Faculty Bibliography

Background: When the first diagnosis of a well-differentiated neuroendocrine neoplasm (WDNEN) is made on a biopsy, crush artifact may impede mitotic counting, and the Ki-67 proliferative index (KPI) plays a more important role in grading. Few studies have examined the reliability of KPI in the grading of metastatic (met) WDNEN.
Design(s): Cases were retrieved from 2008-19. For each primary (1degree) and met, a 40x hotspot image of a Ki-67 stained slide was taken. KPI was analyzed by the ImmunoRatio Plugin using ImageJ software. All were validated by independent manual counting. In 1 case, crush artifact precluded use of ImageJ. If multiple mets were present, the largest was selected. Cytology and cases with fewer than 100 cells were omitted. Tumors were graded as G1(KPI<3%), G2(KPI 3-20%), or G3(KPI>20%). Grade and KPI were compared between each 1degree and met.
Result(s): 67 cases, including 38 mets from 29 1degree WDNEN, were evaluated. There were 12, 2, 2, 1, 17, and 4 mets from lung, thymus, middle ear, pancreas, small bowel, & colon respectively. The greatest variations in KPI from 1degree to met were seen in lung compared to all other sites. In 24/38(63%) of all mets, the grade was the same as 1degree. In 14/38(37%) of all mets, the grade was different: 4/14(29%) were lower while 10/14(71%) were higher than 1degree. In mets from lung, 2 had lower, 6 had the same, & 4 had higher grade. In mets from middle ear, the grades increased. In mets from small bowel 2 had lower, 12 had the same, and 3 had higher grade. In mets from colon 3 had the same and 1 had higher grade. And in mets from thymus & pancreas, the grades remained the same. See Fig 1. 3 mets were diagnosed before 1degree (2 days to 2 months). Mets with higher grade than 1degree tended to have longer time interval between 1degree and met, but this was not significant at the 95% confidence level (Kruskal-Wallis test, p=0.08). 28 mets were regional and 10 were distant. There was no correlation between met site and grade change (Person Chi-square, p=0.33). Also see Table 1. (Table presented)
Conclusion(s): Our study showed that in most met WDNEN (63%), the grade remained the same as the 1degree. The grade was higher in 10/38(26%) and lower in 4/38(11%). There was a trend toward higher grade in mets that occurred at a longer time interval after the 1degree. Fig 2 shows a potential diagnostic pitfall when the met shows much higher KPI than 1degree. In conclusion, if a met WDNEN is suspected as a firsttime diagnosis, KPI must be used cautiously for classification of WDNEN since over/under-grading may occur

Background: Spread through air spaces (STAS) has been reported to be associated with a worse prognosis in adenocarcinoma of lung. Recently it has been proposed that STAS be reported on frozen sections (FS) as an indication for more aggressive surgery (lobectomy vs sublobar resection). We undertook this study to evaluate the reliability of STAS assessment on FS compared to FS controls (FSC) and non-frozen remaining tumor (RT).
Design(s): Cases of adenocarcinoma that had FS of the tumor were identified retrospectively from two institutions. For each case, the following was recorded: Presence(+)/absence(-) of STAS on FS, FSC, and RT; and % of tumor patterns: Lepidic(L), acinar(A), papillary(P), micropapillary(M), solid(S). Grades were defined as follows: G1=L predominant with A/P G2=A/P predominant with <20% M/S G3=M/S predominant or >=20% M/S Cross-tabulations and Spearman's correlations (rs) were performed in SPSS (see Table). rs 0.3-<0.5 = low correlation.
Result(s): 165 cases were found. In 2 cases the tumor was only present on FS/FSC slides. STAS+ was present on FS in 47/165(28%), of which 28/47(60%) had STAS+ on FSC (rs=0.39) and 22/46(48%) had STAS+ on RT (rs=0.34) (1 tumor was only present on FS/FSC). Of the 40 STAS+ cases on RT, 18/40(45%) did not have STAS (STAS-) on FS (rs=0.34). 118/165 of cases were STAS- on FS; of these, 18/117(15%) were STAS+ on RT (rs=0.34) (1 tumor was only present on FS/FSC). Fig 1. Of the 47 cases with STAS+ on FS, 4(15%) were G1, 15(32%) were G2, and 28(60%) were G3 (rs =0.30). Of the 15 G2 cases with STAS+ on FS, 7 had 10% to <20% high grade pattern (M/S). Of the 28 G3 cases with STAS+ on FS, 13 had >= 30% high grade pattern. Of the 40 cases with STAS+ on RT, 1(2.5%) case was G1, 7(18%) cases were G2, and 32(80%) cases were G3 (rs=0.46). Fig 2. (Table presented)
Conclusion(s): The correlations among FS, FSC, and RT are low. FS STAS+ cases remain STAS+ only in 60% of FSC and 48% of RT. STAS shows higher correlation with grade on RT than it does on FS. These results show a lack of reliability in the assessment of STAS on FS, and do not support the proposal of reporting STAS in FS to make intraoperative clinical decisions, as doing so may subject patients to unnecessarily aggressive surgery

