December 2007
50th episode of NEWSPath
Special Problems in the
Diagnosis and Management of Melanocytic Neoplasms
The diagnosis and management of malignant melanoma continues to be one of the most important and vexing problems in clinical dermatology, dermatopathology as well as in general anatomic pathology. The number of malignant melanomas diagnosed clinically and histologically has increased dramatically in recent years and, while it is somewhat controversial, most experts agree that there has been an overall increase in the true incidence of melanoma. This is likely due to many factors but perhaps one of the most important is that the “baby boomer” generation is now reaching the age when these neoplasms typically present, so that there is a large number of individuals now at risk. However, the incidence of melanoma in young individuals is also rising, one factor probably being the consequence of unhealthy behaviors such as use of tanning beds. Certainly other factors that have yet to be determined are responsible as well, as not all melanomas are associated with ultraviolet radiation exposure. Nevertheless, this trend is disturbing as there have been major efforts to educate the public about melanoma self-detection, self-examination, skin-safe behaviors, and even histologic diagnosis, yet some subsets of the population such as teens and older men remain recalcitrant to these messages. It has been shown that the diagnosis of melanoma increases in spring and summer months, which indicates that patients are harboring undiagnosed lesions during fall and winter.
Physicians are taught that melanoma demonstrates characteristic clinical and pathologic features and can be diagnosed using them. However, there are many unusual variants of melanoma and the diagnosis may not be readily apparent either clinically or histologically. Furthermore, given the sheer number of these lesions in the population, there are more and more of these unusual variants that clinicians are encountering. Any physician who deals with melanoma must be aware of these unusual variants and must understand the limitations of current diagnostic criteria and how this may affect treatment and prognosis.
Thus, melanoma continues to pose major challenges in diagnosis, treatment, and public health and will do so for years to come. This edition deals specifically with these aspects of melanoma as well as with entities that can pose difficulty in the diagnosis such as dysplastic nevi, Spitz nevi, and special site nevi. While not a comprehensive treatise on all elements of melanoma, we hope that you find this educational and that it will assist you in rendering more accurate diagnoses of this capricious lesion.
Pathology Case Reviews, Volume
12(6), November/December 2007, pp 223-224
The Most Common, Clinically Significant Misdiagnoses in Testicular
Tumor Pathology, and How to Avoid Them
Ulbright,
Thomas M. MD
Testicular tumors are both increasing in frequency
and disproportionately occur in young men; furthermore, different forms of
neoplasm require different treatments. These considerations make the accurate
diagnosis of testicular tumors especially important. Many of the critical
distinctions involve the differentiation of seminoma
from one or more potential mimics because seminoma is
not only the most common testicular neoplasm but it is also the only malignant
testicular tumor that is commonly treated with radiation, which is ineffective
in other malignancies of the testis. For the most part, accurate diagnosis can
be achieved by careful light microscopic evaluation, although appropriate immunostains can provide diagnostic assistance if doubt
persists. This article discusses a number of clinically important differential
diagnoses in the testis that are common sources of
misinterpretations. These include: seminoma versus embryonal carcinoma, seminoma
versus yolk sac tumor, seminoma versus Sertoli cell tumor, seminoma with
syncytiotrophoblast cells versus choriocarcinoma,
granulomatous seminoma
versus granulomatous orchitis,
intertubular seminoma versus
orchitis, lymphoma versus seminoma
or embryonal carcinoma, dermoid
cyst versus teratoma, scar versus regressed germ cell
tumor, and "anaplastic" spermatocytic
seminoma versus usual seminoma
or embryonal carcinoma.
Advances in Anatomic Pathology, 15(1):18-27, January 2008.
