A histological comparison of adenomatous and hyperplastic parathyroid glands.

The histological findings in 18 cases of parathyroid hyperplasia associated with chronic renal failure and haemodialysis have been compared with a series of 35 cases of primary adenomatous hyperparathyroidism. Analysis of several features suggests that there are no definite criteria for distinguishing microscopically between individual enlarged glands in primary and secondary hyperparathyroidism, although nuclear pleomorphism is more common in primary adenoma and nodules are more common in secondary hyperplasia. These findings are discussed.     

The cytology of the adenomatous,atrophic, and hyperplastic parathyroid glands of man

Summary Light- and electron-microscopic studies of two parathyroid adenomas and two cases of primary chief cell hyperplasia have demonstrated the presence of secretory granules similar to those in normal parathyroid glands. The atrophic parathyroid around the two adenomas contained only inactive chief cells identical to those in the normal parathyroid. These cells had few secretory granules, and small Golgi apparatuses. The oxyphil cells were shown to be chief cells with an altered structure, but still capable of producing parathyroid hormone. The vacuolated chief or transitional water-clear cell was demonstrated in one adenoma. Water-clear cells and transitional oxyphil cells were not clearly demonstrated. Other ultrastructural features of parathyroid adenomas and primary chief cell hyperplasias were demonstrated.

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Zusammenfassung In zwei Epithelkörperchenadenomen und in den Epithelkörperchen von zwei Patienten mit primärer Hauptzellhyperplasie (Cope) konnten sowohl lichtoptisch mit der Bodianfärbung, wie elektronenoptisch Sekretgranula nachgewiesen werden. Dagegen enthielt das atrophische Drüsenrestgewebe am Rande der zwei Adenome nur inaktive Hauptzellen, die mit denjenigen normaler Epithelkörperchen übereinstimmten. Sie enthielten nur wenige Sekretgranula und einen nur kleinen Golgiapparat. Die oxyphilen Zellen sind modifizierte Hauptzellen, denen immer noch die Fähigkeit Parathormon zu sezernieren, zukommt. Das eine der Adenome enthielt vacuolisierte Hauptzellen und Übergangsformen zu den wasserhellen Zellen. Voll entwickelte wasserhelle Zellen und Übergangsformen zu den oxyphilen konnten dagegen in den Adenomen nicht mit Sicherheit nachgewiesen werden.Es wird eingehend die Ultrastruktur der epithelialen Zellen in den Epithelkörperchenadenomen und bei primärer Hauptzellhyperplasie beschrieben.

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This study was supported in part by grant No. E201A, American Cancer Society.     

Nuclear DNA-content of parathyroid cells in adenomas, hyperplastic and normal glands.

Nuclear DNA-content in parathyroid cell imprints from adenomas, hyperplastic and normal glands was determined. Two principally different staining procedures were applied: paratoseaniline-Feulgen and ethidium-bromide staining. All nuclei, particularly with the ethidium-bromide method were registered as containing even multiples of the normal human diploid DNA-content. Normal and hyperplastic glands showed greater than or equal to 98 per cent diploid nuclei, the remaining fraction was tetraploid. In adenomas the frequency of diploid nuclei varied from 50-98 per cent; the remaining were predominantly tetraploid, but octaploid and higher even ploidity also occurred. A good correlation was found between nuclear DNA-content and nuclear diameter. The findings indicate that determination of nuclear DNA-content of parathyroid cells may be a valuable contribution in the differentiation between hyperplasia and adenoma.     

Storage and degradation of secretory proteins in adenomatous and secondary hyperplastic parathyroid cells

Summary Parathyroid hormone (PTH) and chromogranin A/secretory protein-I (SP-I) have been localized on immunoelectron microscopy in double-fixed tissues from adenomatous and secondary hyperplastic parathyroid glands. Storage organelles, identified on the basis of their consistent labelling, included two morphologically distinct varieties of granules/vesicles; the mature granules and the progranules. The former consisted of dense, mostly rounded, medium to large-sized bodies which were strongly labelled and predominant in the proximity of the cell membrane. The other variety of body included a spectrum of small pale vesicles/granules which were mainly located in the Golgi area. Because their morphology and their labelling pattern varied other bodies were assumed to be engaged in degradation or cleavage of the secretory proteins. These bodies comprised crinophagic structures, that is to say multivesicular bodies and large Golgi-related vesicles, as well as a number of atypical solid bodies. Whereas most of the granulated cells stored a mature or a maturing population of vesicles/granules, the process of maturation appeared to be either absent or incomplete in a number of cells from some glands. The major defects were frequently associated with an unusual labelling pattern of the Golgi area and selectively affected groups of cells from all the transitional oxyphil cell adenomas. The minor defects concerned individual cells of different types present in both categories of glands. The present data suggest that in hyperfunctioning glands, the type of hormone processing depends on the capacity of each cell in progranule maturation and that the maturation capacity may decrease dramatically in adenomatous or chronically hyperstimulated cells of the transitional oxyphil type.Visiting research fellow from the Department of Histology and Embryology, IBM Academy of Medicine, Lodz, Poland     