OBJECTIVES/OBJECTIVE:The 2014 Bethesda System (TBS 2014) guidelines for reporting cervical cytology revised the age for reporting benign endometrial cells (BECs) from 40 years or older to age 45 years or older. We evaluated this change and further investigated if extending the reporting age to 50 years or older may be acceptable. METHODS:We reviewed cases with BECs reported on Papanicolaou tests in women age 40 years or older and 45 years or older before and after implementation of TBS 2014. Follow-up endometrial biopsy/curettage results were categorized as benign, endometrial hyperplasia with or without atypia, or malignant. Hyperplasia and malignant follow-up were considered clinically significant. Clinical data were documented. Results were compared for women age 40 to 44, 45 to 49, and 50 years or older. RESULTS:Follow-up in 15 (100%) women age 40 to 44 years was benign. In women age 45 to 49 years, 61 (96.8%) had benign follow-up, one (1.6%) had atypical hyperplasia, and one (1.6%) had malignant follow-up. In women age 50 years or older, 57 (86.5%) had benign follow-up, four (6%) had malignant follow-up, and seven (7.5%) had atypical or nonatypical hyperplasia. There was a significant difference in follow-up between the age groups of 40 to 49 and 50 or older (P = .023). CONCLUSIONS:We conclude that the TBS 2014 revision was justified. Our data suggest that age 50 years or older rather than age 45 years or older may be an acceptable cutoff for reporting BECs.

BACKGROUND:Ultrasound has become the initial approach to evaluating thyroid nodules, facilitating the distinction between benign and malignant nodules based on composition, echogenicity, nodule border or margin, shape, the presence of calcifications, and nodule dimensions. The American College of Radiology (ACR) recommended the Thyroid Imaging Reporting and Data System (TI-RADS) as a classification system to standardize thyroid ultrasound reports and to predict the probability of malignancy in thyroid nodules using a scoring system (TR1-TR5) based on multiple ultrasound characteristics and nodule size. Fine-needle aspiration (FNA) is recommended as the next step for nodules that warrant further workup. The authors assessed the accuracy of the ACR TI-RADS based on the corresponding FNA cytology results (Bethesda system diagnoses I-VI). METHODS:ACR TI-RADS ultrasound reports and corresponding FNA cytology diagnoses from January 1, 2018 to August 30, 2018 were evaluated. RESULTS:From January 1, 2018 to August 30, 2018, 2306 thyroid ultrasound-guided FNAs were performed at our institution. Of 2306 cases, 361 had ACR TI-RADS reports available. The majority of FNAs were TR4 (180; 49.9%) or TR3 (108; 29.9%). No TR2 or TR3 nodules were associated with Bethesda category V or VI diagnoses. The majority of TR4 nodules (142 of 180; 78.9%) and TR5 nodules (42 of 65; 64.6%) exhibited benign (Bethesda category II) cytology. Fourteen TR5 cases (21.5%) had malignant (Bethesda category VI) cytology. CONCLUSIONS:Although there were no TR2 or TR3 malignant (Bethesda category VI) diagnoses, and there were only a few malignancies in the TR4 and TR5 categories, the current results reassert the notion that the ACR TI-RADS scoring system shows at least some correlation between benign or malignant cytology diagnoses, as illustrated by the greater number of malignant cases in the higher ACR TI-RADS categories.

