary nodule in the right lower lung field. The nodule was resected for definitive diagnosis and histopathologically proved to be pulmonary hyalinizing granuloma. In previously reported cases, most patients had ill-defined margins and usually bilateral, multiple lesions radiographically. In our case, the subpleural location is an uncommon location of this rare entity.

Primitive neuroectodermal tumor of the kidney with hyaline cells.

Primitive neuroectodermal tumor (PNET) of the kidney is a rare disease with high malignant potential. It affects young adults and has the tendency towards early metastasis. Relying on recently available immunohistochemistry and cytogenetic investigations, today most authors define PNET as part of the same nosologic entity as Ewing's sarcoma. We present the case of a 22-year-old man with a PNET arising from the kidney with, to our knowledge, a previously undescribed finding of hyaline cells within the tumor.

Focal hyalinization during experimental tooth movement in beagle dogs.

The aim was to study morphological differences between the periodontal structures of beagle dogs showing different rates of tooth movement under identical experimental conditions. An orthodontic appliance was placed on the mandibular second premolar and the first molar to exert a continuous and constant reciprocal force of 25 cN. Tooth movement was recorded weekly. The dogs were killed after 1, 4, 20, 40, and 80 days for histological evaluation. Haematoxylin and eosin staining was used for tissue survey, alkaline phosphatase staining was used as a marker for active osteoblasts, and tartrate resistant acid phosphatase staining was used for osteoclasts. After 24 hours, osteoclastic and osteoblastic activity had already increased at the pressure and tension sides, respectively, and, in some samples, hyalinization was found. In case of fast-moving teeth, areas of direct bone resorption at the pressure side and deposition of trabecular bone at the tension side were found throughout the experimental period. In the periodontal ligaments of teeth showing little movement, small patches of hyalinization were found at the pressure side, mostly located buccally or lingually of the mesiodistal plane. These phenomena were found in both molars and premolars and at all time points. It is concluded that small focal hyalinizations might be a factor that could explain individual differences in the rate of tooth movement.

Ultrastructural, tomographic and confocal imaging of the chondrocyte primary cilium in situ.

Hyaline cartilage chondrocytes express one primary cilium per cell, but its function remains unknown. We examined the ultrastructure of chick embryo sternal chondrocyte cilia and their interaction with extracellular matrix molecules by transmission electron microscopy (TEM) and, for the first time, double-tilt electron tomography. Ciliary bending was also examined by confocal immunohistochemistry. Tomography and TEM showed the ciliary axoneme to interdigitate amongst collagen fibres and condensed proteoglycans. TEM also revealed the presence of electron-opaque particles in the proximal axoneme which may represent intraciliary-transport (ICT) particles. We observed a wide range of ciliary bending patterns. Some conformed to a heavy elastica model associated with shear stress. Others were acutely deformed, suggesting ciliary deflection by collagen fibres and proteoglycans with which the cilia make contact. We conclude that mechanical forces transmitted through these matrix macromolecules bend the primary cilium, identifying it as a potential mechanosensor involved in skeletal patterning and growth.

Mammary mucinous carcinoma with marked cytoplasmic hyalinization. A report of 2 cases with emphasis on fine needle aspiration cytologic findings.

BACKGROUND: Cytoplasmic eosinophilia in breast tumors is due mainly to abundance of secretory granules, lysosomes and/or mitochondria. Diffuse cytoplasmic hyalinization caused by intermediate filaments has not been described before. CASES: Two cases of pure mammary mucinous carcinoma occurred with marked cytoplasmic hyalinization among 556 wide excision/mastectomy specimens of mammary ductal carcinoma, either in situ or invasive, encountered at Pamela Youde Nethersole Eastern Hospital, Hong Kong, during the period from 1994 to the end of 2001. Preoperative fine needle aspiration cytology was available in 1 case, showing cohesive clusters and micropapillae of tumor cells in abundant background mucin. The tumor cells had low mitotic activity and possessed round to oval nuclei, solitary macronucleoli; ample, eosinophilic cytoplasm and discrete cell borders. Cytoplasmic granularity, intracytoplasmic vacuoles or "cometlike" cells were not found. Histologic examination of the surgical specimens in both cases revealed pure mucinous carcinoma with diffuse and marked cytoplasmic hyalinization. There was no evidence of peritumoral lymphovascular permeation or regional lymph node metastasis. Ultrastructural examination showed minimal secretory activity, with abundant, loose aggregates of intermediate filaments in the cytoplasm. There was a relative paucity of other organelles. CONCLUSION: Diffuse cytoplasmic hyalinization is a peculiar morphologic change in mammary ductal carcinoma and apparently unique to pure mucinous carcinoma. Recognition of this phenomenon may help to avoid misdiagnosis of other types of ductal carcinoma with cytoplasmic eosinophilia, such as apocrine carcinoma and ductal carcinoma with neuroendocrine differentiation, which sometimes are also associated with pools of extracellular mucin.

Enchondroma: a benign osseous lesion with high F-18 FDG uptake.

A woman was referred for fluorodeoxyglucose positron emission tomography for the staging of a malignant melanoma. Although no signs of metastatic melanoma were evident on the whole-body scan, focally increased uptake within the femoral metaphysis was noted. Radiographic and magnetic resonance examinations revealed an enchondroma as the cause of the increased uptake. Histopathologic verification was obtained. The final diagnosis was actively proliferating enchondroma. A grade I chondrosarcoma could be ruled out. Enchondromas may be responsible for focally increased FDG uptake in bone lesions and must be considered when positron emission tomographic scans obtained with FDG are evaluated in cancer staging.

Imaging articular cartilage defects in the ankle joint with 3D fat-suppressed echo planar imaging: comparison with conventional 3D fat-suppressed gradient echo imaging.

PURPOSE: To shorten the examination time for articular cartilage imaging, using a recently developed three-dimensional (3D) multishot echo planar imaging (EPI) sequence with fat saturated (FS), compared to a conventional 3D fat-saturated spoiled gradient echo sequence (3D FS GRE). MATERIAL AND METHODS: There were 32 consecutive patients with ankle joint disorders who underwent magnetic resonance imaging (MRI) in a 1.0-T unit. Hyaline cartilage was imaged with a 3D FS EPI sequence and a 3D FS GRE sequence. Image assessment criteria included lesion conspicuity, contrast between different types of normal tissue, and image artifacts. In addition, contrast-to-noise ratios (CNRs) of cartilage vs. joint fluid and bone marrow were measured. RESULTS: The 3D FS EPI sequence provided a high CNR between cartilage and subchondral bone, similar to that of the 3D FS GRE sequence. The CNR between cartilage and effusion was significantly lower on the 3D EPI sequence due to the higher signal intensity of fluid. Both sequences were equal in lesion detection ability. The image quality of the 3D FS GRE sequence was slightly higher than that of the 3D FS EPI, but the difference was not statistically significant. CONCLUSION: We conclude that the 3D FS EPI sequence is comparable to the 3D FS GRE sequence in the detection of cartilage lesions, with the additional advantage of reduction in scan time by a factor of 4.