Humeral brown tumor as first presentation of primary hyperparathyroidism caused by ectopic parathyroid adenomas: report of two cases and review of literature

Two cases of brown tumor of the humerus caused by ectopic parathyroid adenomas were presented, which to our knowledge has not been previously documented in the international literature. There are two highlights in these two cases. First, brown tumors of the long bones may commonly involve femur and tibia, rarely involve humerus in association with primary hyperparathyroidism. Second, ectopic parathyroid adenomas of our patient had an unusual location of this disorder. We explored the role of ultrasound, MIBI scintigraphy as well as FNAB (fine needle aspiration biopsy) in diagnosis of brown tumor especially simultaneously occurrence of ectopic parathyroid adenomas and the importance of a thorough diagnostic work-up. The contemporary diagnosis and treatment options will be emphasized.     

The two-hit theory of neoplasia: implications for the pathogenesis of hyperparathyroidism

Knudson's two-hit or two-mutational-event hypothesis for the initiation of neoplasia suggests that two somatic mutations are necessary for initiation of sporadic neoplasms, and that a genetic plus a somatic mutation are required for hereditary neoplasms. Glucose-6-phosphate dehydrogenase (G6PD) studies of parathyroid tumors of 11 heterozygotes with hyperparathyroidism (HPT), including one with hereditary HPT, have shown both A and B isoenzymes. These findings suggest multicellular development of parathyroid tumors and are compatible with tumors being manifestations of either nonneoplastic hyperplasia or a genetic first mutational event. Parathyroid carcinoma may be the result of a second mutation in cells made susceptible by previous genetic or somatic mutations. Comparison of parathyroid cancer in families with hereditary HPT with sporadic cases from the literature reveals a generally younger onset with hereditary HPT compatible with the two-hit theory. Consideration of these age-of-onset and G6PD findings suggest that hyperparathyroidism may result from either non-neoplastic or mutational-induced processes even though no histologic distinctions have been observed in the hyperplasia associated with these processes.     

Vitamin D and retinoids in parathyroid glands (review)

Vitamin D and retinoids are important regulators of differentiation and proliferation in a number of tissues, and have been implicated as chemopreventive agents in several different tumors. While vitamin D is known to be important for regulation of parathyroid function and proliferation, it has recently been established that parathyroid cells also are targets for retinoids. Hyperparathyroidism (HPT) is a common disorder, and evaluation of the disease has indicated high prevalence of subclinical disease, as well as clear benefits of offering treatment for the disease. This review summarizes the data so far gathered concerning parathyroid cells, vitamin D and retinoids, with clear implication on prospects of possible medical treatment of hyperparathyroidism.     

Multiple brown tumors in a patient with nutritional secondary hyperparathyroidism

Summary For years, brown tumors have been considered to be a characteristic of primary hyperparathyroidism. However, since 1963 several reports indicate the incidence of brown tumors in patients with renal secondary hyperparathyroidism to be 1.5%–1.7%. The appearance of multiple brown tumor lesions is rather uncommon in secondary hyperparathyroidism which is also true for malabsorption as its cause. We report on a 56-year-old man presenting with pain in the bones and multiple osteolyses. A bone biopsy specimen and the laboratory examinations were indicative of secondary hyperparathyroidism caused by malabsorption most likely due to Billroth's II/I gastric resection. Thus, the patient's osteolyses represent brown tumors which have been induced by nutritional secondary hyperparathyroidism.     

Fine‐needle aspiration of brown tumor of bone: Cytologic features with radiologic and histologic correlation

We report the case of a 40‐year‐old man with tertiary hyperparathyroidism due to end stage renal disease who initially presented with acute‐onset paraplegia, elevated serum parathyroid hormone, and multiple bone abnormalities, including a large extradural intraspinal mass seen by magnetic resonance imaging. In contrast with imaging features, fine‐needle aspiration cytology showed numerous benign‐appearing multinucleated osteoclast‐type giant cells that are the characteristics of either brown tumor or benign giant cell tumor of bone. Sheets of mononuclear spindled stromal cells were also noted. A core‐needle biopsy confirmed the diagnostic features of brown tumor of hyperparathyroidism. Diagn. Cytopathol. 2009. © 2008 Wiley‐Liss, Inc.     

Gastric accumulation of bone seeking agent in a patient with advanced gastric cancer

Soft tissue uptake of Tc-99m labeled bone seeking agents, such as Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid (DPD), is commonly seen in clinical practice, even though bone scintigraphy is mainly used to detect bone disease. However, gastric uptake of bone agents in patients with gastric cancer is very rare. And it has been reported that calcified gastric adenocarcinoma appears in only about 5% of all gastric cancer. We report a rare case of bone scintigraphy, single photon emission computed tomography and computed tomography fusion images that demonstrated diffuse gastric uptake of Tc-99m DPD in a patient with advanced gastric cancer.     