Subepithelial Extension of Squamous
Cell Carcinoma in the Esophagus: Histopathological
Study Using D2-40 Immunostaining for 108 Superficial
Carcinomas
Amano,
Takayuki ; Matsumoto, Toshiharu ; Hayashi, Takuo et al
Squamous cell carcinoma (SCC) of the
esophagus occasionally produces subepithelial
extension (SEE) in the stroma below the non-cancerous
epithelium. Little information on SEE has been obtained,
therefore the purpose of the present study was to carry out a clinicopathological study using D2-40 immunostaining
in 108 cases of superficial (mucosal and submucosal)
SCC of the esophagus. SEE occurred in 24 cases (22.2%). The SEE was present in
both mucosa and submucosa in 19 cases, but in five
cases SEE was located in the mucosa. Lymphatic invasion of tumor cells was well
determined on D2-40 immunostaining. In the SEE group
lymphatic invasion was found in 15 cases, and in two cases there was lymphatic
invasion in the lamina propria mucosa of the edge of
SEE. In the SEE group 23 (95.8%) had infiltrative growth of tumor cells.
Lymphatic invasion and growth pattern of tumor cells were statistically
correlated with SEE. Lymph node metastases were found in 48 cases, but SEE was
not correlated with nodal metastases statistically. In conclusion, esophageal
SCC produces SEE from the early stage by infiltrative growth and lymphatic
invasion of tumor cells. The detection of lymphatic invasion on D2-40 immunostaining in the mucosal edge of SEE is useful for
evaluation of endoscopic mucosal resection tissue.
Pathology International, 57(12):759-764, December 2007.
Validation of World Health Organization/International Society of
Urologic Pathology 2004 Classification Schema for Bladder Urothelial
Carcinomas using Quantitative Nuclear Morphometry:
Identification of Predictive Features using Bootstrap Method
Kapur
U, Antic T, Venkataraman G,
et al
OBJECTIVES: Despite the introduction of the new World Health Organization 2004 grading classification, the grading of urothelial carcinoma remains difficult and subjective. The aim of this study was to evaluate the role of computer-assisted image morphometric analysis as a tool to improve the objectivity of histologic grading of urothelial carcinoma.
METHODS: A total of 75 urinary bladder biopsies from a cohort of patients with a first-time diagnosis of urothelial carcinoma representing low-grade (n = 19) and high-grade (n = 56) urothelial carcinoma were evaluated. Quantitative nuclear morphometry was performed on these biopsies using approximately 80 to 100 cells per case. A total of 17 nuclear morphometry features were extracted, and a bootstrap-based predictor selection using stepwise logistic regression analysis was performed. Subsequently, a validation was performed using the five top features from the logistic regression analyses by implementing a nonparametric discriminant analysis to identify the most discriminative features that predicted for high-grade cases.
RESULTS: The bootstrap technique included nuclear pleomorphism as the most frequently selected predictor of high-grade urothelial carcinoma (in 213 of 500 replicates). Validation using the top five features in the logistic regression analysis method (pleomorphism, configuration run length, DNA mass, feret-Y, and age) using discriminant analysis gave a resubstitution error of 4%, indicating the usefulness of the selected predictors.
CONCLUSIONS: The present study is the first to provide a morphometric validation of the World Health Organization 2004 system for pathologic grading of bladder cancer. Furthermore, quantitative nuclear morphometry could aid in the objective grading of urinary bladder biopsies. This information might aid the treating physicians in better risk stratification of patients with urothelial carcinoma.
Urology,
2007 Nov; 70(5):1028-33.
New Binary System of Grading
Oral Epithelial Dysplasia
[News in Brief]
Oral mucosa carcinogenesis, manifested histologically as progressive squamous dysplasia, results from cumulative genetic and epigenetic alterations induced by exposure to carcinogens, particularly alcohol and tobacco, and less commonly by oncogenic human papilloma viruses.
The current histopathologic grading of oral epithelial dysplasia (OED) lesions is notoriously unreliable, primarily because dysplasia can be seen as a spectrum that cannot be precisely divided into mild, moderate, and severe categories by any reproducible criteria, thus fueling the search for better grading systems and diagnostic aids. Although a widely recognized study has shown the high predictive value of DNA aneuploidy in OED, histopathologic evaluation based on morphologic criteria remains the routine method for diagnosing and grading OED.
