Abstract
Parathyromatosis is displaced parathyroid tissue in the neck and mediastinum related to prior surgery. Parathyromatosis can be difficult to distinguish from atypical adenoma and parathyroid carcinoma. The aim of this study is to evaluate clinical and morphologic features that may differentiate parathyromatosis, atypical adenoma, and parathyroid carcinoma. Cases of parathyromatosis, atypical adenoma, and parathyroid carcinoma were identified. Index cases were reviewed by consensus for histologic features, including stromal, cytologic/architectural, and invasive features. Ki67 was performed on index cases and scored using the Adsay method. Clinical information was gathered from the electronic medical record. 4 parathyromatosis, 17 atypical adenoma, and 6 parathyroid carcinoma were included. Parathyroid carcinomas were more likely to display coarse chromatin with nucleoli (P = 0.04), infiltrative invasion (P < 0.01), and metastasis (P < 0.01). Only parathyromatosis showed circumscribed invasion. Infiltrative invasion was more common in cases with progression (P = 0.046) and metastasis (P < 0.001). Necrosis and perineural invasion were only present in cases with progression and were more frequent in cases with metastasis (P = 0.079 and P = 0.19, respectively). There were no differences in presence of a fibrous capsule, capsular invasion, intralesional fibrous bands, random endocrine atypia, solid growth, Ki67 index, gland size/weight, serum PTH/calcium levels, and locoregional recurrence rates. There is overlap in the histologic features in parathyromatosis, atypical adenoma, and parathyroid carcinoma. While perineural, vascular, and infiltrative soft tissue invasion should remain diagnostic of malignancy, other atypical features such as solid growth, coarse chromatin with nucleoli, and necrosis should raise concern for recurrence and/or metastasis, and can be present in parathyroid lesions with and without recurrence.
Keywords: Parathyromatosis, Atypical parathyroid adenoma, Parathyroid carcinoma
Introduction
Parathyromatosis has been defined as the presence of parathyroid tissue, either in the neck or mediastinum, due to mechanical displacement related to prior parathyroid surgery. Even though it is regarded as benign, the clinical management is problematic since the sequelae of parathyromatosis often manifest as clinically apparent hyperparathyroidism with hypercalcemia [1–6]. The differential diagnosis, both clinically and histologically, includes parathyroid neoplasms with potentially aggressive behavior. Single or multiple routine benign parathyroid adenomas should not pose a diagnostic challenge, but differentiating parathyromatosis from atypical parathyroid adenomas and parathyroid carcinomas may be difficult. The WHO Classification of Tumors of Endocrine Organs defines atypical adenoma as an adenoma “that exhibits some of the features of parathyroid carcinoma, but lacks unequivocal invasive growth.” [7] Parathyroid carcinoma is defined by invasive growth, either invasion into surrounding tissues, blood vessels, or nerves, or by the presence of distant metastatic disease [7]. Distinguishing between parathyroid carcinoma and atypical adenoma is also challenging, and is confounded by the concept of parathyromatosis. However, parathyromatosis and atypical adenoma should not manifest distant metastases. These challenges are not restricted to pathology, as all these entities may exhibit multiple local and biochemical recurrences, creating an unclear clinical picture. While recent advancements in genetics (such as CDC73 gene mutation) and immunohistochemistry (such as parafibromin) offer some hope that pathologists may soon have tools to aid in this differential diagnosis, most pathology laboratories do not currently have specialized immunohistochemistry and/or genetic testing readily available for this specific task. The aim of this study is to evaluate the clinical and morphologic features that may differentiate parathyromatosis, atypical adenoma, and parathyroid carcinoma utilizing clinical records, routine hematoxylin and eosin stained sections, and Ki67 expression, as is commonly employed in the evaluation of other endocrine neoplasms.
