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Fulltext Nuclear IHC enumeration: A digital phantom to evaluate the performance of automated algorithms in digital pathology

Niazi MKK, Abas FS, Senaras C, Pennell M, Sahiner B, Chen W, et al.

PLoS One, 2018;13(5):e0196547.
PMID: 29746503 DOI: 10.1371/journal.pone.0196547

Automatic and accurate detection of positive and negative nuclei from images of immunostained tissue biopsies is critical to the success of digital pathology. The evaluation of most nuclei detection algorithms relies on manually generated ground truth prepared by pathologists, which is unfortunately time-consuming and suffers from inter-pathologist variability. In this work, we developed a digital immunohistochemistry (IHC) phantom that can be used for evaluating computer algorithms for enumeration of IHC positive cells. Our phantom development consists of two main steps, 1) extraction of the individual as well as nuclei clumps of both positive and negative nuclei from real WSI images, and 2) systematic placement of the extracted nuclei clumps on an image canvas. The resulting images are visually similar to the original tissue images. We created a set of 42 images with different concentrations of positive and negative nuclei. These images were evaluated by four board certified pathologists in the task of estimating the ratio of positive to total number of nuclei. The resulting concordance correlation coefficients (CCC) between the pathologist and the true ratio range from 0.86 to 0.95 (point estimates). The same ratio was also computed by an automated computer algorithm, which yielded a CCC value of 0.99. Reading the phantom data with known ground truth, the human readers show substantial variability and lower average performance than the computer algorithm in terms of CCC. This shows the limitation of using a human reader panel to establish a reference standard for the evaluation of computer algorithms, thereby highlighting the usefulness of the phantom developed in this work. Using our phantom images, we further developed a function that can approximate the true ratio from the area of the positive and negative nuclei, hence avoiding the need to detect individual nuclei. The predicted ratios of 10 held-out images using the function (trained on 32 images) are within ±2.68% of the true ratio. Moreover, we also report the evaluation of a computerized image analysis method on the synthetic tissue dataset.

Matched MeSH terms: Cell Nucleus/pathology*
Leave methamphetamine to be alive--Part II

Islam MN, Khan J, Jaafar H

Leg Med (Tokyo), 2009 Apr;11 Suppl 1:S143-6.
PMID: 19345604 DOI: 10.1016/j.legalmed.2009.02.045

Series of experiments have been completed with Methamphetamine (MA). Some were with the higher, medium or lower duration of MA administration and some were with acute or chronic doses. Whatever may be the dose or duration the ultimate result came out with the further establishment of cardio-toxic effect of this drug. Cardiovascular symptoms related to MA toxicity include chest pain, palpitations, dyspnoea, hypertension, tachycardia, atrial and ventricular arrhythmias, and myocardial ischemia. MA abusers often go through a repeated pattern of frequent drug administrations followed by a period of abstinence. Previous studies have focused largely upon the chronic effect of MA intake to major organs, such as the brains and the heart, by using animal experiments. However, there is a lack of research into the effects of acute dose of MA, especially pertaining to the heart. To clarify the effect of MA on myocardium, 22 male Wister rats aged six weeks were divided into MA, Placebo (P) and Control (C) group were examined following single intraperitoneal administration of MA at a dose of 50 mg/kg body weight. Normal saline was similarly injected in P group. Light microscopic changes was seen in the myocardium of MA treated group including cellular infiltration, with clusters of macrophage-like cells having large nuclei and little cytoplasm evident in the sub-endocardium region. There were presence of few macrophages, leucocytes, and spindle-like fibroblasts. Bringing in to account of cardiac changes by a single dose of MA, slogan should be voiced out to leave methamphetamine.

