August 2007
ANATOMIC PATHOLOGY
Two-Tier Grading
System for Ovarian Epithelial Cancer: Has its Time Arrived?
[Editorial]
In this issue of the American Journal of Surgical Pathology, Malpica and associates validate a two-tier system for grading ovarian serous carcinoma based primarily on the assessment of nuclear atypia. Their study demonstrates that the system is easy to learn and shows excellent agreement among both gynecologic and general surgical pathologists at different institutions.
The most commonly used grading system in the past was that of the International Federation of Gynecology and Obstetrics (FIGO). The FIGO grade is a three-tier system based on tumor architecture that divides neoplasms according to the ratio of glandular or papillary structures to solid growth. As currently applied to ovarian epithelial cancer by the Gynecologic Oncology Group, grade 1 tumors contain 5% or less solid areas, grade 2 neoplasms from 6% to 50%, and grade 3 tumors greater than 50%. The unpublished grading system of the Gynecologic Oncology Group is widely used and eclectic; both architectural and nuclear features are assessed. The criteria vary according to the histologic type of ovarian neoplasm, and the validity of the grading system has never been tested. Silverberg most recently reviewed the subject of grading of ovarian epithelial carcinoma in separate articles published in both gynecologic oncology and pathology journals.
Although three or four-tier grading systems in various forms have been in vogue for grading ovarian epithelial malignancy for many decades, these systems do not currently provide optimal benefit to clinicians, who often have only 2 main therapeutic options. It is essential that information derived from pathologic examination facilitate future translational research that can lead to an improved clinical outlook for patients with ovarian cancer. To reach this goal requires refinement of classification and grading systems at appropriate intervals of time. Development of optimal systems may require sophisticated statistical methodology to correlate surgical pathologic observations with survival and molecular data.
Recent evidence has demonstrated 2 distinct molecular pathways in the development of serous carcinoma with differing clinicopathologic features and survival. Low-grade serous carcinomas typically arise from low malignant potential (borderline) tumors and have a survival advantage, whereas high-grade tumors arise for the most part de novo and have a considerably worse prognosis. A recent study demonstrated that serous neoplasms of low malignant potential and low-grade serous carcinoma have KRAS and BRAF mutations in 60% of cases and p53 mutations in less than 10% of cases, whereas high-grade serous carcinomas are characterized by p53 mutations in over 50% of cases and lack KRAS and BRAF mutations. Another study found that BRAF mutations were limited to low-grade serous tumors; however, 12% of high-grade tumors had KRAS mutations.
Using a two-tier grading system based primarily on the degree of nuclear atypia and secondarily on mitotic rate, a prior study from the University of Texas M.D. Anderson Cancer Center (MDACC) showed excellent correlation between grading and survival; the median survival for patients with low-grade serous carcinomas was 4.2 years, whereas the survival for those with high-grade tumors was 1.7 years. The utility of a two-tier grading system based on nuclear atypia has been confirmed by the study of Hsu and associates, who demonstrated by computerized morphometry that nuclear size as measured by mean nuclear area and volume percentage of epithelium is an excellent adjunctive tool for distinguishing low-grade from high-grade serous tumors. Although it has not yet been directly demonstrated that the MDACC grading system can predict the molecular pathway by which the tumor has arisen, a prior study from the same group suggests that it might.
Less progress has been made in the grading of epithelial ovarian cancer of other glandular histologic types, perhaps because they are less common. Nuclear grade has been shown to be an independent predictor of prognosis in mucinous adenocarcinoma; in a study of 34 cases, those with high nuclear grade had a significantly worse prognosis. An increasing frequency of KRAS mutations is noted in the progression of benign mucinous tumors, through low malignant potential tumors, to frank carcinoma. The most common scheme in use for evaluation of ovarian endometrioid carcinoma is a three-tier system using a modified FIGO grade that is identical to that employed by Zaino and associates in the assessment of endometrioid carcinoma of the corpus. As might be expected, patients with grades 1 and 2 ovarian endometrioid carcinomas have a higher survival rate than those with grade 3 neoplasms. The most common somatic mutations in endometrioid carcinoma involve [beta]-catenin (CTNNB1) and PTEN; both these mutations are associated with early stage neoplasms that have a favorable prognosis and have also been observed in endometriosis. Traditionally, clear cell carcinoma of the ovary, like its counterpart in the endometrium, is not graded. In a clinicopathologic analysis of 44 cases, grading of ovarian clear cell adenocarcinoma by conventional architectural and cytologic criteria had no predictive value with regard to survival. In a study of ovarian endometrioid carcinoma, clear cell carcinoma, and mixtures of the 2 types, it was demonstrated that ovarian clear cell adenocarcinoma often expresses matrix metalloproteinase-7 in the absence of [beta]-catenin expression and has a poor prognosis.
