Faculty Bibliography

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

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

Cardiac amyloid A (AA) amyloidosis is rare. We present the case of a 72-year-old woman with obstructive hypertrophic cardiomyopathy (HCM) and biopsy-proven renal AA amyloidosis whose dyspnea and exercise intolerance had worsened over the previous year. Her AA amyloidosis was suspected to be secondary to chronic diverticulitis for which she had undergone hemicolectomy and sigmoidectomy 3 years prior. Echocardiographic findings were consistent with worsening left ventricular outflow tract obstruction at rest. Cardiac magnetic resonance imaging revealed patchy areas of midwall late gadolinium enhancement. Right ventricular endomyocardial biopsy did not reveal amyloid deposition, and cardiac technetium-99m pyrophosphate scintigraphy did not suggest transthyretin amyloidosis. The patient underwent septal myectomy with resection of an accessory papillary muscle. Pathological examination of the myectomy specimen was consistent with HCM. In addition, there was a thick layer of diffuse endocardial and vascular amyloid deposition that was identified as AA type by laser-microdissection with liquid chromatography-coupled tandem-mass spectrometry. This case report highlights the presence of 2 distinct disease processes occurring simultaneously and the importance of tissue diagnosis of AA amyloidosis, a condition that is not commonly associated with HCM.

Background Arrhythmogenic cardiomyopathy (ACM) can mimic inflammatory processes. We present a complex patient with scleroderma (Sc)-dermatomyositis overlap syndrome (Sc-DM) and cardiac disease. Case A 57-year-old woman with family history of Sc presented with progressive weakness, dyspnea, edema, and Raynaud's (1A). Troponin was 1.6 ng/mL and CRP was 13.2 mg/L. EKGs revealed sinus rhythm with RBBB and AV sequential pacing with multifocal PVCs (1B-C). CT chest showed bibasilar fibrosis (1D). Echocardiography revealed biventricular dysfunction. Cardiac catheterization showed non-obstructive coronaries and a cardiac index of 1.8 L/min/m2. Cardiac MRI had diffuse biventricular subendocardial late gadolinium enhancement (1E). Electromyography revealed proximal myopathy. Rheumatologic workup was consistent with seronegative Sc-DM. Decision-making She was treated with steroids, mycophenolate, IV immunoglobulins, diuretics, and inotropes. Her course was complicated by recurrent VT cardiac arrests, prompting escalation to VA-ECMO. She underwent cardiac transplant on day 9 of ECMO. Pathology revealed biventricular fibrofatty replacement consistent with ACM (1F-G), patchy fibrosis of the pericardium, and mitral valve with thickened and fused chordae suggestive of inflammatory changes from Sc (1H-I). Conclusion This case highlights an atypical presentation of ACM in a patient with Sc-DM and the multidisciplinary approach necessary for proper diagnosis and management. [Figure presented]
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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

OBJECTIVE:=0.08). CONCLUSIONS:F-NaF PET/CT may improve risk-stratification.

BACKGROUND:Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content. OBJECTIVES/OBJECTIVE:This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis. METHODS:) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI. RESULTS:cells in the heart after MI. CONCLUSIONS:The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP⁺ exosomes. Moreover, uptake of CEMIP⁺ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.