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The Evolving Role of Molecular Diagnostics in Surgical Pathology and Cytology

Silverman, Jan F. MD

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doi: 10.1097/PCR.0000000000000020
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It has been said that molecular diagnostics is the future of diagnostic anatomic pathology. We believe that in many ways the future has arrived. This issue of Pathology Case Reviews is dedicated to an update on current and emerging uses of molecular diagnostics in surgical pathology and cytology.

Drs Elsheikh and Rossi discuss the current utilization of molecular testing in the workup of indeterminate fine-needle aspirations of the thyroid. The authors present the value and limitations of current testing platforms and discuss how molecular testing can contribute to the patient’s management as an ancillary tool, but not as a reflex test. This article is followed by Dr Silverman and Elsheikh discussing the value of molecular analysis in the workup of metastasis of unknown primary. Metastasis of unknown primary origin is not uncommon, occurring in up to 10% of all noncutaneous malignancies. Routine histology, cytology, and immunohistochemistry can often make the correct diagnosis, but there is a percentage of patients in which the primary site cannot be identified. Therefore, molecular assays have been proposed as a better alternative in these challenging cases. The authors discussed the value and limitations of commercial testing as well as the concept that future targeted therapies may rely not on the identification of the primary site in cases of metastasis of unknown primary origin, but on identification of the molecular signature of the malignancy.

Her2-neu oncoprotein is expressed in up to 20% of breast cancers, and testing and treatment for Her2-neu–positive breast carcinoma are the standard of care when Her2-neu gene amplification is identified. Krishnamurti and Silverman discuss the significance of centromere 17 copy number alteration without Her2neu amplification and its treatment implications. Another problematic topic area in the breast carcinoma literature is the clinical significance of micrometastasis to sentinel/regional lymph nodes. There is considerable controversy over whether micrometastasis represents iatrogenic displacement of cancer cells from the primary site to the draining lymph nodes secondary to a core needle biopsy or a true metastasis. Up until this time, definitive separation of these 2 scenarios has not been possible. Dr Bokhari et al present a novel approach to determining whether micrometastasis represents displaced malignant cells or a true metastasis using molecular analysis with its pathologic staging and treatment implications.

Pancreatic cysts represent a diverse group of lesions that vary in its clinical, radiological, and pathologic findings. Molecular diagnostics has been assuming a greater role in the workup of pancreatic cysts, especially when the cytologic examination is indeterminate because of acellular or paucicellular specimens and/or atypia that may represent reactive atypia or a dysplastic process. Drs Deftereos et al discuss the molecular diagnostic testing of pancreatic cysts, which when used in combination with carcinoembryonic antigen levels and cytology can better classify these lesions. Drs Bivin et al take a similar approach in discussing the value of molecular diagnostics in the workup of Barrett esophagus and progressive lesions such as low- and high-grade dysplasia and carcinoma. Standard histologic examination and the determination of the degree of dysplasia often is not definitive with considerable interobserver variability. The authors present the role of molecular studies in better stratifying these lesions with obvious surveillance and treatment implications. Finally, Dr Dacic presents the role of molecular testing in the workup of non–small cell lung carcinoma, which has become the standard of care in many centers. Dr Dacic’s review discusses testing for EGFR and ALK and its association with different subtypes of non–small cell lung cancer as well, EGFR resistance, and whether immunohistochemistry has any role in determining the status of these mutations.

I would like to thank Dr Stephen Silverberg for the opportunity to present this timely and contemporary topic on molecular diagnostics. Yogi Berra once said, “The future ain’t what it used to be,” and that is certainly true as we discuss the continuing evolution of molecular testing in surgical pathology and cytology.

© 2014 by Lippincott Williams & Wilkins.