Methods
Identification of Cases and Histologic Review
With IRB approval, the surgical pathology archives of The University of Chicago Medicine and its principle teaching affiliate, Northshore University HealthSystem, were queried for any case diagnosed as parathyromatosis, atypical adenoma, or parathyroid carcinoma between the years 1980–2018. For cases that had prior or subsequent resection, the case that was first diagnosed as parathyromatosis, atypical adenoma, or parathyroid carcinoma was assigned as the index case. All H&E slides from index cases and all singular cases that carried a diagnosis of parathyromatosis, atypical adenoma, or parathyroid carcinoma, were simultaneously reviewed in group consensus by five pathologists (JJS, NAC, GP, JBT, and CH). During review of H&E sections, stromal features, cytologic/architectural features, and invasive features were recorded: For stromal features, the presence or absence of a peripheral fibrous capsule, capsular invasion, and intralesional fibrous bands was noted; For cytologic/architectural features, nuclear atypia (further classified as either coarse chromatin with easily-identifiable nucleoli, or random endocrine atypia), solid growth, and necrosis was recorded; For invasive features, invasive growth was classified as soft tissue invasion (further classified as infiltrative or circumscribed), vascular, or perineural invasion (PNI). Infiltrative soft tissue invasion included angulated nests or individual tumor cells which dissect through neck soft tissue structures, often eliciting a desmoplastic response, while circumscribed invasion included multiple well-circumscribed nests of tumor cells present in soft tissue, without destruction of existing tissue/structures or desmoplastic response. Vascular invasion was considered present if tumor was identified inside a vessel, attached to the wall of the vessel with associated fibrin thrombi. PNI was considered present if the tumor demonstrated peri- or intraneural invasion or nerve entrapment.
Ki67 Proliferation Index
Ki67 immunostain was performed on one representative section per index case, when the block was available. After deparaffinization and rehydration, the tissue slides were treated with Tris–EDTA ph 9 buffer and heated in a steamer for 20 min at 100 °C. 1:200 dilution of anti-Ki67 antibody (rabbit monoclonal, clone SP6 (Thermo Fisher Scientific, Waltham, MA, USA)) was applied on the slides for 1 h incubation at room temperature. The antigen–antibody reaction was detected with Envision + anti-rabbit detection kit and DAB kit (Agilent/DAKO, Santa Clara, CA, USA). The slides were counter stained with hematoxylin and glass cover slipped.
One author (CH) determined the proliferation index (KI) in each instance using the technique described by Adsay [8, 9]. Briefly, a digitally-captured image of a Ki67-stained section at a “hot-spot” at 200 × (Spot Insight Firewire 2 camera (Spot Imaging, Sterling Heights, Michigan, USA) on an Olympus BX51 microscope (Olympus, Tokyo, Japan)) was utilized to manually count the positively-stained lesional nuclei (circled) and negatively-stained lesional nuclei (crossed-out). All lesional cells in the captured field were thus counted, generating the numbers used to calculate the KI.
Clinicopathologic Data
The surgical pathology report and electronic medical records (including operative reports) were reviewed for information regarding gland size, weight, and serum parathyroid hormone (PTH) and calcium (Ca) levels. Disease progression was defined as any of the following: local recurrence, biochemical recurrence, lymph node metastasis, or distant visceral organ metastasis. Type of progression was recorded when follow-up was available. Time to last follow-up was recorded in months.
Cases were then grouped into four possible categories depending on outcome: (1) cases with no progression versus (2) cases with any progression; (3) cases without lymph node or distant metastasis (including cases with no progression and cases with locoregional/biochemical recurrence only) versus (4) cases with either lymph node or distant metastasis.
Statistical Analysis
Categorical data was analyzed as two groups (parathyromatosis/atypical adenoma vs parathyroid carcinoma) and compared using Fisher’s exact test. Continuous variables were analyzed utilizing Student’s T test or analysis of variance (ANOVA). These analyses were also performed on the clinical outcome groups (group 1 vs group 2 and group 3 vs group 4). Statistical analyses were completed utilizing GraphPad Prism version 8.2.0 (GraphPad Software, San Diego, CA).
Results
Twenty-seven index cases were identified including 4 (14.8%) with a diagnosis of parathyromatosis, 17 (63%) with a diagnosis of atypical adenoma, and 6 (22.2%) with a diagnosis of parathyroid carcinoma (results summarized in Table 1).
Table 1.