Matched MeSH terms: Cell Nucleus/pathology
Pilomatrixoma as a diagnostic pitfall in fine needle aspiration cytology: a case report

Sivakumar S

Acta Cytol., 2007 Jul-Aug;51(4):583-5.
PMID: 17718128 DOI: 10.1159/000325801

BACKGROUND: Pilomatrixoma (pilomatrixoma, calcifying epithelioma of Malherbe) is a relatively uncommon, benign neoplasm arising from the skin adnexa. The tumor can cause diagnostic difficulty not only for the clinician but also for the cytologist.

CASE: A 62-year-old woman presented with a right submandibular swelling of 4 months' duration. The clinical findings were highly suspicious for malignancy. A fine needle aspiration biopsy was performed. Three preliminary differential diagnoses were offered: mucoepidermoid carcinoma of the submandibular salivary gland, squamous cell carcinomatous deposit in a submandibular lymph node and calcifying odontogenic tumor. Computed tomography demonstrated no bony lesion. No primary site of squamous cell carcinoma could be identified. An excisional biopsy of the swelling was performed, and the histologic diagnosis of pilomatrixoma was made.

CONCLUSION: The cytologic presentation of pilomatrixoma of the right submandibular region can masquerade as that of a malignant tumor, in this case mucoepidermoid carcinoma, squamous cell carcinoma or odontogenic tumor. This case delineates the cytomorphologic features of pilomatrixoma that may mimic carcinoma.

Matched MeSH terms: Cell Nucleus/pathology
Intraventricular squamous papillary craniopharyngioma: report of a case with intraoperative imprint cytology

Madhavan M, P JG, Abdullah Jafri J, Idris Z

Acta Cytol., 2005 Jul-Aug;49(4):431-4.
PMID: 16124175

BACKGROUND: Squamous papillary craniopharyngioma is a distinct entity, and its cytologic features may be misleading. Because of the rarity of this tumor, this case is being reported with a note on the cytologic features.

CASE: A 56-year-old Malay man who had 1-month history of generalized lethargy was admitted for altered sensorium. On examination, he was found to have neck stiffness, bilateral papilledema and generalized atrophy of muscles, with reduced power in all limbs. Magnetic resonance imaging of the brain showed a solid mass in the third ventricle causing obstructive hydrocephalus. Intraoperative cytology of the mass diagnosed intraventricular meningioma. However, the final histopathologic examination revealed squamous papillary craniopharyngioma.

CONCLUSION: Craniopharyngioma, squamous papillary type, is a rare entity and usually occurs in adults as an intraventricular solid tumor. Awareness of this entity will aid in arriving at the correct cytologic diagnosis.

Matched MeSH terms: Cell Nucleus/pathology
Cytologic appearances in invasive lobular carcinoma of the breast. A study of 21 cases

Jayaram G, Swain M, Chew MT, Yip CH

Acta Cytol., 2000 Mar-Apr;44(2):169-74.
PMID: 10740602

OBJECTIVE: To examine the fine needle aspiration cytologic features of invasive lobular carcinoma of breast and to discuss problems that may occur in cytodiagnosis.

STUDY DESIGN: Fine needle aspiration cytologic smears from 21 cases of invasive lobular carcinoma (ILC) of breast were subjected to detailed cytomorphologic analysis. Features studied included pattern of cells, size of cells, nuclear placement, pleomorphism, presence of intracytoplasmic lumina (ICL) and signet ring cells.

RESULTS: Cellularity was generally moderate or high, and the pattern was predominantly or partly dissociated in 86% of cases. Rosettelike pattern was discerned in alveolar-type ILC. Cell size was usually small or intermediate, with nuclei placed eccentrically in most cases. ICLs with or without signet ring cells were present in 12 cases (57%).

CONCLUSION: A cytologic picture consisting of predominantly dissociated small or intermediate-sized tumor cells with eccentric nuclei, with some of the cells showing ICLs, is highly suggestive of ILC. Indian file pattern, another characteristic feature of ILC, is, however, focal and inconsistent. Variant patterns of ILC may show other cytologic features, such as rosettelike pattern (alveolar variant of ILC) or large cell pattern (pleomorphic variant of ILC) and may consequently be difficult to categorize on cytologic smears.