Recently, Kujan et al proposed and evaluated a new binary system for grading OED that describes lesions as either high risk (having the potential for malignant transformation) or low risk (not having this potential). In their study, the authors assessed interobserver variability on the agreement of diagnosis, the grading of OED lesions, and predictive value in terms of progression to malignancy by using both their proposed binary system and the World Health Organization (WHO) Classification of Tumours (2005). The authors evaluated their new system according to the morphologic criteria (architectural and cytologic changes) provided in the WHO classification. They graded lesions as low grade or high grade by scoring the features. The cutpoint for a high-risk lesion was at least 4 architectural changes and 5 cytologic alterations. The cutpoint for a low-risk lesion was less than 4 architectural changes or less than 5 cytologic changes. Four observers blinded to the clinical outcome reviewed the same set of hematoxylin-eosin stained slides of 68 OED lesions using the 2 grading systems.
The overall interobserver unweighted and weighted [kappa] agreement values for the WHO grading system were [kappa]s=0.22 [95% confidence interval (CI), 0.11-0.35] and [kappa]w=0.63 (95% CI, 0.42-0.78), respectively, whereas [kappa]=0.50 (95% CI, 0.35–0.67) for the new binary system. The sensitivity and specificity of the new binary grading system for predicting malignant transformation in OED were 85% and 80%, respectively, and the accuracy was 82%. The authors were able to predict clinical outcome with certainty in 84.8% (28 of 33) of dysplastic lesions, whereas the negative predictive value of the new binary system was 85%. All pathologists showed satisfactory agreement about the distinction between mild and severe dysplasia and carcinoma in situ, using the most recent WHO classification. However, the assessment of moderate dysplasia remains problematic.
The new 2-scale grading system distinguished between 2 subtypes of moderate dysplasia according to clinical outcome. Of 16 patients with moderate dysplasia that was described as high risk, 14 (87.5%) developed oral squamous cell carcinoma. These results further demonstrated that patients with high-risk OED lesions tended to have significantly greater transformation rates than did those with low-risk lesions (P=0.004 by log-rank test). In contrast to those of other studies, the results of the binary grading system suggest that the new system has the potential to help clinicians make more appropriate treatment decisions for patients with OED.
The authors concluded that (1) the new binary grading system complements the 2005 WHO Classification of Tumours and may help clinicians make critical clinical decisions, particularly for patients with moderate dysplasia; (2) more consensus on the degree of dysplasia, the clinical prediction, and the presence of each morphologic characteristic can be achieved by joint sessions behind the microscope and should be encouraged; and (3) further research to evaluate the new binary grading system in prospective multicenter settings is needed.
Advances in Anatomic Pathology, Volume
15(1), January 2008, pp 61-62
Will
Micro RNAs Become a New Class of Tumour
Marker?
A particular group of molecules generated renewed
interest in 2002: micro RNAs (miRNA).
These are short, non-coding RNA molecules playing regulatory roles in animals
and plants by repressing translation or cleaving RNA transcripts. The rationale
behind this phenomenon is: destroy the mRNA that will be translated in viral
proteins so that viral replication is blocked. The idea itself is not new. RNA interference
(RNAi) is a mechanism of post-transcriptional gene
silencing (PTGS) that was described earlier in plants, invertebrates and
mammalian cells. It protects plants, fungi and lower organisms (worms and
flies) against invading genetic elements such as transposons,
transgenes and viruses. These small molecules have
generated renewed interest as they now have the potential to become a
completely new class of tumour markers, for the
specific modulation of several microRNAs has been
recently associated to some forms of human cancer.
After the discovery of micro RNAs,
the eyes of the scientific world turned towards viruses and their destruction.
In a paper published in June 2002, Novina et al . described a series of tests that showed how RNAi pathways could be exploited as anti-HIV therapy. The
purpose of the first test was to silence CD4 expression (by blocking the host
cell's mRNA that codes for the structural protein CD4) and thus prevent HIV
entry, but later tests showed that the viral proteins could also be blocked
out, thus inhibiting viral multiplication.
