Mini-symposium: endocrine pathology
Pathology of the parathyroid glands

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Abstract

Abnormalities of the parathyroid glands are the commonest cause of hypercalcaemia and the histopathologist has an important role in classifying the underlying pathological condition. Diagnostic assessment includes confirmation that the tissue removed is parathyroid versus, most commonly, lymph nodes or thyroid, possibly requiring intra-operative assessment, and in hyperparathyroidism, establishing whether excised parathyroid glands represent hyperplasia or neoplasia. The commonest neoplastic diagnosis is of an adenoma, usually single, and ‘atypical adenoma’ and carcinoma are much less common. It is important to distinguish the worrisome histopathological features of atypical adenoma, which if precisely defined has an excellent prognosis, from the frankly malignant features of parathyroid carcinoma. Parathyromatosis, presenting most frequently after previous parathyroid surgery, must be distinguished from dissemination from a carcinoma. Less common lesions include parathyroid cysts, parathyroiditis and rare metastases to the parathyroid glands. The molecular and genetic events underlying parathyroid disease are complex, heterogeneous, overlapping and poorly understood. Newer antibodies, including parafibromin and PGP9.5, have been proposed to be useful in separating adenoma from carcinoma but overlapping patterns occur and clinicopathological assessment remains the yardstick of diagnosis.

Introduction

Parathyroid glands most commonly come to the attention of the histopathologist when hyperfunctional glands are surgically removed to treat hyperparathyroidism, usually in the clinical context of primary, secondary or tertiary hyperparathyroidism.1 In addition, parathyroid cysts may be found in the neck or mediastinum and normal parathyroid glands may be found in thyroidectomy and other surgical specimens from the neck and mediastinum. Recurrent benign thyroid implants, parathyromatosis, may occur following surgery and, very rarely, metastases from parathyroid carcinoma may be submitted for diagnosis (Box 1).

Section snippets

Historical background

Strangely, the first description of the parathyroid gland followed an autopsy on a rhinoceros by Sir Richard Owen in 1849. Sadly, the glands still await histological examination, an early example of poor Turn Around Time!2, 3 The parathyroid glands were the last major organ to be recognized in man and were discovered in 1880 by Ivar Sandström, a Swedish medical student in Uppsala.3 Later, the relationship of the glands to severe bone disease was established and in the early 1900's, Jacob

Embryology and anatomy

Usually there are four parathyroid glands, weighing 30–40 mg each but supernumerary parathyroid glands are found at autopsy in 2%–13% of healthy individuals, most commonly with a fifth gland located in the cervical thymus.4 Reportedly, 1%–3% of people have only three parathyroid glands and 0.6% has six.5 There are rare reports in the literature of the presence of seven and up to 12 parathyroid glands.2 The combined weight of all parathyroid gland tissue in adult men 120 ± 3.5 mg and in adult

Hyperparathyroidism

The level of parathyroid hormone (PTH) is inversely proportional to the level of calcium in the blood, which is tightly regulated between 8.8 and 10.2 mg/dL. Hypercalcaemia above this level leads to cessation of PTH production. Primary hyperparathyroidism is characterized by the autonomous production of parathyroid hormone resulting in hypercalcaemia and is the most common cause of hypercalcaemia in the non-inpatient setting, in people without an underlying malignancy.2 The incidence of

Hyperplasia

Hyperplasia affects classically effects multiple parathyroid glands, typically all, but asymmetrical and even asynchronous presentation may occur (Box 4).1

Primary and secondary hyperparathyroidism are indistinguishable. The hyperplasia tends to be diffuse and uniform between different parathyroid glands in early secondary hyperparathyroidism but with progression, the glands progress to become nodular and more variable in size (Figure 8). In tertiary hyperparathyroidism, the glands are larger

Parathyroid adenoma (Boxes 5 and 6)

Parathyroid adenomas are usually single with multiple adenomas accounting for approximately 20% of cases and rarely carcinoma in 0.5–5.2% of cases.2, 8 Multigland disease is usually hyperplasia, but ‘double’ or ‘multiple’ adenomas are also described, accounting for 1.9–15% of cases, more commonly in older patients.10 Carcinoma and adenoma can be seen in different parathyroid glands in the same patient.22 Non-functional parathyroid adenomas and carcinomas are rare.23