Histopathologic and clinical features in parathyroid neoplasms
| PTM (n = 4) | AA (n = 17) | PCA (n = 6) | P | |
|---|---|---|---|---|
| FC | 50% (n = 2) | 47% (n = 8) | 33% (n = 2) | 0.66 |
| CI | 0% (n = 0) | 6% (n = 1) | 0% (n = 0) | 0.99 |
| FB | 50% (n = 2) | 77% (n = 13) | 100% (n = 6) | 0.28 |
| CCN | 25% (n = 1) | 18% (n = 3) | 67% (n = 4) | 0.04 |
| REA | 0% (n = 0) | 18% (n = 3) | 33% (n = 2) | 0.30 |
| SG | 50% (n = 2) | 35% (n = 6) | 83% (n = 5) | 0.15 |
| Nec | 0% (n = 0) | 12% (n = 2) | 17% (n = 1) | 0.53 |
| STI | 0% (n = 0) | 23% (n = 4) | 83% (n = 5) | < 0.01 |
| STC | 100% (n = 4) | 0% (n = 0) | 0% (n = 0) | 0.54 |
| VI | 0% (n = 0) | 0% (n = 0) | 33% (n = 2) | 0.04 |
| PNI | 0% (n = 0) | 0% (n = 0) | 17% (n = 1) | 0.22 |
| Size | N/A | 2.9 cm | 2.8 cm | 0.90 |
| Weight | N/A | 7,263 mg | 4,399 mg | 0.70 |
| PTH | 615 pg/mL | 601 pg/mL | 957 pg/mL | 0.90 |
| Ca | 13.2 mg/dL | 11.5 mg/dL | 11.8 mg/dL | 0.40 |
| R | 75% (n = 3) | 24% (n = 4) | 17% (n = 1) | 0.63 |
| M | 0% (n = 0) | 6% (n = 1) | 67% (n = 4) | < 0.01 |
| Ki67 | 8.2% | 2.8% | 4.3% | 0.20 |
AA atypical adenoma, Ca serum calcium, CCN course chromatin with easily-identifiable nucleoli, CI fibrous capsule invasion, FB intralesional fibrous bands, FC fibrous capsule, VI vascular invasion, M lymph node or distant metastasis, Nec necrosis, PNI perineural invasion, PCA parathyroid carcinoma, PTH serum parathyroid hormone, PTM parathyromatosis, R locoregional or biochemical recurrence, REA random endocrine atypia, SG solid growth, STC circumscribed soft tissue invasion, STI infiltrative soft tissue invasion
Stromal Features
A peripheral fibrous capsule was noted in all three types of lesions (33–50% of cases). Invasion of the fibrous capsule was noted only in atypical adenoma (6%). (While expected in parathyroid carcinoma, the absence of this feature may be related to the low number of parathyroid carcinoma cases). Intralesional fibrous bands were commonly-identified in all lesion types including 100% of parathyroid carcinoma, 77% of atypical adenoma, and 50% of parathyromatosis. There was no statistical difference between parathyromatosis/atypical adenoma when compared to parathyroid carcinoma for the presence of a fibrous capsule, capsular invasion, or the presence of intralesional fibrous bands (P = 0.66, P = 0.99, and P = 0.28 respectively).
Cytologic/Architectural Features
Nuclear atypia, when defined as coarse chromatin with easily-identifiable nucleoli (Fig. 1), was identified more frequently in parathyroid carcinoma compared to parathyromatosis/atypical adenoma (P = 0.04). Nuclear atypia, when defined as random endocrine atypia, was not observed in parathyromatosis, and while observed more often in parathyroid carcinoma than atypical adenoma (33% vs 18%, respectively), this finding was not statistically significant (P = 0.30). Solid growth (Fig. 2) was identified in all three lesions, with this finding most common in parathyroid carcinoma (83%, P = 0.15). Necrosis (Fig. 3) was identified in parathyroid carcinoma (17%) and atypical adenoma (12%; P = 0.53).
Fig. 1.
Parathyroid neoplasm showing coarse chromatin with easily identifiable nucleoli (H&E, 600X)
Fig. 2.
Parathyroid neoplasm showing solid growth (H&E, 200X)
Fig. 3.