Nucleolar organizer regions in normal,hyperplastic and neoplastic parathyroid glands

Summary Using a one-stage silver staining technique, nucleolar organizer regions (AgNORs) were studied in paraffin sections of parathyroid glands (and in two lymph node metastases) from patients operated upon because of hyperparathyroidism or thyroid disease. The parathyroids were microscopically differentiated into normal, hyperplastic, adenomatous and carcinomatous glands. AgNORs were observed as distinct black dots of varying size and somewhat varying configuration in the nuclei of all glands. The mean number of AgNORs in the hyperplastic and adenomatous glands was not significantly different from that in the normal glands, whereas the carcinomatous glands exhibited significantly increased mean AgNOR number. No evidence was obtained for a role of AgNOR counting in the differentiation between normal and hyperplastic or adenomatous parathyroids, but the results suggest a potential role of enumeration of AgNORs in the discrimination between benign and malignant parathyroid neoplasms.     

Calcitonin immunoreactivity in neoplastic and hyperplastic parathyroid glands: an immunohistochemical study

Background Previous studies have established that calcitonin (CT) and the calcitonin generelated peptide (CGRP) are synthesized and stored in subsets of hyperplastic parathyroid cells that also contain chromogranin B (Schmid, KW, et al. Lab Invest 73:90, 1995). The purpose of the current study was to determine whether other generic but variably expressed neuroendocrine markers, i.e., synaptophysin (SYN) and CD57 (Leu7), are also present in normal, hyperplastic, and neoplastic parathyroid tissue and to assess their relationships to the presence of CT. Design Immunoperoxidase stains for chromogranin A (CgA), chromogranin B (CgB), SYN CD57, and CT were performed on 54 hyperplastic, 17 neoplastic (adenoma), and 16 normal parathyroid glands. Sequential sections were stained with antibodies to CgA, CgB, SYN, CD57, and CT using standard avidin-biotin-peroxidase techniques. Results: CgA was diffusely expressed in all normal, hyperplastic, and neoplastic glands. In hyperplasia, CgB was variably expressed in 6 cases (11%), SYN in 6 (11%), CD57 in 15 (28%), and CT in 8 (15%). In adenomas, CgB was variably expressed in 3 (17%), SYN in 3 (17%)., CD57 in 4 (23%), and CT in 4 (23%). All normal glands were negative for CgB, SYN, and CT, while CD57 was variably expressed in 17%. Of the 12 glands that were CT positive, 8 were also positive for CgB, 2 for SYN, and 9 for CD57. Four glands that were strongly and diffusely positive for CT were CgB and SYN negative. Conclusions: CgB, SYN, and CD57 are markers for subsets of hyperplastic and neoplastic parathyroid glands. CT is also expressed in a significant proportion of hyperplastic and neoplastic parathyroid glands, and may be independent of the presence of CgB, SYN, or DD57. The significance of these findings in relationship to the abnormal calcium metabolism in patients with parathyroid hyperplasia remains to be determined.     

AgNOR quantity as a prognostic tool in hyperplastic and neoplastic parathyroid glands

Prediction of evolution of secondary hyperplasia and tumours of the parathyroid glands is still a problem in histopathology. To assess whether the quantity of silver-stained nucleolar organiser region (AgNOR) proteins might be used as a prognostic tool in parathyroid pathology, a standardised AgNOR analysis has been performed on 19 cases of parathyroid hyperplasia caused by secondary hyperparathyroidism (PH), 8 cases of adenoma (PA) and 10 cases of carcinoma (PC). Clinico-pathological data and follow-up information were available. On formalin-fixed and paraffin-embedded sections, the visualisation and quantification of AgNORs were achieved according to the 1995 guidelines of the Committee on AgNOR Quantification. Then, the mean area (square micrometres) of AgNORs per nucleus (NORA) was evaluated by means of an image analyser and specific softwares. After testing the normal distribution of NORA values, statistical parametric tests were utilised; Kaplan-Meier and Cox multivariate analyses were also performed. In parathyroid lesions, a progressive increase of mean NORA values was observed from PH (2.895 μm²; SE 0.171) through PA (3.638 μm²; SE 0.125) to PC (4.701 μm²; SE 0.179); these differences were highly significant (P<0.001), although some degree of overlap was found among single NORA values. A significantly higher mean NORA value was revealed in PC with distant metastases than was noted in cases with no current clinical evidence of disease progression. Furthermore, a significantly (P<0.001) higher mean NORA value was encountered in the group of PH with recurrences (3.600 μm²; SE 0.106) than in nonrecurrent PH (2.261 μm²; SE 0.087). Multivariate analyses indicated that the NORA value was an independent prognostic parameter determining the risk of recurrence in PH. We suggest that AgNOR quantity may be a promising additional tool for predicting the biological behaviour of parathyroid lesions. Received: 2 December 1999 / Accepted: 1 March 2000     

