The case with associated descriptions was previously shown during a slide seminar entitled “The lesson hidden in a single case” during the 2023 European Congress of Pathology in Dublin, Ireland.
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Case History
A male in his early thirties, without any prior medical history, presented with a history of fatigue. Upon examination, mild hypercalcemia and elevated levels of parathyroid hormone (PTH) were observed. The patient was subsequently referred to our endocrine surgery department. Ultrasound and sestamibi scintigraphy revealed an enlarged right superior parathyroid gland measuring 20 mm. The patient had no family history suggestive of parathyroid disease or MEN1-related manifestations. A focused parathyroidectomy was performed.
During gross examination, the weight was 1.1 g. The gland measured 20 × 15 × 7 mm and displayed a brownish cut surface. No macroscopic features indicative of malignancy, such as a grey/white cut surface or unclear relations to the surroundings, were observed. The entire tumor was submitted for microscopic evaluation.
Histology revealed a hypercellular parathyroid gland characterized by chief cells arranged in microacinar patterns and solid areas containing eosinophilic cells (Fig. 1A). The stromal fat content was diminished. Notably, there was a general absence of mitotic activity and tumor necrosis. The tumor was circumscribed, and invasive growth was not observed. No atypical histological features such as trabecular growth, fibrous bands, or prominent nuclear pleomorphism were noted. Upon closer examination, the eosinophilic cells exhibited a distinct pinkish cytoplasm but lacked the characteristic cytoplasmic granularity of oxyphilic cells (Fig. 1B). Additionally, these cells showed perinuclear cytoplasmic clearing (“halo”). Some regions also displayed microcystic features and arborizing vasculature (Fig. 1C, D). These morphological features have been associated with parafibromin-deficient parathyroid tumors [1]. Tumor cells were positive for PTH and APC but negative for galectin-3 and PGP9.5 (Fig. 2A). The Ki-67 index was low (2.4%). Parafibromin exhibited positive staining in cells at the tumor margin and in the majority of chief cells (Fig. 2B). However, the nuclear stain was negative in the eosinophilic cell component, displaying a vague, granular cytosolic stain, interpreted as aberrant (Fig. 2C, D).
The favored diagnosis was a parafibromin-deficient parathyroid adenoma, and the patient was found to harbor a pathogenic CDC73 gene mutation involving the nuclear localization signal of parafibromin.
Comment
When pathologists discuss parafibromin, it is typically in the context of diagnosing an atypical parathyroid tumor or parathyroid carcinoma, as these conditions are more frequently associated with CDC73 gene mutations compared to parathyroid adenomas [2, 3]. However, this case illustrates how morphological indicators can guide pathologists to order relevant immunohistochemical stainings, assisting the clinical team in identifying a potential syndromic case even in a benign scenario. In our clinical practice, immunohistochemistry is not routinely applied to screen parathyroid adenomas. Recognizing sheet-like eosinophilic tumor cells with a perinuclear halo and associated arborizing vasculature could therefore be important, offering endocrine pathologists a valuable genotype–phenotype correlation [1].
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Speculatively, the identified CDC73 mutation could potentially disrupt the nuclear localization of parafibromin, leading to its sequestration in the cytosolic compartment. Previous studies have demonstrated a crucial role for nuclear parafibromin to function as a tumor suppressor, implying that CDC73 mutations in the NLS sequence could be pathogenic [4]. Similarly, parafibromin possesses a nucleolar localization signal (NoLS), and the loss of nucleolar parafibromin has been linked to CDC73 mutations within the NoLS region [5]. Therefore, meticulous microscopic examination at high magnification is essential when evaluating parafibromin.
Declarations
Ethical Approval
Ethical approval was granted by the Swedish Ethical Review Authority, and written informed consent was obtained from the patient.
Competing Interests
The authors declare no competing interests.
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The case with associated descriptions was previously shown during a slide seminar entitled “The lesson hidden in a single case” during the 2023 European Congress of Pathology in Dublin, Ireland.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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