Parathyroid neoplasm with abrupt area of necrosis (H&E, 200X)
Invasive Features
Infiltrative soft tissue invasion (Fig. 4) was not identified in parathyromatosis, was present in 23% of atypical adenoma, and was more likely to be identified in parathyroid carcinoma (83%; P < 0.01). Conversely, albeit non-significant, identification of circumscribed, nested soft tissue invasion (Fig. 5) was only identified in parathyromatosis (100%; P = 0.54). Vascular invasion (Fig. 6) was identified in one third of parathyroid carcinoma and in no cases of atypical adenoma or parathyromatosis (P = 0.04). PNI was identified in only parathyroid carcinoma (17%), but no case of atypical adenoma or parathyromatosis (P = 0.22).
Fig. 4.
Parathyroid neoplasm with infiltrative soft tissue invasion into skeletal muscle (H&E, 200X)
Fig. 5.
Case of parathyromatosis showing “buckshot” scattering of numerous well-circumscribed nodules of benign parathyroid tissue (H&E, 20X)
Fig. 6.
Intravascular tumor plug with associated fibrin thrombi, consistent with true vascular invasion (H&E, 200X)
Ki67 Proliferation Index
Ki67 was performed on all but one case (an atypical adenoma). At least 546 cells were scored per case (average 1743 cells scored/case). The average Ki67 proliferation index, while highest in parathyromatosis (8.2%) was not statistically different from atypical adenoma (2.8%) and parathyroid carcinoma (4.3%; P = 0.20).
Clinicopathologic Data
The tumor greatest dimension and weight were available for atypical adenoma and parathyroid carcinoma cases, but were not recorded for parathyromatosis, likely secondary to the fragmented and discontinuous nature of the specimens. There was no difference in average size between atypical adenoma (2.9 cm, range 0.5–8 cm) and parathyroid carcinoma (2.8 cm, range 1.3–3.7 cm; P = 0.90). Likewise, no difference in average weight was identified between atypical adenoma (7263 mg, range 20–52,000 mg) and parathyroid carcinoma (4399 mg, range 399–13,800 mg; P = 0.70). There was no difference in average serum PTH levels (P = 0.90) between parathyromatosis (615 pg/mL, range 266–1992 pg/mL), atypical adenoma (601 pg/mL, range 101–2518 pg/mL), and parathyroid carcinoma (957 pg/mL, range 79–2250 p/mL). There was no difference in average serum calcium levels (P = 0.40) between parathyromatosis (13.2 mg/dL, range 12.8–13.6 mg/dL), atypical adenoma (11.5 mg/dL, 9.3–15.6 mg/dL), and parathyroid carcinoma (11.8 mg/dL, range 11–14.2 mg/dL).
Follow-up was available for all patients with average follow-up of 95.3 months (range 8–293 months). While locoregional/biochemical recurrence was more often identified in parathyromatosis (75% of cases) compared to atypical adenoma (24% of cases) and parathyroid carcinoma (17% of cases), this finding was not significant (P = 0.63). In contrast, lymph node or distant metastasis was more likely in parathyroid carcinoma, occurring in two-thirds of parathyroid carcinomas and 6% of atypical adenoma, but in no case designated parathyromatosis (P < 0.01). Further characterization of the cases with recurrence can be found in Table 2. Of note, 1 case of parathyromatosis (case 3) recurred as parathyroid carcinoma (characterized by infiltrative growth, intersecting fibrous bands, solid to nested growth patterns, variably enlarged nuclei with focal pleomorphism, coarse nuclear chromatin with prominent nucleoli, mitoses > 10/10 high power fields, Ki67 proliferative index up to 20%, perineural invasion, and foci consistent with vascular invasion with tumor thrombus). Another case of parathyromatosis (case 1) with multiple recurrences eventually had atypical histologic features including fibrosis, atypia, possible vascular invasion, and occasional mitoses (case not reviewed). One case of atypical adenoma (case 10) recurred locally with features consistent with parathyroid carcinoma (solid growth, coarse chromatin with nucleoli, increased mitotic activity, tumor necrosis, and capsular and vascular invasion). One case of atypical adenoma (case 6) recurred locally with concern for parathyroid carcinoma (invasion into thyroid (case not reviewed)), and 1 case of atypical adenoma (case 21) presented with distant metastasis without locoregional recurrence. Analyzing the data based on clinical outcome groups (Tables 3, 4) showed that infiltrative soft tissue invasion was more common in cases with any progression (P = 0.046) as well as those with metastasis (P < 0.001). Necrosis and perineural invasion were only present in cases with progression and were more frequent in cases with metastasis (P = 0.079 and P = 0.19, respectively). Two of 3 cases with necrosis showed metastasis. The single case of necrosis without metastasis was an atypical adenoma that showed histologic features worrisome for carcinoma upon local recurrence. Cases with metastasis had significantly higher rates of solid growth (P = 0.016).