Immunohistochemical study of nodular hyperplastic parathyroid glands in patients with secondary hyperparathyroidism

Summary Thirty-seven nodular hyperplastic parathyroid glands obtained by subtotal parathyroidectomy from 11 haemodialysed patients with secondary hyperparathyroidism were examined both pathologically and immunohistochemically. Four consecutive sections of the largest section-surface of each gland were subject to 4 different stains (haematoxyline-eosin, Grimelius, and the immunohistochemical stains for parathyroid hormone and chromogranin A) for comparison of each nodule.It was found that the major part of each nodule consisted of a single cell type with a single pattern of cells. These reacted uniformly to each stain. The mechanism involved in the storage and secretion of the secretory granule appeared to be regulated at the nodule and not at the cell level. The results suggest that the nodules may come from a monoclonal proliferation of a single parathyroid cell.Our present light microscopic immunohistochemical study, failed to demonstrate completely identical immunoreactive positivity of each nodule or each parathyroid cell to PTH. Chromogranin A or secretory protein-I did not indicate the coexistence of PTH and SP-I in the same secretory granule, which was in good agreement with the electron microscopic immunocytochemical study of Arps using bovine parathyroid glands. Our present study, however, provides good evidence that chromogranin A positivity is demonstrable in the human parathyroid gland outside the adrenal medulla and sympathetic nerves.     

Cox-2 expression in the oxyphilic cells of the normal, hyperplastic, and adenomatous parathyroid gland

We investigated cyclooxygenase expression in parathyroid glands from patients with various pathological conditions in order to coordinate levels of immunoreactivity with histology, with preoperative serum levels of calcium, phosphate, and intact parathyroid hormone, and with clinical diagnoses. Surgical specimens were obtained from 38 patients diagnosed with adenoma and primary, secondary, and tertiary hyperplasias. Incidentally removed parathyroids served as controls. After routine histological processing, approximations of total area and area of oncocytic nodules were calculated for each section of gland. Immunohistochemical reactivities for Cox-1, Cox-2, and values for integrated Cox-2 reactivity were quantified and compared with the clinical diagnoses and preoperative serum biochemistry. For the pooled cases, serum phosphate and PTH were directly related to each other, to total glandular area, and to integrated oncocytic area. Serum calcium was inversely related to serum phosphate and PTH levels as well as to total gland size. Within the adenoma group, the pure chief cell adenoma patients were younger and their tumors showed greater proliferative activity than those in the oncocytic adenoma group. For secondary and tertiary hyperplasias, the number of oncocytic nodules was significantly higher than in the adenomas and primary hyperplasias. In our study, the oncocytic cells are the only demonstrable site of Cox activity. It is suggested that the oncocytic cells play a role in prostaglandin metabolism within the parathyroids and may have a role in the regulation of PTH secretion.     

Immunocytochemical localization of parathyroid hormone in bovine parathyroid glands and human parathyroid adenomas.

Light and electron microscopic localization of parathyroid hormone (PTH) in human and bovine parathyroid tissue has been achieved using an indirect peroxidase labeled antibody method. Granular deposition of the reaction product was found throughout the chief cell cytoplasm. There was no nuclear staining. At the ultrastructural level, parathyroid hormone localized by this method appeared to be largely confined to the secretory granules in the cytoplasm of cells. Mitochondria and nuclei were free of reaction product. Aggregated sacs of granular endoplasmic reticulum were minimally reactive, and Golgi apparatuses did not show reaction product.     

Intestinal spirochaetosis associated with hyperplastic and adenomatous colonic polyps

Intestinal spirochaetosis is a human colonic infection due to Brachyspira aalborgi and Brachyspira pilosicoli causing various abdominal complaints. Although the presence of healthy epithelial cells was hypothesized to be essential for the adhesion of spirochaetes to the colonic mucosa, their adhesion to hyperplastic and adenomatous colonic polyps has been observed recently. We report a case of a woman with long-standing abdominal symptoms, in whom spirochaetes were found on the colonic mucosa surrounding an adenocarcinoma in the biopsies collected during eight years of follow-up. Spirochaetes were found attached to normal mucosa, to hyperplastic and to adenomatous polyps, but not to the epithelium of the carcinoma. The rectal biopsy collected during the last follow-up colonoscopy was subjected to histopathology and to a specific examination for brachyspires, demonstrating the presence of B. pilosicoli DNA. This report could stimulate microbiological investigations during the follow-up of colonic polyps in order to explain whether the persistence of abdominal symptoms in such patients could be caused by a colonic spirochaetosis susceptible to eradication by a targeted therapy.     