Matched MeSH terms: Cell Nucleus/pathology
Follicular adenoma with squamous metaplasia and cystic change: report of a case with fine needle aspiration cytological and histological features

Jayaram G, Jayalakshmi P

Malays J Pathol, 1999 Dec;21(2):101-4.
PMID: 11068414

Squamous metaplasia (SM) of thyroid follicular epithelium is known to occur in a variety of non-neoplastic lesions as well in thyroid neoplasms, notably papillary carcinoma (PC). In follicular thyroid tumors, on the other hand, SM is very rare. This case describes cytological and pathological findings in a follicular adenoma (FA) that presented as a cystic lesion with extensive SM. The fine needle aspiration (FNA) cytology sample in this case yielded only necrotic material from the cystic area and squamous cells, which being mostly of immature type, were not recognised as squamous in the cytological smears. The needle missed the solid (neoplastic) component of the lesion and on the whole the cytological picture was considered to be equivocal. FA can now be added to the spectrum of thyroid lesions that can show SM. Awareness of this will enable cytopathologists to consider non-papillary lesions in the differential diagnosis of thyroid nodules that yield squamous cells.

Matched MeSH terms: Cell Nucleus/pathology
Cytology of Ki-1-positive anaplastic large cell lymphoma. A report of two cases

Jayaram G, Abdul Rahman N

Acta Cytol., 1997 Jul-Aug;41(4 Suppl):1253-60.
PMID: 9990253

Ki-1-positive anaplastic large cell lymphoma (Ki-1 ALCL), one of the more recently described pleomorphic types of lymphoma, affects mostly children and adolescents and is sometimes mistaken for carcinoma or sarcoma.

Matched MeSH terms: Cell Nucleus/pathology
Nuclear morphometry and texture analysis on cytological smears of thyroid neoplasms: a study of 50 cases

Deka L, Gupta S, Gupta R, Gupta K, Kaur CJ, Singh S S

Malays J Pathol, 2017 Apr;39(1):33-37.
PMID: 28413203

BACKGROUND: Fine needle aspiration cytology (FNAC) is a reliable and reproducible diagnostic technique for thyroid lesions with certain limitations. Computed morphometric methods have been introduced with a view to improve the diagnostic yield of thyroid aspirates. However, a review of the existing literature revealed conflicting reports regarding morphometric parameters in thyroid neoplasms.
MATERIALS AND METHODS: This study included 50 cases of thyroid lesions (20 cases of colloid goitre, 15 of follicular adenoma, 5 of follicular carcinoma and 10 papillary carcinomas). Digital images of cytologic smears of these cases were captured using a dedicated photomicrography system and nuclear profiles traced manually. With self-designed image analysis software, nuclear morphometric measurements, including texture analysis, were performed. Discriminant analysis was performed including the morphometric parameters and percentage of correctly classified nuclei noted.
RESULTS: Nuclear morphometry parameters showed that papillary thyroid carcinoma had the highest perimeter, area, radius and elongation factor compared to other thyroid lesions. Discriminant analysis revealed that altogether 77.9% of cells could be correctly classified to their lesion category based on the nuclear morphometric and textural parameters. Of the neoplastic cases, 84.5% of cells of follicular neoplasms and 72.5% of papillary carcinoma were classified to the respective category.
CONCLUSION: Nuclear morphometry, including texture analysis, can assist in the cytologic diagnosis of thyroid lesions, considering the high degree of accuracy of classification. Further studies and methodological refinements can achieve higher accuracy.

