The chromatin was usually speckled, often, coarsely so, sometimes with prominent nucleoli. Rather than being arranged in an acinar architecture, the neoplastic cells usually grew in solid sheets. Microcystic change was not uncommon, being found in 21 (48.8%) cases; however, grossly evident macrocystic change was absent. In most cases, there was a conspicuous arborizing vasculature, at least focally. In a few cases, there were some prominent dilated vessels imparting a hemangiopericytomatous quality, which contributed to the microcystic appearance appreciated at low power. Some cases were associated with a thick capsule. Multinucleation was noted in 5 (12%) cases. Broad bands of fibrosis were rare.
The results of molecular testing are presented in Table 3. Of the 39 tumors from 38 patients that underwent molecular testing on FFPE tumor tissue, pathogenic CDC73 variants were confirmed in 23. Eight (34.8%) of these were large-scale deletions. Loss of heterozygosity was confirmed in 4 tumors, and, in an additional 2 tumors, (#6 and #23) putative “second-hit” somatic variants were identified that were absent in germline testing.
Of the 40 patients, 24 had some degree of germline mutation testing as part of their clinical care. In 16 (66.7%), pathogenic germline variants were identified, of which 2 were whole-gene deletions. Of note, 4 of the patients in whom no germline mutations were identified did not undergo MLPA, and 3 of these patients had large-scale deletions in their tumors. Therefore, germline deletions could not be excluded. In 3 tumors, somatic testing was not able to identify the known germline CDC73 variants because of incomplete coverage.
There were no tumors in which we could confidently exclude CDC73 mutation. One case (#4) had neither somatic nor germline testing performed, and, in 13 cases, somatic sequencing data had insufficient coverage in at least some exons. Therefore, a total of 26 of 40 (65%) patients with parafibromin-negative tumors had confirmed pathogenic somatic and/or germline CDC73 mutations, and, in the remaining 14 patients, there was insufficient coverage to exclude a pathogenic mutation.
The long-term follow-up of the parafibromin-negative patients is presented in Table 3—median duration of follow-up 26 months. One patient (2.5%) developed a jaw tumour with the typical characteristics of the type of ossifying fibroma reported in the setting of HPT-JT syndrome.6 Of the 16 patients who fulfilled WHO 2017 criteria for carcinoma at first presentation, subsequent recurrence with the properties of malignant disease rather than metachronous tumors, that is, infiltrative or destructive growth, vascular invasion, and distant metastasis, arose in 5 (31%) patients after intervals of up to 10 years. Several of the patients with histologically benign parathyroid adenoma developed recurrent disease that could be definitively attributed to metachronous tumors arising in a different parathyroid gland.
However, 1 patient, with a noninvasive primary tumor and therefore classified as adenoma under the WHO 2017 system, developed recurrent disease that seemed to represent unequivocal metastatic carcinoma in the absence of a second metachronous or synchronous tumor and is presented in detail. Patient 5 initially presented at the age of 15 with a serum calcium level of 3.2 mmol/L (normal range, 2.2 to 2.7 mmol/L) and a serum parathyroid hormone level of >100 pmol/L (normal range, 1.05 to 6.83 pmol/L). A right inferior parathyroid tumor weighing 4 g was removed. This tumor was fragmented upon receipt. The entire specimen was embedded in 7 blocks. It demonstrated typical features for a parafibromin-deficient tumor, including a solid growth pattern, eosinophilic cytoplasm, and some perinuclear cytoplasmic clearing. Although the fragmentation of the tumor made assessment of the interface with non-neoplastic tissue difficult (Fig. 6), there was no invasive growth evident. Of note, all slides from this initial tumor were reviewed by 3 pathologists (2 with subspecialty expertise in endocrine pathology) and reviewed again for this paper, and all reviewers agreed that there was no invasive growth and therefore the tumor was best classified as adenoma. The hypercalcemia resolved immediately after surgery, and, in fact, the patient developed hungry bone syndrome.
Eight months later the patient developed recurrent hyperparathyroidism. She underwent repeat surgical exploration, and each of the left superior, left inferior, and right superior parathyroid glands were identified and confirmed on biopsy to be histologically normal and to demonstrate retained parafibromin expression. The central neck compartment and the site of the previously resected right inferior parathyroid were also cleared and lacked neoplastic tissue. The hyperparathyroidism did not resolve. Six months later, imaging revealed enlarged level 3/4 lymph nodes, and the patient underwent a modified right neck dissection during which 4 separate deposits of parafibromin-negative parathyroid carcinoma were identified at level 4—an area that was outside the previous operative fields. The hyperparathyroidism resolved but then recurred 14 months later when the patient underwent further resection of parathyroid carcinoma adherent to the recurrent laryngeal nerve and cricothyroid muscle in the central neck compartment. MLPA studies of FFPE tissue from the original tumor demonstrated deletion of exon 17. No germline mutation was identified on clinical sequencing of peripheral blood; however, germline tissue did not undergo MLPA studies, and therefore large-scale deletions could not be excluded. At last follow-up, 7 years after first presentation, she was disease free.