Some information is available regarding grading of nonglandular epithelial ovarian cancer. Roth and Czernobilsky used a two-tier grading system in a series of malignant Brenner tumors. Although the number of cases was too small for statistical analysis, there was an apparent survival difference among malignant Brenner tumors separated into well-differentiated (low-grade) and poorly differentiated (high-grade) groups based on nuclear abnormalities and mitotic rate. Although 3 series have graded ovarian transitional cell carcinoma using different systems, the relationship between histologic grade and patient outcome was not evaluated. In a clinicopathologic study of 37 cases of primary squamous cell carcinoma of the ovary using a modified Broder's grading system based on percentage of undifferentiated cells, Pins and associates showed that high histologic grade is a significant predictor of poor overall survival.
Progress
toward a universal grading system for ovarian epithelial cancer was made by
The ideal grading system should be relatively easy to learn and should be an independent predictor of patient survival. In certain instances correlations with molecular pathways may help lead to the development of specific treatment modalities. A scheme that can be universally applied to the various histologic types of epithelial ovarian cancer would be desirable, but is not essential and indeed may not be possible. The 2 currently most promising methods of grading are the MDACC and Silverberg-Shimuzu systems. The MDACC system has been only applied to serous carcinoma, whereas the Silverberg-Shimuzu system holds promise for glandular tumors of the ovary, but may not be applicable for nonglandular tumors because the architectural component of the score assesses the degree of glandular and papillary formation. In the only study to date comparing these systems, the MDACC grading system showed good overall correlation with the Shimuzu-Silverberg and the FIGO systems for grading serous carcinoma; however, additional independent studies are warranted to determine reproducibility and the prediction of survival and molecular pathways. Ultimately, gynecologic oncologists may play a role in choosing which grading system is most valuable to them in the determination of patient management options as was the case with mammary carcinoma.
American
Journal of Surgical Pathology, Volume 31(8), August 2007, pp
1285-1287
Recently Described and Emphasized
Entities of Renal Neoplasms
Steven S. Shen; Luan D. Truong; Alberto G. Ayala et al
Text Recent advances of molecular biology and cytogenetics of renal cancer have resulted in the new classification of renal neoplasms and a number of subtypes are identified and emphasized. In addition, rare nonepithelial renal neoplasms are identified and characterized. Familiarity with these entities will help make the most accurate diagnosis and guide the treatment and follow-up of patients with renal neoplasm.
Objective To review the clinicopathologic entities of renal neoplasms that are recently defined or emphasized. Their clinical, gross, microscopic, and immunohistochemical features, as well as specific cytogenetic or molecular abnormalities, are discussed. Important differential diagnoses of each entity are also briefly discussed.
Data Sources Extensive review of published literature and our experience.
Conclusions A number of new entities of renal neoplasms or genetically defined renal cell carcinomas have been identified or emphasized because of their unique genetic or molecular changes. Recognition of these entities becomes important as some of them have different biologic behavior and treatment strategies may be different.
Advances in the understanding of cytogenetic and molecular abnormalities of renal neoplasms in the last decade have significantly refined the morphologic classification of these lesions, which has resulted in a 1997 consensus classification of renal cell neoplasms. Accurate histologic subtyping of renal tumors is important as each entity has its own biologic behavior. In the last few years, new types of renal neoplasms have been described and a few of these are listed as specific entities in the new 2004 World Health Organization classification of renal neoplasms Furthermore, emphasis is placed on these variants because they are associated with specific cytogenetic changes or syndromes. Recognition of these morphologically or genetically unique entities then becomes important.
