A 'Rara Avis' has flown under my microscope

I was recently sent a specimen from the cerebellum of a 27-year-old female patient who, during a routine funduscopic exam at her optometrist, was found to have papilledema and retinal hemorrhages. She was completely asymptomatic -- which of course suggests that we are dealing with a slowly progressive process. A head MRI was obtained:

An image-guided craniotomy ensued, yielding a cerebellar specimen. Photomicrographs of that specimen, at progressively higher magnification, follow:

The top picture exhibits normal cerebellar cytoarchitecture on the right giving way, on the left, to an internal granule cell layer that has transformed into larger gangliocytic neurons. The bottom picture demonstrates the cytologic appearance of these transformed ganglion cells.

This is an example of dysplastic cerebellar gangliocytoma, otherwise known as Lhermitte-Duclos disease (LDD). Dr. Peter Burger and colleagues, in their Surgical Pathology of the Nervous System and Its Coverings (4th edition, page 274), make this comment about LDD: "In the parlance of bird-watching, an endeavor with many similarities to surgical pathology, Lhermitte-Duclos disease is an entity not likely to be found on the 'life-list' of most pathologists." Well, this rara avis is now on my life-list!

When I came upon this tumor, I immediately thought of Dr. Ty Abel (pictured to the left), neuropathologist at Vanderbilt, who in 2005 authored an immunohistochemical study of 31 cases of Lhermitte Duclos disease. I emailed him this question: "What is the current thinking on LDD? Is it a hamartoma or a neoplasm or something in between?"

Ty's response: "Something in between may be the best answer. We suggested in our paper that it was a 'hypertrophic phenomenon superimposed upon a developmental malformation'. Our observations, as well as those in Suzie Baker's mouse model of this, suggest that aberrant signaling in the pathway disrupts granule cell migration as well as leading to their hypertrophy. Histologically, there is little proliferation, so the increase in tumor size over time may be due to cellular hypertrophy or to the abnormal myelinization of the molecular layer or both.Still, they do grow and sometimes come back after resection, making them tumor-like. Does your patient have evidence of Cowden's?"

No, my patient does not have other clinical evidence of Cowden syndrome. But Ty put me in touch with a leading authority on Cowden syndrome at the Cleveland Clinic, Dr. Charis Eng (pictured to the right) who emailed me this comment: "What we found in our initial series is that adult-onset LDD is almost always associated with germline PTEN mutations, i.e., has Cowden syndrome."

Whether or not this patient gets germline PTEN testing, she should be closely surveilled for breast, thyroid, and endometrial cancer, as there is a high incidence of these tumors in patients with Cowden syndrome.

And now a recut slide of this rare bird gets filed away in my teaching set, only to be let out of its cage again by the eager inquiry of a resident.