Exposure to ionizing

Atypical adenoma

As with many endocrine neoplasms, the diagnosis of parathyroid carcinoma can be difficult (Box 7). Tumours with some features suggesting malignancy but falling short of unequivocal histological malignancy, are termed “atypical adenoma” (Figures 15 and 16).1, 5, 8

The significance of abnormal mitoses in the diagnosis of atypical adenoma is unclear. Their detection should prompt careful assessment of the specimen in the search for other features of malignancy.2

The interpretation of invasion and

Parathyroid carcinoma

Parathyroid carcinoma is a rare lesion, representing fewer than 4% of cases of parathyroid disease.2, 28 Diagnosis can be difficult based on histology of the resection specimen, and may require the development of metastatic disease to establish a definite diagnosis. The natural history is variable, typically with slow growth and multiple recurrences, sometimes after a long disease-free interval, thus requiring life long follow-up.1 Quoted survival figures vary from <50 to 85% at 5 years and

Intra-operative assessment in parathyroid disease

Frozen sections for histology or imprints or scrapes for cytology were previously routine in parathyroid surgery. The first role of the pathologist was to confirm parathyroid tissue as opposed to thyroid, lymphoid, adipose or thymic tissue. The use of frozen sections is decreasing with the routine use of pre-operative localization and/or real-time assessment of removal of hyperfunctioning parathyroid tissue.1 Frozen sections performed intra-operatively are time-consuming, expensive and

Pathogenesis and molecular pathology

The molecular pathology of the parathyroid glands plays a limited part in non-specialist parathyroid diagnosis and is briefly summarized here (Box 9). Comprehensive recent reviews have been published and should be consulted for more detailed information.1, 20, 37 The difficulty in potential diagnostic use is exemplified by the clonality of parathyroid lesions. Diffuse hyperplasia tends to be polyclonal but the nodules of nodular hyperplasia are often monoclonal. Monoclonality is thus seen in up

Immunohistochemistry

Immunohistochemistry in parathyroid pathology has until recently been of limited use. An antibody to PTH gives strong cytoplasmic staining of PTH in chief cells and is useful in the confirmation of parathyroid tissue. Low-molecular-weight cytokeratins (CKs) such as CK8, CK18, and CK19 and chromogranin A are immunoreactive. Adenomas, in contract to normal parathyroid tissue, express neurofilament and will also label for vimentin and glial fibrillary acidic protein. CD3 and CD4 have been shown to

Parathyroid cysts

Parathyroid cysts (Figure 25) are uncommon and may present as a cervical or retrosternal mass.43, 44, 45 Most parathyroid cysts are non-functional but 10%–15% are functional and can rarely manifest as acute parathyroid crisis.44 Wani and Hao44 reported a rare atypical cystic parathyroid adenoma having some features of carcinoma but lacking the indisputable evidence of malignant disease, such as angioinvasion or metastatic involvement. Behaviour of these lesions is unpredictable. Pre-operative

Ectopic secretion of parathyroid hormone

Ectopic secretion of PTH is rare and has been reported in a cervical neuro-endocrine tumour, papillary and medullary carcinoma of the thyroid, cervical paraganglioma, thymoma, nasopharyngeal rhabdomyosarcoma, squamous cell carcinomas of the tonsil and lung, gall bladder and hepatocellular carcinoma, oesophageal carcinoma, gastric carcinoid, pancreatic islet cell tumours, small intestinal leiomyosarcoma malignant melanoma, and carcinomas of breast, ovary and endometrium.46

Miscellaneous lesions

Parathyroiditis is rare in comparison with other endocrine organs and may result in functional dysregulation.47 Recognized patterns include lymphocytic infiltrates, parathyroiditis with germinal centres and granulomatous inflammation resulting from sarcoidosis, tuberculosis and other granulomatous diseases. Lymphocytic infiltrates are not uncommon, and do not seem to relate to functional hyperparathyroidism or hypoparathyroidism. Talat et al.47 proposed that the term parathyroiditis should be

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