In this article, authors review newly defined clinicopathologic entities of renal neoplasms and variants of renal cell carcinomas (RCCs) that have distinct cytogenetic and molecular changes. Gross and histologic features are described including salient immunohistochemical profiles and specific cytogenetic or molecular changes. The differential diagnosis of each entity is briefly discussed. Other miscellaneous nonepithelial renal neoplasms that have been recently recognized or emphasized are also included.
The entities herein discussed include Xp11 translocation
carcinoma, mucinous tubular and spindle cell
carcinoma, hybrid chromophobe RCC and oncocytoma associated with Birt-Hogg-Dube
(BHD) syndrome, multilocular cystic RCC, subtypes of
papillary RCC, and unclassified RCC. We also include renal neoplasms
other than renal carcinoma, such as mixed epithelial and stromal
renal tumors, primary renal synovial sarcomas,
primitive neuroectodermal tumor (
Archives
of Pathology and Laboratory Medicine: Vol. 131, No. 8, pp. 1234–1243.
Electron Microscopic Insights Into
the Vascular Biology of Atherosclerosis
Study of
Coronary Endarterectomy Specimens
Komarakshi R. Balakrishnan, Sarah Kuruvilla, Aishwarya Srinivasan et al
Coronary artery
disease, typically discrete and proximal in distribution, is sometimes more diffuse in nature, in which case, it is often associated
with poorer outcomes of revascularization. Does diffuse coronary artery disease
represent an advanced and burned-out stage of atherosclerosis, representing a
“metabolically inert graveyard” of atheromatous
tissue, or is there ongoing atherosclerotic activity? To answer this question,
plaques obtained during surgical coronary endarterectomy
were examined using transmission and scanning electron microscopy, and the
results form the basis of this study.
The
various stages of atherosclerotic plaque progression are well known1 and could be clearly
identified in different regions of the same plaque under electron microscopic
examination. In other regions, macrophages were seen phagocytosing
lipid droplets and being transformed into foam cells. Foam cells of
smooth-muscle origin with surrounding collagen deposition could also be seen.
The role of plaque neovascularization in recruiting
macrophages into the plaque was also graphically captured; we have previously
published these observations.2 Transmission electron microscopy offers some unique
insights into the mechanisms of plaque calcification. The process seems to
start as an encrustation around individual microvesicles
of lipid, eventually coalescing to form larger clumps of calcification.
Scanning electron microscopy of the same plaque revealed areas of endothelial
erosion and plaque fissuring. Coronary endarterectomy
plaques show evidence of active, ongoing atherosclerotic activity and are a
valuable source for studying the vascular biology of atherosclerosis.
Circulation 2007; 115;388-390
CYTOPATHOLOGY
Histopathological Changes In Thyroid Tissue After Fine Needle Aspiration Biopsy
Filiz Bolat, Fazilet Kayaselcuk, Tarık et al
Fine needle aspiration biopsy (FNAB) is a method that is frequently used in the diagnosis for neoplastic and non-neoplastic thyroid lesions. However, despite the contribution of this method to diagnosis, varying degrees of histopathological alterations in thyroid tissue occur due to the trauma caused by the aspiration needle. In this study, we compared the histopathology of the thyroidectomy specimens obtained by FNAB with the specimens obtained without the use of FNAB.
A hundred and fifty thyroidectomy specimens obtained by FNAB were compared histopathologically with 150 thyroidectomy specimens (control group) obtained without a FNAB procedure. The thyroidectomy specimens were evaluated for hemorrhage, fibrosis, siderophagia, vascular thrombosis, vascular proliferation, infarction, granulation tissue, cystic degeneration, papillary hyperplasia, nuclear atypia, mitosis, calcification, vascular invasion, capsular distortion (pseudoinvasion), cholesterol clefts, and the presence of metaplasia.
