The role of diagnostic pathology has expanded from mere morphologic
observation. During the last part of the twentieth century, advances
in molecular biology and cell biology have provided us with an understanding
of
the mechanisms of disease at the molecular level. This understanding
can now be translated into diagnostic, prognostic, and therapeutic
tools. It is now possible to phenotype and genotype human tumors
to increase the accuracy and reproducibility of pathologic diagnosis.
Abnormal molecules not only provide a signature for the presence
of a disease, but may also provide the indication for a drug targeting
the specific abnormal function. This circumstance creates a particularly
tight link between diagnostics and therapeutics.
The Laboratory of
Molecular Diagnostics in the Department of Pathology at Yale University
aims to provide a broad menu of tests probing molecular structure and
function in diseased tissues and biological fluids. Contributions of
molecular testing have been particularly dramatic for
the diagnosis of hematolymphoid neoplasms and are becoming increasingly
important in the evaluation of solid tumors.
One of the preeminent
areas of application of molecular diagnostic testing is oncology. Small
numbers of malignant cells can now be detected in cytological preparations
or biopsies through the clinically validated use of clinical markers.
Yale‘s program in Molecular Diagnostics is constantly translating
new discoveries and novel technologies into useful clinical tests that
provide a molecular fingerprint of tumors and that are predictive of
the response to specific therapies.
The detection of clonally rearranged antigen receptor genes in lymphoid
cells is a powerful tool for establishing a diagnosis that can be performed
on limited amounts of tissue or fluid. In addition, to establish primary
diagnoses, genotyping can effectively detect minimal residual disease
and classify lymphoma subtypes. Somatic genetic alterations of solid
tumors are also finding useful clinical applications. Characteristic
mutations can be used as markers for the detection of very small numbers
of tumor cells in small samples (endoscopic biopsies or fine needle
aspirates) to increase the sensitivity and accuracy of pathologic diagnosis.
In specific instances (e.g. selected soft tissue and pediatric tumors),
mutational profiling provides a basis for diagnosis and subclassification.
Molecular signatures can also be important for the detection of minimal
residual or recurrent disease and can help distinguish a metastasis
from a second primary tumor.
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Frequently asked questions by patients:
What types of conditions can molecular diagnostics test for?
Most commonly the tests are used to diagnose lymphoma. Tests are also
available for diagnosis of pancreatic tumors and for comparing two tumors
to determine if one is a metastasis. New tests for other conditions
are also under constant development.
How accurate are the tests?
The tests are highly accurate and sensitive. When interpreted within
the appropriate clinical situation and combined with other diagnostic
procedures, these tests can help your health care providers diagnose
lymphomas and other tumors earlier so that appropriate treatment can
be started.
What are the advantages of molecular diagnostic testing?
As a patient, you will appreciate the fact that molecular diagnostic
testing can be performed on very small amounts of tissue obtained from
many different types of procedures, including small biopsies and fine-needle
aspirates. Testing can even be performed on archival material (material
that has been collected in the past and fixed in formalin). It is usually
not necessary to take extra tissue for these tests, since most of them
can be performed on tissue that is left over after routine diagnostic
analysis.
Does the laboratory matter?
Unlike commercial laboratories, Yale Pathology Labs are able to maintain
a close interaction between the specialist faculty of the Cytology and
the Surgical Pathology services. Fully trained in both molecular diagnostics
and pathology, our pathologists can ensure interpretation of molecular
testing within the appropriate clinical context.
Frequently asked questions by physicians:
Can a molecular test enhance the diagnostic efficacy of a
cytology sample containing “suspicious” cells?
Work done by Yale clinical investigators has demonstrated that cytological
specimens categorized as “suspicious for malignancy” by
morphological examination can be classified as either positive or negative
by assessing the percentage of cells harboring a mutated allele (Deborah
Dillon, M.D., et al. ACTA CYTOLOGICA, 46, no.5 (Sept-Oct 2002): 841-747).
A patient presents with an undifferentiated metastasis and
past medical history indicates two independent primary tumors. Can
molecular diagnostics
help identify the origin of the metastatic deposit?
In some instances, “molecular fingerprints” that can be
attributed to a given histological type can unequivocally help establish
the origin of a metastasis. This approach can be used not only for
sorting out the origin of a secondary deposit, but also for differentiating
a metastasis from a “second primary.”