Table 2.
Follow-up data for parathyroid neoplasms
| Case | Diagnosis of Index Case | R | R Diagnosis | M | M Location | Follow-up (in months) |
|---|---|---|---|---|---|---|
| 1 | PTM | Yes |
Multiple PTM, Last recurrence With atypical features |
No | 60 | |
| 2 | PTM | Yes | PTM | No | 26 | |
| 3 | PTM | Yes |
1 recurrence PTM 1 recurrence PCA |
No | 79 | |
| 4 | PTM | No | No | 118 | ||
| 5 | AA | No | No | 55 | ||
| 6 | AA | Yes | Concern for PCA | No | 57 | |
| 7 | AA | No | No | 37 | ||
| 8 | AA | No | No | 26 | ||
| 9 | AA | Yes | PTM | No | 251 | |
| 10 | AA | Yes | PCA | No | 293 | |
| 11 | AA | No | No | 83 | ||
| 12 | AA | No | No | 41 | ||
| 13 | AA | No | No | 122 | ||
| 14 | AA | No | No | 89 | ||
| 15 | AA | No | No | 218 | ||
| 16 | AA | No | No | 136 | ||
| 17 | AA | No | No | 204 | ||
| 18 | AA | No | No | 62 | ||
| 19 | AA | No | No | 101 | ||
| 20 | AA | Yes | PTM | No | 40 | |
| 21 | AA | No | Yes | Lung | 8 | |
| 22 | PCA | Yes | Biochemical only (↑ PTH) | No | 150 | |
| 23 | PCA | No | Yes |
Supraclavicular Lymph Node |
8 | |
| 24 | PCA | No | Yes | Lung | 55 | |
| 25 | PCA | No | No | 61 | ||
| 26 | PCA | No | Yes | Multiple sites | 76 | |
| 27 | PCA | No | Yes | Multiple sites | 117 |
AA atypical adenoma, M lymph node or distant metastasis, PCA parathyroid carcinoma, PTM parathyromatosis, R locoregional or biochemical recurrence
Table 3.
Characteristics of cases with and without progression
| No progression (n = 14) | Any progression (n = 13) | P | |
|---|---|---|---|
| FC | 36% (n = 5) | 54% (n = 7) | 0.45 |
| CI | 0% (n = 0) | 8% (n = 1) | 0.48 |
| FB | 86% (n = 12) | 69% (n = 9) | 0.38 |
| CCN | 21% (n = 3) | 38% (n = 5) | 0.42 |
| REA | 29% (n = 4) | 8% (n = 1) | 0.33 |
| SG | 36% (n = 5) | 62% (n = 8) | 0.26 |
| Nec | 0% (n = 0) | 23% (n = 3) | 0.097 |
| STI | 14% (n = 2) | 54% (n = 7) | 0.046 |
| STC | 7% (n = 1) | 23% (n = 3) | 0.33 |
| VI | 7% (n = 1) | 8% (n = 1) | 0.99 |
| PNI | 0% (n = 0) | 8% (n = 1) | 0.48 |
| Size | 3.1 | 2.7 | 0.58 |
| Weight | 8478 | 4170 | 0.41 |
| PTH | 556 | 845 | 0.38 |
| Ca | 12 | 12.5 | 0.58 |
| Ki67 | 2.5% | 2.9% | 0.67 |
Ca serum calcium, CCN course chromatin with easily-identifiable nucleoli, CI fibrous capsule invasion, FB intralesional fibrous bands, FC fibrous capsule, VI vascular invasion, Nec necrosis, PNI perineural invasion, PTH serum parathyroid hormone, REA random endocrine atypia, SG solid growth, STC circumscribed soft tissue invasion, STI infiltrative soft tissue invasion
Table 4.