Later, several examples of an existing
association between specific miRNAs and cancer were
shown. miR-15 and miR-16 are either absent or
down-regulated in a majority of chronic lymphocytic leukaemias (CLL). Researchers also showed that 52.5% of
human miRNA genes are frequently located at fragile
sites or genomic regions involved in cancers. Other papers reported reduced
accumulation of miR-145 and miR-143 in colorectal neoplasia.
In children with Burkitt's lymphoma, a high
expression of precursor miRNA 155/BIC RNA is found,
and there is a reduced expression of let-7 miRNA in
human lung cancers. Compared to proteins, miRNAs have
a number of advantages as biomarkers, because the human body has relatively few
miRNAs compared to the manifold number of proteins,
so it is possible to screen the entire genome for all miRNAs.
In addition, only about 200 genes are needed that may have a significant role
in biological processes.
Recently, Ciafrè et
al. examined 245 microRNAs in glioblastoma multiforme, the most
frequent and malignant of primary brain tumours. The
analysis of both glioblastoma tissues and glioblastoma cell lines allowed a group of microRNAs to be identified whose expression is
significantly altered in this tumour. The most
interesting results came from miR-221, strongly upregulated
in glioblastoma, and from a set of brain-enriched miRNAs, miR-128, miR-181a, miR-181b, and miR-181c, which
are down-regulated in glioblastoma. Moreover, it has
recently been found that the pattern of miRNA
expression varies dramatically across tumour types
and that miRNA profiles reflect the developmental
lineage.
All this
research indicates clearly that micro RNAs may
function as tumour markers in the future and that RNA
inhibition could be a new anti-cancer therapy.
Clinical
Laboratory International, cli-online.com
CLINICAL PATHOLOGY
Comparison of the Erythrocyte Sedimentation Rate
Measured by the Micro Test 1 Sedimentation analyzer and the Conventional Westergren Method
Serap Arikan, Nalan
Akalin
BACKGROUND: The
erythrocyte sedimentation rate (ESR) remains the most widely used laboratory
test for monitoring infections, inflammatory diseases and some types of cancer.
Several test methods have been developed recently, and as a result, the safety
and reliability of ESR testing procedures have improved. The purpose of this
study was the comparison of two methods, the traditional manual Westergren method (reference method of the International
Committee on Standardization in Hematology) and a new semiautomated
technique, the Micro Test 1 for determining the ESR.
SUBJECTS AND METHODS:
Blood samples were collected after a night’s fasting from 200 hospitalized and
ambulatory patients. Undiluted blood samples anticoagulated
with K3 EDTA that had Micro Test 1 values ranging from 2-82 mm/h were used for
comparison with the Westergren method.
RESULTS: Linear
regression analysis comparing the Micro Test 1 and the reference method yielded
satisfactory correlations and regression for samples (r=0.910; P=0.0001;
y=4.91+0.86 x; Sy/x=6.85). A Bland-Altman analysis
showed no evidence of systematic bias between the Micro Test 1 and the
reference method.
CONCLUSION: The Micro
Test 1 system was easy to use, had a satisfactory operative practicability,
required minimal maintenance, and reduced contact with potential biohazards.