The thyroidectomy specimens obtained by FNAB had rates of hemorrhage, siderophagia, granulation tissue, papillary hyperplasia, fibrosis, calcification, capsular distortion, cholesterol clefts (P<0.001), and vascular thrombosis (P=0.001) that were statistically significantly higher than those obtained without FNAB. However, there were no clinically significant differences between the two groups in terms of vascular proliferation, nuclear atypia, mitosis, infarction, and oncocytic and squamous metaplasia.
Alterations in thyroid tissue in association with FNAB show a considerable variation. Some of the alterations make diagnosis difficult, even leading to misdiagnosis in favor of carcinoma. Therefore, a thorough knowledge of possible alterations is essential to the differential diagnosis.
Pathology -Research and Practice, Volume 203, Issue 9,
GENOMICS & PROTEMICS
Genomewide Association Analysis of Coronary Artery
Disease
Nilesh J. Samani,
Jeanette Erdmann
Background Modern genotyping
platforms permit a systematic search for inherited components of
complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery
disease.
Methods Authors identified
chromosomal loci that were strongly associated with coronary artery
disease in the Wellcome Trust Case Control
Consortium (WTCCC) study (which involved 1926 case subjects with
coronary artery disease and 2938 controls) and looked for
replication in the German MI [Myocardial Infarction] Family Study
(which involved 875 case subjects with myocardial infarction and
1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary
artery disease in either study (P<0.001) were then combined to
identify additional loci with a high probability of true
association. Genotyping in both studies was performed with the use
of the GeneChip Human Mapping 500K Array Set (Affymetrix).
Results Of thousands of
chromosomal loci studied, the same locus had the strongest
association with coronary artery disease in both the WTCCC and the
German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14
and P=3.40x10–6, respectively). Overall, the WTCCC study
revealed nine loci that were strongly associated with coronary artery
disease (P<1.2x10–5 and less than a 50% chance of being falsely
positive). In addition to chromosome 9p21.3, two of these loci were
successfully replicated (adjusted P<0.05) in the German study:
chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The
combined analysis of the two studies identified four additional loci
significantly associated with coronary artery disease (P<1.3x10–6)
and a high probability (>80%) of a true association: chromosomes 1p13.3
(rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33
(rs17228212).
Conclusions Authors
identified several genetic loci that, individually and in aggregate,
substantially affect the risk of development of coronary artery
disease.
The
CLINICAL PATHOLOGY
How Herbal Remedies affect Clinical
Laboratory Test Results
Amita Dasgupta
Herbal medicines
are readily available worldwide from stores without prescription. In the
|
Herbal product |
Interacting drug |
Comments |
|
Ginseng |
Warfarin |
May decrease the effectiveness of warfarin |
|
|
Paxil |
Lethargy, incoherence, nausea |
|
Digoxin |
Decreased AUC, peak and trough
concentrations of digoxin, may reduce effectiveness
of digoxin |
|
|
Cyclosporin/ tacrolimus |
Lower cyclosporin/tacrolimus concentrations due to increased clearance
may cause transplant rejection |
|
|
Theophylline |
Lowers concentration, thus decreases the
efficacy of theophylline |
|
|
Indinavir, lopinavir |
Lowers concentration, may cause treatment
failure in ritonavir, atazanavir
patients with HIV |
|
|
Statins |
Reduced plasma concentration of simvastatin but no effect on pravastatin |
|
|
Innotecan, imatinib |
Reduced efficacy |
|
|
R- and S-verapamil |
Increased clearance |
|
|
Oral contraceptives |
Lower concentration, failed birth control |
|
Ginkgo biloba
|
Aspirin |
Bleeding because ginkgo can inhibit platelet activating factor |
|
Warfarin |
Haemorrhage |
|
|
Thiazide |
Hypertension |
|
Kava
|
Alprazolam |
Additive effects with central nervous system
depressants, alcohol |
|
Garlic |
Warfarin |
Increases effectiveness of warfarin, bleeding |
|
Ginger |
Warfarin |
Increases effectiveness of warfarin, bleeding |
|
Feverfew |
Warfarin |
Increases effectiveness of warfarin, bleeding |
Dong quai
