Intraoperative Cytology and Frozen Section Pathology of Cushing's Disease Are Useful Additional Diagnostic Tools

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About 90% of pituitary tumors in patients with Cushing's disease are microadenomas, which are often difficult to identify using magnetic resonance imaging (MRI). Surgical exploration may not provide adequate tissue for pathologic diagnosis—up to 35% of tumors can't be confirmed using standard techniques—and failure to detect tumor intraoperatively is a risk factor for persistent hypercortisolism.

In an attempt to preserve all available tissue for pathologic confirmation, starting in 1999, Massachusetts General Hospital began to have cytological smears and/or touch preps prepared by the surgeon at the operative field and sent to the pathology laboratory for intraoperative evaluation. If an adenoma is identified, further specimens from the presumed tumor bed are later sent for frozen section analysis, followed by paraffin histology if enough tissue is available.

Nicholas A. Tritos, MD, DSc, neuroendocrinologist in the Department of Medicine, Nidan Qiao, MD, clinical researcher, Brooke Swearingen, MD, neurosurgeon in the Department of Neurosurgery and neurosurgical oncologist at the Mass General Cancer Center, and Tessa Hedley-Whyte, MD, pathologist in the of the Department of Pathology at Mass General and the Mass General Cancer Center, documented that their approach is a useful additional diagnostic tool. Their report appears in Endocrine Pathology.

Study Details

The researchers reviewed 341 patients with Cushing's disease attributed to a microadenoma (<1 cm) who underwent a total of 403 transsphenoidal surgeries between 1999 and 2017. Dr. Swearingen performed all the procedures. 177 surgeries involved MRI-equivocal tumors.

Utility of Frozen Sections

Intraoperative frozen sections were performed in all cases: 105 operations with an obvious tumor, 52 with no visible tumor at surgery and 246 with an ambiguous or minute tumor. The concordance rate between frozen section and paraffin section histology was 97%. The concordance rate was similar between MRI-equivocal and -unequivocal tumors.

Utility of Cytological Pathology

Intraoperative cytology was performed in 246 operations. The concordance rate between cytology smear and paraffin section histology was 87%. Again, the rate was similar between MRI-equivocal and -unequivocal tumors.

Rate of Pathologic Confirmation

Pathologic confirmation was obtained in 81% of operations by at least one of the three modalities. By comparison, the rate of pathologic confirmation was:

• 67% in 70 operations performed at Mass General between 1990 and 1998, before intraoperative cytology was introduced (P = 0.015)
• 72% in a meta-analysis of published data (1999 to present) conducted by the researchers (P < 0.001)

Outcomes

The remission rate was 79% and the 5-year recurrence-free survival rate after initial surgery was 83%. Outcomes in the historical control group and meta-analysis were similar to these.

In 54 operations (13%) associated with ultimate remission, pathologic confirmation was obtained only on intraoperative frozen section or cytology. This suggests cytopathology and intraoperative frozen section may increase the diagnostic yield of adenoma detection in Cushing's disease.

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