In this report we describe the previously unrecognized but distinctive morphology of parafibromin-deficient (HPT-JT type, CDC73 mutated/inactivated) parathyroid neoplasms and propose that they be considered a distinct subtype of parathyroid tumor. We accept that there were no firm department guidelines for which cases underwent parafibromin IHC and that therefore there may be an ascertainment bias toward a distinct morphology as we became more familiar with the stereotypical morphology of these cases. These tumors are characterized by a sheet-like growth of neoplastic cells. Although this sheet-like pattern is frequently interrupted by an arborizing vasculature, it contrasts with the acinar architecture that is found in the majority of parathyroid neoplasms. A particular feature of these tumors is their distinctive eosinophilic cytoplasm. Usually, at least in some areas, the eosinophilic cytoplasm characteristic of parafibromin-deficient tumors demonstrates a unique appearance that is different to and, with experience, may be distinguished from the very granular cytoplasm of the type of oxyphil cells that commonly occur elsewhere in parafibromin-deficient tumors, but are not uncommon in non-neoplastic parathyroid tissue and other parathyroid adenomas.29 Other features characteristic of parafibromin-negative parathyroid tumors include nuclear enlargement (sometimes with preserved N/C ratios and smudged or coarse chromatin) and distinctive perinuclear cytoplasmic clearing imparting an almost koilocytic-like appearance. Microcystic change or a thick hyalinized fibrous capsule are also commonly present, but these features are not uncommon in usual adenomas. To familiarize pathologists with these morphologic features, whole-slide scanned images from all tumors in this study are available for review at the Cancer Diagnosis and Pathology group website www.cancerdxpathology.org.au.
Clinical experience with parafibromin IHC is mixed.1,18–27 Our prospective experience of parafibromin IHC over the 12-year period of this study during which we performed IHC on 815 tumors is that, while it can be a technically difficult stain to perform and interpret, meaningful results can be achieved with care and time. The very high specificity of negative parafibromin IHC is supported by the confirmation of pathogenic germline or somatic mutations in 26 of 40 (65%) patients, with a high likelihood that there are further mutations that have been missed because of incomplete coverage, and the limited sensitivity of sequencing and MLPA on FFPE tissue. Evidence for the suboptimal sensitivity of sequencing using FFPE tissue includes the fact that we did not identify the known germline mutation in the somatic testing of 3 patients with confirmed HPT-JT syndrome despite the fact that we did not microdissect the tissue.
However, we fully accept the limitations of parafibromin IHC, and our experience is that a diagnostic result cannot always be obtained. In a significant number of cases, we had to repeat the stain with different concentrations and antigen retrieval conditions to achieve an interpretable result—that is, positive staining in non-neoplastic internal controls as well as negative staining in neoplastic cells. We commonly find that, in larger tumors, which were otherwise positive for parafibromin, toward the center of specimens, there is focal nonspecific loss of nuclear expression in neoplastic cells associated with decreased or absent expression in internal positive controls—a pattern of staining we still interpret as positive. All the cases were prospectively identified as parafibromin negative (and confirmed on repeat testing); therefore age in paraffin blocks does not appear to be a significant confounding factor, particularly if attention is payed to the need for internal positive controls.
We note that different criteria have been used for parafibromin interpretation by different groups. We1,21 and others18,20,24 require completely absent nuclear expression of parafibromin in all neoplastic cells in the presence of an internal positive control in non-neoplastic tissue—an approach highly analogous to that commonly used for DNA mismatch repair IHC interpretation in colorectal carcinoma.30 In contrast, some other groups consider focal loss of parafibromin expression as sufficient to indicate negative staining.19,22,23 This study confirms the high specificity of our approach to interpretation but was not intended or designed to assess sensitivity. Indeed, we have previously reported that, although truncation or large-scale deletions of CDC73 are consistently associated with completely negative parafibromin expression, some pathogenic point mutations may be associated with retained positive expression for parafibromin using our criteria.1,21 The reported incidence of large-scale germline deletions of CDC73 is up to 35%,31 similar to our finding of 8 of 23 (34.8%) in the somatic testing in our series. We emphasize that large-scale deletions are usually not detected by sequencing alone, and several of the patients thought to lack germline CDC73 mutations in this and previous studies did not have MLPA studies performed, and therefore may have had unrecognized deletions.
There is an extensive literature linking CDC73 mutations with parathyroid carcinoma.2,11–15,32 However, the role of CDC73 mutation as a marker of malignancy in atypical parathyroid tumors remains controversial. This may be because mutation testing is not readily available, and some groups have found parafibromin IHC unreliable.2,25–27,33 However, we also believe it is partially because the accuracy of parafibromin IHC is commonly compared with morphologic criteria as a gold standard, despite evidence that morphology is an imperfect predictor of biologically malignant behavior. It can be argued that parathyroid carcinoma is both “overdiagnosed” and “underdiagnosed.” That is, the majority of cases diagnosed as carcinoma on the basis of histologic criteria alone do not recur, and the diagnosis of carcinoma is frequently not made by histologic criteria until metastasis/recurrence has occurred.2,34–37 It is therefore worth noting that 16 of the 40 (40%) patients with tumors that fulfilled WHO criteria for malignancy demonstrated complete loss of parafibromin staining in their tumors and, most importantly, in 5 (31%) of these patients, the tumor went on to demonstrate unequivocal malignant behavior. In contrast, although parafibromin IHC was not performed in all tumors, loss of expression was found in only 2 of 1055 (<0.2%) of truly unselected parathyroid tumors.