Intermediate-filament proteins in parathyroid glands and parathyroid adenomas

The intermediate-filament proteins of normal, hyperplastic, and adenomatous parathyroid glands were analyzed immunohistochemically and by immunoblotting with monospecific antibodies. In both normal and adenomatous parathyroid glands, we found keratins with molecular weights of 52, 45, and 40 kilodaltons (Nos. 8, 18, and 19, respectively). Vimentin proteins could be identified only in stromal cells, while glial fibrillary acidic protein was not found. In normal parathyroid glands, neurofilament positivity was seen only in nerve axons. In five of 15 parathyroid gland adenomas some keratin-positive cells expressed neurofilamentlike immunoreactivity also. In cytoskeletal extracts of one adenoma, the 200-kilodalton neurofilament protein was identified by immunoblotting. Thus it appears that some parathyroid gland adenoma cells may acquire neurofilament proteins and coexpress cytokeratin and neurofilament polypeptide in a way comparable with that reported in certain neuroendocrine tumors.     

Histological and clinical features of non-familial primary parathyroid hyperplasia.

Relations between histopathological characteristics and clinical data were retrospectively investigated in patients with sporadic primary hyperparathyroidism due to hyperplasia. The study comprised 100 patients with chief cell hyperplasia and nine with hyperplasia of the water-clear cell type operated on during the period of 1959-1989. The chief cell hyperplasia was associated with a renal stone disorder as the predominant symptom in 41 patients, psychiatric/neuromuscular manifestations in 26 patients, while 23 patients were apparently asymptomatic. The remaining ten patients had miscellaneous symptoms. Patients with renal stones were more frequently of the male sex and generally had lower serum calcium values and less marked increments in total parathyroid glandular weights than patients with other symptoms or those who were overtly asymptomatic. Two main morphological patterns, diffuse and nodular hyperplasia, were encountered in chief cell hyperplasia. Diffuse hyperplasia was usually found in moderately enlarged glands, with a less variable size and morphology. It was also more prevalent among young patients having moderate hypercalcaemia and either recurrent renal stones or neuromuscular/psychiatric symptoms. The glands affected by nodular hyperplasia were asymmetric in size with a variable cellular arrangement and a high proportion of oxyphil cells. Nodular hyperplasia was irrespective of symptoms more frequent in the elderly patients. Water-clear cell hyperplasia was not encountered during the last decade of the study and until then it was an occasional finding in patients with marked hypercalcaemia. In this histological entity the glands were greatly and asymmetrically enlarged.     

Familial disorders of parathyroid glands

The molecular mechanisms underlying familial parathyroid diseases continue to be elucidated. The mechanisms of familial parathyroid diseases are better understood than many sporadic parathyroid diseases. Familial parathyroid disease is associated with multiple endocrine neoplasia type 1 which is associated with MEN1 mutation, multiple endocrine neoplasia type 2A caused by RET mutation, and multiple endocrine neoplasia type 4 is caused with CDKN1B mutation. Sporadic parathyroid tumours are identified with mutations of MEN1 but generally not of RET. CDKN1B mutations are also identified in sporadic forms of primary hyperparathyroidism, although very rarely. Calcium sensing receptor gene mutations are involved in familial hyperparathyroidism and hypoparathyroidism, but are generally not identified in sporadic parathyroid tumours. However, the HPRT2 (CDC73) gene, which is mutated in hyperparathyroidism jaw-tumour syndrome and a subset of cases of familial isolated hyperparathyroidism, is frequently mutated in sporadic parathyroid carcinomas. Germline activating GCM2 mutations were recently found associated with a subset of familial isolated hyperparathyroidism. Parafibromin, a protein encoded by HPRT2, has been used in the diagnostic setting. The understanding and pathogenesis of parathyroid disease continues to evolve.     

Pathology of the parathyroid glands

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.     

Langerhans cell histiocytosis involving the thyroid and parathyroid glands.

Langerhans cell histiocytosis (LCH) is a rare illness, and the disease afflicting the thyroid gland is very uncommon, even in the presence of multisystem involvement. In this report, we document histologically, for the first time, concurrent involvement of the thyroid and parathyroid glands by LCH. A young Chinese woman with a history of diabetes insipidus and hypogonadism underwent a total thyroidectomy for enlarged thyroid gland secondary to LCH causing airway obstruction. Microscopic examination of the excised specimen disclosed CD1a- and S-100-positive LCH cells involving the thyroid and parathyroid glands. In a patient with LCH affecting the thyroid gland, parathyroid gland disease should be suspected when the serum calcium levels are depressed in association with an inappropriate serum parathyroid hormone level, such as a normal parathyroid hormone level in this case.