Characteristics of cases with and without metastasis (including lymph node or distant)
| No metastasis (n = 22) | Metastasis (n = 5) | P | |
|---|---|---|---|
| FC | 45% (n = 10) | 40% (n = 2) | 0.99 |
| CI | 5% (n = 1) | 0% (n = 0) | 0.99 |
| FB | 73% (n = 16) | 100% (n = 5) | 0.56 |
| CCN | 23% (n = 5) | 60% (n = 3) | 0.14 |
| REA | 18% (n = 4) | 20% (n = 1) | 0.99 |
| SG | 36% (n = 8) | 100% (n = 5) | 0.016 |
| Nec | 5% (n = 1) | 40% (n = 2) | 0.079 |
| STI | 18% (n = 4) | 100% (n = 5) | < 0.001 |
| STC | 18% (n = 4) | 0% (n = 0) | 0.56 |
| VI | 5% (n = 1) | 20% (n = 1) | 0.34 |
| PNI | 0% (n = 0) | 20% (n = 1) | 0.19 |
| Size | 2.8 | 3 | 0.66 |
| Weight | 6958 | 6533 | 0.96 |
| PTH | 1,046 | 975 | 0.29 |
| Ca | 12.2 | 12.2 | 0.54 |
| Ki67 | 4% | 4.3 | 0.92 |
Ca serum calcium, CCN course chromatin with easily-identifiable nucleoli, CI fibrous capsule invasion, FB intralesional fibrous bands, FC fibrous capsule, VI vascular invasion, Nec necrosis, PNI perineural invasion, PTH serum parathyroid hormone, REA random endocrine atypia, SG solid growth, STC circumscribed soft tissue invasion, STI infiltrative soft tissue invasion
Discussion
The clinical and morphologic distinction between parathyromatosis, atypical adenoma, and parathyroid carcinoma is often confounded by overlapping features, as confirmed by this study. In most instances there were no significant differences between parathyroid carcinoma and atypical adenoma/parathyromatosis, including the identification of a peripheral fibrous capsule, capsular invasion, intralesional fibrous bands, random endocrine atypia, solid growth, Ki67 index, gland size/weight, serum PTH/calcium levels, and locoregional recurrence. However, coarse chromatin with prominent nucleoli (p = 0.04) and necrosis (p = 0.53) were more frequently identified in parathyroid carcinoma. By definition, vascular and perineural invasion were only identified in parathyroid carcinoma. Features that correlated with disease progression (locoregional/biochemical recurrence or lymph node/distant metastasis) included infiltrative soft tissue invasion (p = 0.046) and necrosis (p = 0.097). Features that correlated with metastasis included solid growth (p = 0.016), infiltrative soft tissue invasion (p < 0.001), and necrosis (p = 0.079).
Numerous studies have attempted to utilize histologic and clinical features to distinguish parathyroid neoplasms. For example, an early study by Scantz and Castleman showed that a majority of parathyroid carcinomas contain intralesional fibrous bands [10], which the authors note is an oft-cited feature of malignancy in parathyroid lesions. This study also emphasized the importance of invasion (both capsular and vascular), and increased mitotic activity. Fibrous bands, fibrous capsule, and capsular invasion have also been mentioned in numerous other papers [11, 12]. Soft tissue invasion, vascular invasion, and perineural invasion all have been documented as being more common in atypical adenoma and parathyroid carcinoma [12]. Other studies highlight the importance of increased mitotic activity in parathyroid neoplasms [10–13]. Necrosis has also been found to be a feature of malignancy [12]. Cytologic atypia, although variably characterized from study to study, is also frequently cited as a feature of parathyroid carcinoma and/or atypical adenoma [12].
While these studies highlight features that may be more commonly found in atypical adenoma and/or parathyroid carcinoma, most studies conclude that the features of malignancy are not 100% specific, are subjective, and diagnosis of malignancy depends on the examining pathologist. Similarly, a study focusing on histologic and operative findings in patients with atypical adenoma and parathyroid carcinoma found that fibrous bands, mitotic activity, and atypical nuclear features were not pathognomonic of malignancy, and concluded in their study that there were no intraoperative findings that could separate atypical adenoma from parathyroid carcinoma [14].