Matched MeSH terms: Cell Nucleus/pathology
Papillary cystic type of acinic cell carcinoma of parotid: fine needle aspiration cytological features of a high grade variant with oncocytic metaplasia

Jayaram G, Othman MA, Kumar M, Krishnan G

Malays J Pathol, 2002 Dec;24(2):107-12.
PMID: 12887170

A 60-year-old female developed a right parotid swelling six months after surgery for intra-oral squamous cell carcinoma. Fine needle aspiration (FNA) cytological smears showed dissociated large and small pleomorphic tumour cells with abundant mitoses and oncocytic features. A cytological diagnosis of parotid acinic cell carcinoma (ACC) was made. Histological study of the subtotal parotidectomy specimen showed a papillary cystic variety of acinic cell carcinoma (ACC-PCV). FNA cytological features in this case of ACC-PCV differs from the two previously reported cases in that it showed prominent oncocytic and high grade features and absence of papillary pattern in the cytological smears. ACC-PCV is an uncommon tumour and knowledge of its varied FNA cytological features is important for the diagnosis of this neoplasm.

Matched MeSH terms: Cell Nucleus/pathology
Nuclear and cellular volumetric alterations in oral lichen planus and lichenoid lesions: a histomorphometric study

Khoo SP, Primasari A, Saub R

J Oral Sci, 2001 Sep;43(3):151-7.
PMID: 11732734

There is presently no line of distinction between oral lichen planus and other oral lichenoid lesions. The aim of this study is to determine using histomorphometry, the differences between these lesions. Paraffin sections from 7 normal buccal epithelium, 19 oral lichen planus (LP), 14 oral lichenoid lesions (LL) and 7 discoid lupus erythematosus-like lesions (DLE-ll) were selected. The nuclear volume (V(N)) and cellular-volume (V(CELL)) of the epithelium were assessed using an image analyser. The V(N) and V(CELL), derived for both basal and spinal strata in LP and DLE-ll were 2.3 times more than that of normal tissues. There was a significant difference between LP and LL (P < 0.005) and between LL and DLE-ll (P < 0.001), but not between LP and DLE-ll. In conclusion, there appears to be a difference between LP, LL and DLE-ll and V(N) and V(CELL) may serve as potential discriminators between these groups of lesions.

Matched MeSH terms: Cell Nucleus/pathology
Adrenal cytomegaly associated with diaphragmatic hernia: report of a case

Ong BB, Wong KT

Malays J Pathol, 1996 Dec;18(2):121-3.
PMID: 10879233

A rare case of a 22-week-old foetus with unilateral adrenal cytomegaly and left diaphragmatic hernia is reported. Typical cytomegalic cells were found focally in the left adrenal but the right adrenal was normal. There was no stigmata of the Beckwith-Wiedermann syndrome. The association of adrenal cytomegaly with various congenital malformations, the significance and possible pathogenesis of this condition is discussed.

Matched MeSH terms: Cell Nucleus/pathology
Fine-needle aspiration cytology in Kimura's disease

Jayaram G, Peh KB

Diagn Cytopathol, 1995 Nov;13(4):295-9.
PMID: 8599911

Three patients presenting with parotid, submandibular, and/or lymph node masses were subjected to fine-needle aspiration cytology. Smears showed dissociated and clustered endothelial cells, eosinophils, lymphocytes, and Warthin Finkeldey giant cells. In two cases a diagnosis of Kimura's disease was suggested from the FNA cytologic smears. In the third case the presence of mononucleate cells with prominent nucleoli led to a suspicion of Hodgkin's disease. Excision biopsy and histopathologic study established a diagnosis of Kimura's disease in all three cases.

Matched MeSH terms: Cell Nucleus/pathology
Minichromosome maintenance protein 2 is a reliable proliferative marker in breast carcinoma

Reena RM, Mastura M, Siti-Aishah MA, Munirah MA, Norlia A, Naqiyah I, et al.