Pathogenic variants in COCH, encoding cochlin, cause DFNA9 deafness disorder with characteristic histopathologic findings of cochlin deposits in the inner and middle ears. Here, we present the first case of deafness associated with bilateral external auditory canal (EAC) cochlin deposits, previously unreported evidence suggestive of cochlin-derived amyloid formation, and a novel COCH variant. A 54-year-old woman presented with progressive sensorineural hearing loss and bilateral EAC narrowing by subcutaneous thickening. Excision and histologic evaluation of tissue from both EACs showed paucicellular eosinophilic aggregates containing multiple Congo red-positive foci with yellow and green birefringence under crossed polarization light microscopy. Mass spectrometry performed on both the Congo red-positive and Congo red-negative areas identified cochlin as the most abundant protein, as well as a low abundance of universal amyloid signature peptides only in the Congo red-positive areas. Peptides indicative of a canonical amyloid type were not detected. Electron microscopy showed haphazard, branched microfibrils (3-7 nm in diameter) consistent with cochlin, as well as swirling fibrils (10-24 nm in diameter) reminiscent of amyloid fibrils. Cochlin immunohistochemical staining showed positivity throughout the aggregates. Sequencing of the entire COCH gene coding region from the patient's blood revealed a novel variant resulting in a non-conservative amino acid substitution of isoleucine to phenylalanine (c.1621A>T, p.I541F) in the vWFA2 domain at the protein's C-terminus. Our findings reveal a new pathologic manifestation of cochlin, raise the possibility of previously undescribed cochlin-derived amyloid formation, and highlight the importance of thoroughly investigating all aggregative tissue findings in the practice of diagnostic pathology.

Background & Objectives: Ciliated muconodular papillary tumour (CPMT) is a rare benign lesion, which occurs in the periphery of the lung and is characterised by papillary architecture, intra-alveolar mucin and the presence of non-atypical ciliated-columnar, basal and mucous cells. Since its introduction in 2002 by Ishikawa et al, this entity counts a few reports in the literature, which have primarily occurred in East Asia. Although not in the 2015WHO classification, CPMT represents a frank neoplastic process, harbouring genetic alterations including BRAF and EGFR mutations. The goal of this study was to characterise the clinicopathologic features of CPMT diagnosed at a tertiaty care institution in the U.S.
Method(s): Nine cases with characteristic features of classic and nonclassic CPMT from New York University Tisch Hospital and Bellevue Hospital from 2016 to 2019 were identified. Clinical and pathologic data were reviewed.
Result(s): CPMTs were identified in 3 Male and 6 Female patients, whose age ranged from 47 to 82 years old. The lesions were predominantly found in the right lung and had a median size of 6 mm. Six (6) cases represented classic CPMTs, while 3 cases lacked the full spectrum of CPMT diagnostic features, and were classified as non-classic CPMTs. While in 7 cases, surgical resection was performed due to radiologic diagnosis of a peripheral nodule, in 2 cases, small CPMTs were incidental findings in resections performed for a dominant lesion, which was either adenocarcinoma, non-mucinous type (case 2) or atypical carcinoid (case 8). All lesions showed the characteristic immunohistochemical TTF-1 stain of columnar cells and p63 or p40 stain of basal cells. Two out of four (2/4) cases stained for BRAF-V600E showed uniform staining of all 3 cellular components of the lesion. The data are summarized on Table 1.
Conclusion(s): CPMTs although infrequent are now increasingly recognized and their incidence appears higher than reported in western literature. Interestingly, this self-limited tumour shares similar driver mutations with lung adenocarcinoma. Further studies will include a comprehensive immunohistochemical and molecular characterization of these nine cases and comparison with morphologically similar non-neoplastic processes, like bronchiolar metaplasia