When confronted with an atypical parathyroid tumor that does not fulfill WHO 2017 criteria for malignancy, we have taken the pragmatic approach that tumors lacking immunohistochemical evidence of CDC73 mutation/inactivation are very unlikely to recur and can be safely followed-up similarly to benign adenomas.33 Of course, this is useful in the great majority of cases primarily because CDC73 mutation and recurrence after resection of an atypical adenoma are both rare events. However, it leaves the very real difficulty of how to classify parafibromin-negative parathyroid tumors that do not fulfill WHO criteria for malignancy. We now believe that these are best classified simply as “parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors” and considered a distinct entity.
There are isolated case reports of CDC73 mutated but noninvasive and therefore “histologically benign” parathyroid tumors that have subsequently metastasized.38 Some of these events may be attributable to metastasis from other unrecognized synchronous or metachronous primary tumors.6 Our experience with patient 5 in this report, where every possible effort was made to exclude a second primary tumor, adds another case of a noninvasive parathyroid tumor associated with CDC73 mutation which subsequently behaved in a malignant manner. This supports our approach that parafibromin-deficient parathyroid tumors have some metastatic potential.2 However, it is clear that the metastatic potential is very low in the absence of invasive growth. When care was taken to exclude second primary tumors, none of the 26 other parafibromin deficient tumors that did not fulfill WHO criteria for carcinoma behaved aggressively at long-term follow-up. Therefore, although we believe that recurrence and metastasis may occur in parafibromin-deficient tumors lacking WHO 2017 criteria for malignancy, we emphasize that this is an unusual event. Indeed, the risk of metastasis in noninvasive parafibromin-deficient tumors is probably even lower than the 3.7% estimated in our study, given that it was subject to a selection bias toward identifying such patients (as recurrence/metastasis would be considered an indication for parafibromin IHC).
In our experience, much more common than metastasis from a noninvasive parafibromin-deficient tumor are cases where malignant features were only recognized on pathologic review of parafibromin-deficient tumors that subsequently behaved in a malignant manner.39 Because of the very low risk of metastasis from noninvasive tumors we do not recommend altering the WHO criteria for parathyroid carcinoma to include all parafibromin-deficient tumors. However, we would recommend that particular care should be taken in examining all parafibromin-deficient tumors, perhaps with a lower threshold for diagnosing invasive growth, and therefore parathyroid carcinoma, in equivocal cases.
Patients with confirmed HPT-JT syndrome have a very high risk of recurrence in the same or other glands, which is at least 25%, but which may occur in the majority of patients at follow-up extending to 30 years.6,8,9,38,40–43 Therefore, the diagnosis of parafibromin-deficient (HPT-JT type) parathyroid tumors should precipitate long-term follow-up for the possibility of late recurrence or metachronous disease, whether or not WHO criteria for malignancy are met. That is, simply identifying these unique tumors not as benign or atypical adenomas but as parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors should be sufficient to justify long-term follow-up and adequately convey the risk of recurrence, which is usually attributable to metachronous disease in patients with germline mutations and only very rarely to true metastasis from non-invasive tumors. Confirmation of germline CDC73 mutation in such patients also allows for cascade testing of family members, to identify carriers for whom screening for parathyroid disease is then appropriate.1,10,12,17–24,44–48
In conclusion, we report that parafibromin-deficient (HPT-JT type, CDC73 mutated) parathyroid tumors demonstrate distinctive morphologic features including sheet-like rather than acinar architecture, eosinophilic (but not very oxyphilic) cytoplasm, nuclear enlargement with distinctive chromatin and perinuclear cytoplasmic clearing, a prominent arborizing vasculature sometimes with a hemangiopericytomatous quality, and, frequently, a thick capsule. Other important clues to the diagnosis include a younger age of onset (mean, 36 vs. 63 y; P<0.001), a larger size (mean, 3.04 vs. 0.62 g; P<0.001) and more marked hypercalcemia (average 3.12 mmol/L in our series). Although parafibromin IHC can be technically difficult to perform and interpret, recognition of these tumors is important because of their strong association with malignancy (rare in all other circumstances) and HPT-JT syndrome. If a parafibromin-deficient (HPT-JT type) parathyroid tumor is identified, we recommend particularly careful assessment for malignancy by conventional morphologic criteria and genetic testing by both sequencing and MLPA for germline CDC73 mutation/deletion—present in at least 40% of patients in our series but probably more. For noninvasive parafibromin-deficient (HPT-JT type, CDC73 mutated) tumors, we still recommend long-term follow-up, primarily because of the risk of metachronous disease but also because of the risk of aggressive behavior in a small minority of cases.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
parathyroid; parathyroid carcinoma; CDC73; parafibromin; hyperparathyroidism jaw tumor syndrome