|
Warfarin |
Contains coumarin,
increases international normalized ratio (INR) for warfarin, causes bleeding |
|
Dan shen |
Warfarin |
Increases effectiveness of warfarin due to its reduced elimination |
|
Comfrey |
Phenobarbital |
Increases metabolism of comfrey producing a
lethal metabolite, severe hepatotoxicity |
The National Medical Journal
of
Oral Fluid-Based Rapid Hiv 1/2 Antibody Test
Evaluation of
diagnostic accuracy, feasibility, and client preference for rapid oral
fluid-based diagnosis of HIV infection in rural
Pant Pai N, Joshi R, Dogra S et
This cross-sectional, hospital-based study was done on
450 patients to evaluate the diagnostic accuracy, feasibility and client
preference for a rapid, oral fluid-based diagnostic test for HIV infection in
rural
COMMENT
The HIV epidemic
has been particularly explosive in
Rapid,
point-of-care HIV testing remains an important component of HIV control
initiatives and programmes. In resource-constrained
settings as in rural
This study examined the OraQuick Rapid HIV 1/2 test, a rapid test that can be done with oral fluid, finger-stick blood as well as whole blood and plasma obtained by venepuncture. The aims were:
- To evaluate the diagnostic accuracy of
the test
- To determine if subjects would prefer
this method
- To ascertain if this would be a feasible
modality of testing for HIV in rural and resource-constrained settings.
Recruitment of participants was done from patients attending the Internal Medicine and Sexually Transmitted Disease clinics. It was based on inclusion criteria that were dependent on presenting symptoms suggestive of HIV infection and the presence of risk factors. The sampling was based on convenience. The participants were initially tested with one OraQuick oral fluid test, one OraQuick finger-stick test and an ELISA. If the ELISA was reactive, a second ELISA, followed by a western blot test were done on the sample. The technician doing the ELISA and western blot tests was blinded to the OraQuick oral fluid and finger-stick tests. Had logistics permitted, blinding of the person doing the Oraquick oral fluid test with the OraQuick finger-stick test might have added more strength to the study.
While the OraQuick oral fluid test had a 100% specificity and sensitivity in this study, the OraQuick finger-stick test had a sensitivity of 100% and a specificity of 99.7%, with one false positive test. Previous studies reported sensitivities ranging from 75% to 100%, and specificities ranging from 99.9% to 100%. The wide variation in sensitivity can be partly explained by the fact that these studies had participants from other settings, for example, pregnant women and patients from emergency departments and correctional facilities. On the other hand, given that these studies had sample sizes ranging from 1258 to 135 724 participants, which were larger than that of the current study, it is possible that their results reflect a wider spectrum of factors influencing the test. In addition, the authors of this study state that they have used a new and improved OraQuick rapid HIV 1/2 test. They do not mention what the improvements are. It is probable that some, or all, of the previous studies used a different version of the test, and this might explain some of the differences in diagnostic accuracy.
In
this study, the participants had an 87% preference for the oral fluid-based
test for initial testing, while only 60% preferred it for repeat testing.
Though this level of client preference is the highest as compared with previous
studies it, is not clear why 13% of the participants did not prefer the test
for initial testing and 40% for retesting. Details of the reasons would help
understand factors influencing client preferences in different cultures.
The
term 'oral fluid' requires some clarification, and so does the methodology of
collection of the sample. Oral fluid is not saliva. It is fluid present in the
oral cavity, which is like a plasma transudate, and
has a high concentration of IgG. The sample is
collected by gently swabbing the absorbent pad (attached to the kit) around the
gingival capillary margin. This allows the oral fluid to soak the pad, after
which it is put into the test solution
provided with the kit. It works as a lateral flow immunoassay, showing a
visible colour change in the test area, if the test
is positive.