Introduction: Desmoplastic mesothelioma (DMM), a rare histological subtype of malignant pleural mesothelioma (MPM), is lethal and has very poor prognosis. Metastasis is commonly reported in DMM compared to other histological subtypes. Here we report a case of DMM with good survival (>1 year) despite lymph node metastasis. Case Report: A 62-year-old female with a history of smoking and possible asbestos exposure presented with cough and wheeze in 2012. Computed tomography (CT) revealed left-sided pleural plaques and multiple groundglass pulmonary nodules. In 2017, repeat CT showed increased diffuse left nodular pleural thickening. Positron emission tomography revealed hypermetabolic, nodular pleural thickening in the hemithorax, compatible with neoplasia. Needle biopsy in January 2018 showed pleural tissue with haphazard, nodular growth of spindled mesothelial cells, suspicious for desmoplastic mesothelioma. Definitive diagnosis was not possible due to lack of fat invasion and absence of supportive evidence by immunohistochemical stains. The patient underwent pleurectomy in February 2018. On histopathology, the majority of the tumor showed a desmoplastic pattern, composed of malignant spindled cells arranged haphazardly in a dense hyalinized stroma with chronic inflammatory infiltrate. AE1/AE3, calretinin, and D2-40 immunohistochemical stains highlighted the infiltrating neoplastic cells, which were negative for WT-1. BAP-1 was retained. The pattern of immunoreactivity supported the diagnosis of DMM. The tumor also involved visceral pleura, pulmonary parenchyma, and pericardium. It invaded into fat and displayed lymphovascular invasion. A metastatic focus of DMM was present in a lymph node. The tumor was staged as pT3N1. On recent examination, the patient only had complaints of mild breathlessness and stable hydro-pneumothorax, without any other comorbidities.
Conclusion(s): Our finding is unusual, since among the mesothelioma subtypes, DMM has the shortest survival, usually not more than 6 months. We report an extremely rare case of DMM with survival of >1 year despite invasion of lung parenchyma and lymph node metastasis

Introduction: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive hereditary disorder characterized by oculocutaneous albinism and bleeding diathesis. Transplantation is often conducted to treat lung fibrosis, which is the most fatal complication of this disease. While the literature discusses the diagnosis of HPS based on genetic testing, radiology, and electron microscopic (EM) findings of platelet granules, there is a paucity of images in the literature illustrating the pulmonary histopathologic and EM features of HPS. Case Report: Here we present striking histopathologic and EM images from a case of pulmonary fibrosis due to HPS in a 48-year-old female. The patient presented with restrictive lung disease and bilateral decreased breath sounds with diffuse crackles. She was clinically diagnosed with HPS and underwent bilateral lung transplant. On histopathology, both pneumonectomy specimens showed diffuse interstitial fibrosing and cellular pneumonitis with end-stage remodeling and type II pneumocyte (PC-II) hyperplasia. The PC-IIs had abundant foamy cytoplasm and compressed scalloped nuclei. Alveolar macrophages contained fine brown granules positive for PAS-D stain. EM analysis revealed that the PC-IIs contained numerous lamellated myelin bodies (so-called giant lamellar body degeneration) suggestive of surfactant admixed with lipid and luminal microvilli. The pigmented alveolar macrophages also contained lamellated myelin bodies, as well as clusters of single membrane-bound structures with varying size and electron density admixed with vacuolar and granular debris suggestive of ceroid deposits.
Conclusion(s): Based on light microscopy, histochemical analysis, EM, and clinical presentation, it was concluded that our findings were consistent with pulmonary changes as seen in HPS