Ann Diagn Pathol, 2008 Oct;12(5):340-3.
PMID: 18774496 DOI: 10.1016/j.anndiagpath.2008.04.001

This is a study aimed to examine the distribution pattern of a specific minichromosome maintenance protein 2 (MCM2) in benign and malignant breast tissue. We also aim to correlate the frequency of expression of MCM2 with the degree of tumor differentiation. We used immunohistochemistry to examine the distribution and expression pattern of MCM2 on formalin-fixed paraffin-embedded tissue sections of benign (n = 30) and malignant breast tissue (n = 70) (IDC 56, DCIS 4, ILC 2, nonductal 4, mixed type 4). We quantified MCM2 expression by calculating a labeling index, which represents the percentage of epithelial nuclei that stained positively. Immunoreactivity was heterogenous in all the 70 malignant cases examined. Epithelial cells in cycle are most frequent at the tumor periphery. Labeling index of MCM2 was greatest in grade 3 (poorly differentiated) and lowest in grade 1 tumors (well differentiated). Minichromosome maintenance protein 2 expression in breast cancer showed a positive association with histologic grade (P < .05). In all the benign breast tissue examined, no proliferating compartments could be characterized. Minichromosome maintenance protein 2 is a useful proliferative marker of breast carcinoma. The frequency of expression of MCM2 showed an inverse correlation with the degree of tumor differentiation.

Matched MeSH terms: Cell Nucleus/pathology
Cutaneous metastasis of hepatocellular carcinoma diagnosed by fine needle aspiration cytology and Hep Par 1 immunopositivity

Isa NM, Bong JJ, Ghani FA, Rose IM, Husain S, Azrif M

Diagn Cytopathol, 2012 Nov;40(11):1010-4.
PMID: 21563319 DOI: 10.1002/dc.21706

Cutaneous metastasis of hepatocellular carcinoma (HCC) is very rare, accounting for less than 0.8% of all known cutaneous metastases and occurring in 2.7-3.4% of HCCs. With less than 50 such cases reported worldwide, most of which were diagnosed histologically on excised lesions, it can only be expected that diagnosis made on cytological features alone would be challenging. We report a case of cutaneous metastasis of HCC diagnosed based on cytological features and confirmed by Hep Par 1 immunopositivity of the cell block material. An 81-year-old man, who was known to have unresectable HCC, presented with a 1-month history of painless, left nasal alae mass. The mass measured 1.5 cm in diameter, and was multilobulated with a central necrosis. Fine needle aspiration of the mass was done. Smears were cellular, comprising of malignant cells in loose clusters and aggregates as well as singly dispersed. The malignant cells displayed moderate nuclear pleomorphism, occasional prominent nucleoli, and intranuclear pseudoinclusion. Cell block material demonstrated the trabeculae pattern of the malignant cells and Hep Par 1 immunopositivity. The final diagnosis of a metastatic cutaneous HCC was made. In conclusion, cutaneous HCC metastasis is rare and should be considered in the differential diagnosis in patients with a history of HCC presenting with suspicious skin lesion. In the right clinical setting, a confident diagnosis can be made in such cases by using the fine needle aspiration technique aided with immunopositivity for Hep Par 1 antibody of the aspirated material.

Matched MeSH terms: Cell Nucleus/pathology
Claudin expression and tight junction protein localization in the lining epithelium of the keratocystic odontogenic tumors, dentigerous cysts, and radicular cysts

Siar CH, Abbas SA

Oral Surg Oral Med Oral Pathol Oral Radiol, 2013 May;115(5):652-9.
PMID: 23601220 DOI: 10.1016/j.oooo.2013.02.013

The aim of this study was to evaluate the expression and localization of tight junction proteins (TJPs) or claudins in the keratocystic odontogenic tumor (KCOT) and to correlate with its biological behavior.

Matched MeSH terms: Cell Nucleus/pathology
Breast carcinoma in women 35 years and younger: a pathological study

Fernandopulle SM, Cher-Siangang P, Tan PH

Pathology, 2006 Jun;38(3):219-22.
PMID: 16753742

To document the pathological features of breast carcinoma diagnosed in women aged 35 years or less.

Matched MeSH terms: Cell Nucleus/pathology

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