Molecular oncology tumor board: Pathologist, oncologist dip into head and neck case

Karen Lusky

February 2022—Up first in a CAP21 molecular oncology tumor board session was an unusual case of head and neck cancer, one that raises questions about what salivary duct carcinoma is and the role of next-generation sequencing.

Justin Bishop, MD, the Jane B. and Edwin P. Jenevein, MD, distinguished chair in pathology and professor and chief of anatomic pathology, UT Southwestern, along with Saad Khan, MD, assistant professor of medicine (oncology) at Stanford, teamed up to present the case, along with a second case that will be reported in the March issue. (Dr. Khan practiced at one time at UT Southwestern, so this wasn’t their first tumor board together.)

Dr. Khan described the first case as one in which “pathologic diagnosis remains a real challenge, where using traditional stains is very difficult, and the clinical behavior is uncertain.”

The case is that of a 56-year-old woman who presented after three years of left parotid mass enlargement slowly growing over time. An FNA indicated epithelial cells in a stromal background suggestive of a salivary gland neoplasm of unclear etiology. CT imaging indicated an asymmetrically enlarged left parotid mass with enlarged cervical lymph nodes on the same side. The recommendation was surgical resection with removal of lymph nodes.

In the parotid gland (Fig. 1) were what Dr. Bishop said appear to be multifocal masses. “Some of these end up being lymph nodes,” but there are “very irregular tan white-appearing masses on gross examination.”

On histology, at low power (Fig. 2), they see it is a “bad tumor,” he said, “very infiltrative,” with skeletal muscle at bottom right. “This tumor is invading quite extensively beyond the parotid gland into nearby periparotid tissues as these kind of variably sized nests and cords of cells.” At top center he noted the comedo-type pattern necrosis.

In Fig. 3 Dr. Bishop noted the infiltrative nests and cords of cells, and (at bottom and top right) cystic-like areas with “interesting architecture, this lollipop projecting into the cysts,” and a kind of “Roman bridging, and an apocrine-looking snout formation.” Perineural invasion was not difficult to find (Fig. 4). “So this is a very aggressive, high-grade tumor,” Dr. Bishop said.

At high power (Fig. 5), they notice the tumor cells have “abundant pink eosinophilic cytoplasm with a slight hint of granularity,” he said. There is some nuclear pleomorphism but the nucleoli are large. The chromatin is vesicular; many have a single prominent nucleolus. There’s “almost a vaguely squamoid look in areas, but no overt squamous differentiation at the histologic level.” Enlarged lymph nodes were seen on CT exam. “And some of the lymph nodes in the neck dissection were positive for metastatic tumor.” (Fig. 6).

The differential diagnosis consists of salivary duct carcinoma, squamous cell carcinoma, high-grade mucoepidermoid carcinoma, metastasis, and high-grade adenocarcinoma not otherwise specified.

With p40 immunostaining (Fig. 7) the majority of the tumor is negative, he said, which rules out squamous cell carcinoma and mucoepidermoid carcinoma. In some of the cribriform areas (top left), “there appears to be a residual myoepithelial cell layer around it, suggesting this was either a precursor in situ lesion or, more likely, it’s extension of the tumor within a duct secondarily,” Dr. Bishop said.

BRST2 was strongly positive (Fig. 8). That the patient is a woman and BRST2 is a breast marker could suggest a metastasis from the breast, he said, but the estrogen receptor and progesterone receptor were negative. “And in fact the androgen receptor was incredibly strongly positive.” The BRST2 and androgen receptor, in addition to the morphology, indicated to Dr. Bishop that it was a high-grade carcinoma with apocrine differentiation.

It was sent out for next-generation sequencing to look for targetable alterations, “and this surprisingly had an ETV6-NTRK3 fusion, which was unexpected because this is the defining fusion for a mammary analogue secretory carcinoma.” Although not required, pan-TRK immunohistochemistry was done (Fig. 9). “And sure enough, this had diffuse nuclear staining.” (ETV6 rearrangement studies also could have been done, he noted, and they too would have been positive.) “So the final diagnosis in this case ends up being a high-grade salivary duct carcinoma harboring an ETV6-NTRK3 fusion. A very unusual case,” Dr. Bishop said.

Parotid masses can be static for a long time, Dr. Khan said, but then suddenly begin to change. “And there almost is a disconnect between the clinical course and the pathologic appearance, where it looks like it should be a very benign, almost non-malignant neoplasm. But when you look at the areas of necrosis, the invasion into the surrounding muscles and vasculature, you are shocked it’s been there for three years and didn’t double or triple in size during that time.”

In this case, he said, the ETV6-NTRK3 fusion was not only critical in reaching the correct diagnosis but has significant treatment implications. Refining the diagnosis makes it possible, Dr. Khan said, “to parse out those salivary gland cancers that we think may be susceptible to broad-based anti-DNA destructive agents such as cisplatin and radiation, versus those that may be more precisely targeted genomically,” which increasingly in salivary gland cancers are able to be identified only with NGS.

More and more salivary duct carcinomas are known to have fusions, Dr. Bishop agreed, and he said it has “humbled” him because he thinks of these fusions as being defining of lower-grade tumors. “ETV6-NTRK3 fusion means secretory carcinoma, for example, and yet we are starting to find these in salivary duct carcinomas. And it’s not only ETV6-NTRK3. We have found assorted RET fusions and even ALK fusions in some salivary duct carcinomas, all of which are targetable,” he said.