Parathyroid neoplasms often, although not uniformly, present with clinical hyperparathyroidism (fatigue, muscle weakness, abdominal pain, bone disease, and nephrolithiasis) largely related to hypercalcemia; patients with parathyroid carcinoma may also have a neck mass [15–20]. Regardless of the commonality of these findings in parathyroid carcinoma, there are no specific clinical findings (serum PTH, Ca, gland weight) which are useful discriminatory tools in the workup of parathyroid neoplasms [21–24]. Similarly, our study did not reveal specific differences in these features between the groups of parathyroid neoplasms.
The aforementioned studies mostly focus on the separation of atypical adenoma and parathyroid carcinoma, and sometimes include a category of parathyroid adenoma. Few studies have been performed that include the category of parathyromatosis. One study by Fernandez-Ranvier et al. [25] evaluated capsular invasion, fibrous trabeculae, a trabecular pattern of growth, mitotic activity (> 1 mitosis/10 HPF), nuclear pleomorphism, vascular invasion, and lymph node metastasis. They found that many features of malignancy are also observed in parathyromatosis, including trabecular growth pattern, fibrous trabeculae, mitotic activity, and nuclear pleomorphism. They also concluded, similar to the current study, that there was no difference between the groups in regard to serum PTH. However, Fernandez-Ranvier did find that cases of parathyroid carcinoma had a higher serum Ca than atypical adenoma and parathyroid carcinoma. Their conclusion was that histopathologic criteria alone were not sufficient to differentiate parathyromatosis and parathyroid carcinoma.
In the present study, coarse chromatin with easily-identifiable nucleoli, infiltrative soft tissue invasion, and distant metastases were found more commonly in cases diagnosed as parathyroid carcinoma than parathyromatosis/atypical adenoma. Only one case diagnosed as an atypical adenoma developed lung metastasis. By definition, PNI and vascular invasion were only present in parathyroid carcinoma. While necrosis was present in both atypical adenomas and parathyroid carcinomas, its rarity (only 3 total cases) should alert the pathologist to possible aggressive behavior. In contrast to these features which highlight possible aggressive behavior, the presence of well-circumscribed soft tissue invasion was only identified in parathyromatosis, and the presence of this finding may be an indicator of a benign process.
In the present series, follow-up data was available for all patients. Of note, the majority of atypical adenoma cases (71%) did not recur or present with distant metastasis. Two cases (12%) did recur as parathyromatosis, one case (6%) recurred with a diagnosis of parathyroid carcinoma, one case (6%) recurred with a diagnosis concerning for parathyroid carcinoma, and one case (6%) presented with a distant metastasis. This is consistent with the literature that suggests that most atypical adenoma exhibit a benign clinical course [6]. As predicted, in the present study, all but one parathyroid carcinoma showed disease progression (either locally or with distant metastasis). Also, in accordance with prior studies that suggest an increased risk of recurrence in patients with parathyromatosis, 75% of parathyromatosis cases in our series recurred, including one with histologic features concerning for parathyroid carcinoma.