On
the whole, this study is well designed and ably conducted. It addresses a felt
need, given the rate of HIV seroconversion in
The National Medical Journal
of
BOTTOM LINE
Approaching the Unknown Glass Slide
Ed Friedlander
This guide will help you stay focused when you do your mock signout. "Pathology" must include some traditional classroom / reading / exam work. But learning is most meaningful and effective when you are practicing a skill, with supportive guidance and feedback. It is our intention that everybody come away from this exercise with a genuine feeling of satisfaction and accomplishment.
We will tell you the organ. You may use the histology textbooks in the office while you are working. if none of the familiar histologic structure is present, this must be a tumor.
Find the epithelium. Is it normal for that organ? If it is gone, and replaced by an inflamed crater, you are looking at an ulcer. If there is anaplasia confined to a portion of the epithelium, it is dysplasia / carcinoma in situ / intraepithelial neoplasia.
Look for other landmarks in the organ. Is something too thick? Too thin? Absent? Is the change focal or generalized?
Look for pigments. Black is probably carbon. Brown is probably melanin, hemosiderin, bile, or lipofuscin. WARNING: Brown pigment among red cells (and identical pigment appearing on the same slide) is an artifact. Ignore it. Cholesterol needles usually come from atherosclerotic plaque but can occur in necrotic areas. If it stains dark blue but isn't a nucleus / nuclear dust, it's bacteria or calcium.
Look for hyaline. Inflamed hyaline is probably fibrin. Non-inflamed extracellular hyaline is probably collagen or amyloid. Intracellular hyaline can be diagnosed based on its context.
Look for necrosis. Unless there is advanced coagulation necrosis (i.e., eosinophilic cell ghosts), your best tipoff will be nuclear dust and/or totally-pyknotic nuclei. If you can still see the outlines of cells, it is coagulation necrosis. If it's fine-granular and fairly homogeneous, it's caseous necrosis. If a portion of the tissue is absent, it's probably undergone liquefaction necrosis. Dead fat with a blue tinge is enzymatic fat necrosis.
Look for inflammatory cells. Distinguish neutrophils (acute inflammation), lymphocytes and plasma cells (lymphoid tissue or chronic inflammation), and eosinophils (less helpful in this exercise). Look for pus (neutrophils with little or nothing else). Giant cells are your best sign of a granuloma. Parallel small blood vessels are your best sign of granulation tissue. With acute inflammation, there is likely to be edema. With chronic inflammation, there is likely to be fibrosis.
Red cells outside of vessels are hemorrhage. Look at how it is positioned relative to the normal architecture or tumor architecture -- and think how the hemorrhage must have occurred. Inside a vessel or cardiac chamber, a thrombus can usually be recognized by lines of Zahn -- alternating erythrocyte-rich (red) and erythrocyte-poor (pink) layers.
If a portion of the tissue (or all of it) lacks the architectural features you remember from "Histology", this is a tumor. If a tumor exhibits anaplasia (i.e., cells with dark, oversized, irregular nuclei), necrosis, easy-to-find mitotic figures, hemorrhage, and/or obvious invasion (i.e., tentacles, or epithelial elements where they couldn't possibly belong), this is probably cancer. Otherwise, it is probably a benign tumor. A benign tumor with glands is an adenoma. A benign tumor with melanin in its cells is probably a nevus. And so forth.
If it is cancer, try to tell the kind. Cells lining up, adhering to one another, and moulding one another indicates carcinoma. Papillae, signet ring cells, lumens, back-to-back glands (swiss-cheese; it must be easy to find cells that are part of two different glands), and lakes of mucin say adenocarcinoma. Squamous pearls, desmosomes, and lone apoptotic cells say squamous cell carcinoma. Spindle-cell cancers (i.e., those with lots of nuclei oriented parallel) are often sarcomas. Melanin in cancer cells says melanoma. The infamous oat cell carcinoma features small blue cells, about 20 microns across, moulding each other, without a visible stroma. Lymphoma features sheets of relatively uniform round cells, not moulding each other but effacing the architecture of a lymphoid organ.
This will enable you to make a diagnosis on most of your mock-signout cases. There will be a few which will require you to recognize something more. But if you can recognize these key features on a slide, you will get credit for the slide even if you cannot exactly put the diagnosis together.