DISCUSSION
The ESR test is one of
the most common and traditional laboratory tests in the world. The method is
easy to perform and inexpensive and therefore it is used as a routine test for
many clinical conditions worldwide. The ESR should be used only as a clinical
guide to aid the diagnosis, management, and follow-up of these different
clinical situations. In 1988, the ICSH described an ESR validation procedure as
well as a method for producing ESR reference material in the laboratory. To
determine the factors affecting ESR values, correlations were analyzed between
the ESR obtained by the standard Westergren method
for red blood cell concentration, haematocrit, and
plasma proteins including fibrinogen, albumin and globulins. The ESR has some
disadvantages since it requires a large volume of sodium citrate and at least 1
hour of testing time. In this context, several kinds of simple, rapid and safe
methods have been developed. These methods offer the advantages of speed,
safety, and uniform specimen handling. Systems utilizing sedimentation columns
less than 200 mm in length may be less sensitive to changes at higher ESR than
the Westergren method. In our study, Micro Test 1
results correlated satisfactorily with the ICSH recommended method. The Bland-Altman
analysis showed no evidence of a systematic bias between the Micro Test 1 and
the reference method. The mean difference that we found of 2.38 in our study is
nearly the same with the studies performed with Micro Test 1. This difference
can be explained with higher values measured with Micro Test 1 at elevated ESR
values (>25 mm/h). In our comparison of Micro Test 1 and the standard method
of Westergren, good agreement was obtained. The Micro
Test 1 technique produced results similar to those obtained by the Westergren method. The probability of obtaining the same
results for all samples using the two different methods to measure the same
parameter is unlikely, but it is possible to find the differences between the
results of the new and the reference method. If this difference does not affect
the interpretation, then one could use the two measurements. In addition, due
to its operational characteristics it is a suitable tool for clinical
laboratories with a high workload as well as for emergency laboratories. The
Micro Test 1 system was easy to use, had a satisfactory operative
practicability, required minimal maintenance, and reduced contact with
potential bio-hazards.
Ann Saudi
Med 2007; 27(5): 362-36
BOTTOM LINE
Pathology
and the Humanities
Michael B. Cohen
“Medicine, that
subdivision of the humanities.” - Thomas Mann
“The Language of Cells: Life
as seen under the Microscope” by Spencer Nadler, a retired pathologist in the
The
1910 Flexner Report ushered in the scientific era of medicine in this
country. Abraham Flexner,
a former secondary school teacher
and principal who later founded the Institute
for Advanced Studies
at Princeton which
Albert Einstein joined in 1933, used Johns Hopkins University as his
model.
Over the
last 2 decades
there has been
a growing pushback to
reintroduce more of the humanistic aspects into medicine. I
believe at its
core humanism is
about the caring physician, and
pathologists do wonderful things for
patients, most often indirectly. Unfortunately, humanism is only a small to
modest part of the current medical student curriculum, largely
ignored during pathology
residency training, and has largely escaped the everyday practice of our
specialty. In short, humanism in pathology receives little, if any, attention. A PubMed search of
“humanism and pathology”
(accessed June 20, 2007) turned up 24 citations not one
of which was
in a pathology
journal. Similarly, whereas a
Google search engendered
about 274000 hits a
perusal of the
first few pages
did not uncover
anything meaningful (accessed June 20, 2007). A few of the Google hits
identified an important link to the Arnold P. Gold Foundation and a specific
faculty member in a pathology department.
The foundation (http://humanism-in-medicine. org/ ), a public foundation fostering humanism in medicine, has as its
mission “to perpetuate the tradition of the caring doctor” and has become a
cornerstone in the reestablishment of humanism to the next generation of
physicians. The Gold Foundation does not have a role in humanism in pathology
per se.
Literature is one form of
the arts from which we can learn about
humanism in medicine.
There have been
many physician writers such as Anton Chekhov, William Somerset
Maugham, and William
Carlos Williams (the
latter is, of course,
best known for
his poetry) who
have shared their experiences through
their writing. More recently, Richard Selzer,
Oliver Sacks, Jerome Groopman, and Atul Gawande, among others, have
followed that rich tradition. There are, however, relatively few pathologist
writers, and pathology and literature have received little attention in our
professional journals. One notable exception
is Walker Percy,
a gifted writer who wrote The Second Coming, but is
probably best known for The Moviegoer.
Percy contracted tuberculosis while doing an autopsy as an intern and
thereafter switched careers. Percy described himself as a pathologist of modern
culture and
in The Second
Coming addresses the
tension between the art
and science of
medicine. Lewis Thomas was a
pathologist and later the head of
Human
Pathology (2008) 39, 1–2