There are some ancillary studies that may supplement the histologic examination of parathyroid neoplasms. Mutational analyses of parathyroid tumors show that CDC73, GCM2, MEN1, RET, RB1, and TP53 mutations have all been found in parathyroid carcinoma [26, 27]. The reader is referred to a recent review on the genomics and epigenetics of parathyroid neoplasms for a more detailed discussion on this topic [28]. CDC73, specifically, has been implicated in the pathogenesis of parathyroid tumors [29]. Notably, germline mutation of CDC73 is associated with the autosomal dominant hyperparathyroidism-jaw tumor (HPT-JT) syndrome, and patients with this syndrome, or those who have parathyroid neoplasms with a sporadic mutation in CDC73, should be monitored closely, given the propensity of this mutation to lead to the development of parathyroid carcinoma, as it is not commonly found in sporadic adenomas [26, 27, 30–32]. CDC73 encodes parafibromin which can be evaluated by IHC. Loss of parafibromin by IHC is considered by some authors to be specific for parathyroid carcinoma, but sensitivity varies from study to study, and its specificity is unclear when atypical adenoma is considered [33–36]. Previous studies have also described distinctive morphologic features of parafibromin-deficient parathyroid tumors, and the reader is referred to work by Gill, et al., for a detailed illustration of this topic [29]. In addition, alterations in DNA methylation have been described in parathyroid tumors, with the possibility that differences in 5-hydroxymethylcytosine (5-hmC), may be able to differentiate atypical adenoma from parathyroid carcinoma [37, 38]. A recent review on the utility of immunohistochemistry in the diagnosis of parathyroid neoplasms concludes that the two most useful markers at present include Ki67 (with proliferation index > 5% worrisome for carcinoma) and parafibromin (complete nuclear or nucleolar loss supporting malignancy) [32]. The reader is referred to a review by Erickson and Mete for detailed discussion on other potentially useful immunohistochemical markers, including galectin-3, PGP9.5, Rb, bcl2, p27, hTERT, mdm2, and APC [32]. While ancillary studies may prove to be useful adjuncts to histologic examination, gene sequencing and parafibromin immunostain may not be routinely available or utilized by pathologists, and results of these ancillary studies may still not yield a definitive diagnosis of carcinoma due to overlap with atypical adenoma.
The distinction among parathyromatosis, atypical adenoma, and parathyroid carcinoma may not have a major impact on patients’ post-operative courses. All lesions are prone to recurrence, but, by definition, only parathyroid carcinoma can metastasize. Most morbidity attributed to these parathyroid lesions is a result of hypercalcemia. Initial en bloc surgical resection offers the best chance of tumor control and limiting morbidity due to repeat surgical procedures. Recurrence should also be managed by surgical resection, if possible [39–42]. Postoperatively, these patients are followed clinically and radiographically for signs of recurrence, including periodic serum PTH and calcium levels. A large series of parathyroid carcinoma patients showed that positive lymph nodes and older age predicted lower overall survival, but notes that lymphadenectomy could not be routinely recommended in patients with parathyroid carcinoma, as patients with unknown lymph node status had similar survival [43]. Others have argued for lymph node sampling to be a component of the surgery performed on any patient with suspected parathyroid carcinoma [18]. Regardless of the risk associated with various histopathologic parameters (lymph node status, vascular invasion, etc.), patients with parathyroid carcinoma would not be offered surgical or medical treatment in the absence of clinical or biochemical signs of hyperparathyroidism. Considering the similarities in management, the distinction between parathyromatosis, atypical adenoma, and parathyroid carcinoma becomes clinically less important. No patient with a diagnosis of parathyromatosis, atypical adenoma, or parathyroid carcinoma should undergo surgery without postoperative follow-up, and post-operative management of these patients (observation) does not differ except for frequency and timing of follow-up, regardless of the diagnosis rendered by the pathologist.
The limitations of the present study mainly involve the few number of cases evaluated, due to the rarity of this disease. Future studies could include additional centers to increase sample size, immunohistochemical evaluation of parafibromin, and molecular sequencing (including CDC73 gene). Also, mitotic counts were not performed due to overall low mitotic activity. Instead, Ki67 was utilized as a surrogate marker.
In conclusion, there is significant overlap in the histopathologic features observed in parathyromatosis, atypical adenoma, and parathyroid carcinoma. The presence of a peripheral fibrous capsule, capsular invasion, intralesional fibrous bands, random endocrine atypia, solid growth, Ki67 index, gland size/weight, serum PTH/calcium levels, and locoregional recurrence were present in all groups. Perineural and vascular invasion were definitional of parathyroid carcinoma (and were therefore not present in parathyromatosis or atypical adenoma). Infiltrative soft tissue invasion was identified in both atypical adenoma and parathyroid carcinoma, but was more frequently associated with cases that showed progression and/or metastasis, consistent with it being a recognized feature of malignancy in parathyroid neoplasia. Coarse chromatin with nucleoli was present in both atypical adenoma and parathyroid carcinoma, in patients both with/without recurrence and with/without metastasis. While necrosis was present in both atypical adenomas and parathyroid carcinomas, its rarity should alert the pathologist to possible aggressive behavior. The future integration of histologic findings with molecular studies may yield more precise methods of classification of parathyroid tumors.
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