Parathyroid tumors develop alternative blood vessel networks characterized by reduced or absent CD31 expression as they progress from benign to malignant lesions, according to a study published in the Journal of Clinical Pathology.
Researchers evaluated 99 parathyroid specimens, including 4 normal glands, 50 adenomas, 35 atypical tumors, and 10 carcinomas, using CD31/Periodic acid-Schiff double staining to assess microvessel density, mosaic vessel density, and vascular mimicry density.
"'Alternative' vessel identification in parathyroid tumors is crucial because it explains the paradox of nonangiogenic tumors, consisting in a new bloody nonendothelial vessel network and helps pathologists to unmask worrisome lesions," wrote lead author Monica Falleni, of the Unit of Pathology at the University of Milan, ASST Santi Paolo e Carlo in Milan, Italy, and colleagues.
Microvessel density increased in adenomas compared with normal tissue but declined in atypical tumors and was lowest in carcinomas, showing a significant inverse relationship across the four groups with neoplastic progression.
In contrast, mosaic vessels and vascular mimicry vessels, which were absent in normal tissue, appeared in nonbenign parathyroid lesions. Isolated and peripheral mosaic vessels were observed in 16% of adenomas, with significantly higher densities in atypical tumors and carcinomas compared with adenomas. Vascular mimicry vessels were absent in normal parathyroid tissue and adenomas but were found in 46% of atypical tumors and in all carcinomas.
Vascular mimicry density was higher in carcinomas than in normal glands and adenomas, with significant increases also seen in atypical tumors. Density rose progressively across tissue groups and correlated directly with neoplastic progression, with nonbenign lesions showing more vascular mimicry vessels than benign tumors. Declining microvessel density in atypical tumors and carcinomas was inversely related to increases in mosaic vessel and vascular mimicry densities. Adenomas showed a homogeneous vascular pattern, whereas borderline and malignant lesions displayed irregular, predominantly peripheral vessels with vascular rarefaction and irregular lumina.
Glycophorin A-positive erythrocytes were documented in both classic and alternative vessels in all cases, confirming blood perfusion throughout the neoplastic network, even in nonangiogenic areas lacking CD31 immunoreactivity.
The study cohort included 99 patients: 28 men and 71 women aged 20 to 85 years (median age, 59 years), diagnosed at the Division of Pathology of San Paolo Hospital, University of Milan, Italy, from 2012 to 2022. None of the patients had cancer or received chemotherapy or radiation therapy before surgery.
Histological definition of parathyroid tumors was performed according to the 2022 World Health Organization histopathological classification. Adenomas were benign, well-circumscribed masses composed of an mixture of chief, oncocytic, transitional, or water-clear cells, with absent or sparse stromal fat. Atypical tumors were worrisome neoplastic growths sharing with carcinomas atypical cytological and architectural features and increased mitotic activity exceeding 5 mitoses per 50 high-power fields, but lacking unequivocal capsular, vascular, or perineural invasion or invasion into adjacent structures or metastases.
CD31 cytoplasmic or membrane immunostaining was detected in neoplastic cells of all categories investigated. The staining appeared very faint and finely granular in adenomas but increased in atypical tumors and carcinomas, where it appeared as coarse cytoplasmic granular deposits. Glycophorin A cytoplasmic immunoreactivity was detected in 3 carcinomas (33%).
Patients with atypical tumors and carcinomas underwent follow-up programs. The median follow-up was 68 months (range, 20 to 264 months) for atypical tumors and 56 months (range, 33 to 165 months) for carcinomas. None of the patients developed recurrences or distant metastases.
The researchers noted that vascularization of parathyroid tumors was investigated only in 2 studies about 20 years ago. Those studies reported that adenomas were highly hypervascularized compared with control tissue, while carcinomas showed an apparent paradox with a very low angiogenic profile similar to other aggressive endocrine carcinomas.
The current findings suggest that CD31-dependent vascularization progressively disappears during parathyroid neoplastic evolution to cancer, with intermittent CD31-positive mosaic vessels replacing classic vascularization before giving way to the CD31−negative/PAS-positive channels of vascular mimicry in carcinomas. The biological relevance in atypical tumors is that in mosaic vessels, some tumor cells are directly exposed to blood flow with possibility to disseminate, thus explaining the metastatic potential of these lesions. Vessels of vascular mimicry in parathyroid carcinomas can elucidate how low-angiogenic cancers can metastasize.
Study limitations include the lack of data on biomolecular pathways involved in the origin and organization of new neoplastic parathyroid perfusion. The pathogenesis of mosaic and vascular mimicry vessels, and whether mosaic vessels anticipate the channels of vascular mimicry during neoplastic progression toward cancer, remains a matter of debate.
The researchers emphasized that detection of alternative vascular systems in human tumors might explain the limited success of antiangiogenic therapies and encourage new oncological studies.
The authors declared no conflicts of interest or funding sources.
Source: Journal of Clinical Pathology