A case report of brown tumor in a patient with chronic renal failure and renal cell carcinoma

We report a case of a 72 year old male with hyperparathyroidism secondary to end stage diabetic renal disease and coexisting bilateral chromophobe renal cell carcinomas. The patient presented with back and groin pain, right pelvic hemorrhage, and multiple lytic bone lesions concerning for metastatic renal cell carcinoma. Fine needle aspiration cytology demonstrated benign appearing osteoclasts and spindled cells. A concurrent core biopsy showed foci of spindled cell proliferation populated by osteoclast‐like giant cells with stromal hemorrhage without evidence of metastatic carcinoma. The cytologic and histologic findings, in correlation with the clinical history, radiographic features, markedly increased parathyroid hormone levels and other serologic studies, were diagnostic of the reactive lesion seen in brown tumor of hyperparathyroidism secondary to chronic renal failure.     

Multiple maxillofacial brown tumors as primary hyperparathyroidism manifestation

OBJECTIVE: In order to analyze the differential diagnosis of giant-cell lesion in facial bones, we present a case of a patient without a previously diagnosed primary hyperparathyroidism that displayed multiple maxillofacial brown tumors as the initial clinical manifestation of the disease. CASE DESCRIPTION: A 70 year-old female with amandible tumor and one year of disease progression. Tumor biopsy confirmed the presence of a giant-cell lesion. Radiologically, we confirmed the presence of another two lytic lesions in the maxillofacial region. During biochemical evaluation prior to surgery, the possibility of hyperparathyroidism was considered. Using computed tomography, we noted a parathyroid tumor in an atypical location. Surgical resection confirmed the presence of an adenoma. Postoperatively, the patient developed symptomatic hypocalcemia and was managed with calcium supplementation in addition to calcitriol. At 4 months after surgery mandibular swelling had regressed partially and serum calcium levels returned to normal levels. CONCLUSION: The detection of giant-cell bone lesions in the maxillofacial region is a strategic diagnostic finding as several entities, among these brown tumor hyperparathyroidism can display similar histologic imaging findings. Only systematic clinical, radiologic, and biochemical evaluation can allow for a definitive diagnosis. The presence of multiple simultaneous maxillofacial brown tumors in primary hyperparathyroidism is an infrequent ocurrence, and only on rare occasions can this be the first sign of the disease.     

Ultrastructural morphometry on human parathyroid tissue. Morphological and functional implications

Ultrastructural morphometry was performed on human parathyroid tissue from adenomas in chronic and acute (pernicious) hyperparathyroidism (HPT) including contralateral atrophic glands with the aim to compare the observed alterations with the corresponding clinico-functional findings. Quantitative assessment of various cell organelles, nucleus and cell perimeter revealed that significant correlations between ultrastructural features and laboratory parameters were only calculable by regarding extreme ranges of functional stages, i.e. adenomas of acute HPT (hyperparathyroid crisis) and contralateral atrophic glands. In chief cells of chronic HPT there was an inhomogeneity of measurements due to the disparate composition of the adenomatous tissue. Our results show that large complex lipid bodies and extensive accumulations of glycogen are valuable indicators of a functionally suppressed chief cell in atrophic parathyroid glands. An increased number of coated pits and vesicles is amongst other features (increase in size or number of Golgi apparatus, rough endoplasmic reticulum, mitochondria, nucleus and nucleolus as well as extension of the plasma membrane) characteristic of an endocrine stimulation.     

99Tcm-MIBI SPECT/CT显像联合超声检查在甲状旁腺功能亢进症合并甲状腺癌诊断中的应用

目的 探讨⁹⁹Tc^m-甲氧基异丁基异腈(MIBI)单光子发射计算机断层成像/计算机断层扫描(SPECT/CT)显像联合超声对甲状旁腺功能亢进症(HPT)合并甲状腺癌(TC)的术前诊断价值。方法 回顾性研究。纳入2013年9月—2019年12月经东南大学医学院附属江阴医院乳甲科手术及病理证实的HPT合并TC患者15例,其中男3例、女12例,年龄35～57岁(中位年龄49岁);继发性HPT 10例,原发性HPT 5例。统计术中检出并经术后病理证实的甲状旁腺病灶及TC病灶数;由多学科团队分析术前⁹⁹Tc^m-MIBI SPECT/CT显像及超声检查,比较⁹⁹Tc^m-MIBI SPECT/CT显像及超声对病变甲状旁腺及TC的检出率有无差异。结果 15例HPT合并TC患者术中检出并经术后病理证实的甲状旁腺病灶44枚,⁹⁹Tc^m-MIBI SPECT/CT显像的检出率为86.4%(38/44),高于超声的检出率65.9%(29/44),差异有统计学意义(P＜0.05)。10例继发性HPT合并TC患者手术检出39枚甲状旁腺病灶,⁹⁹Tc^m-MIBI SPECT/CT显像及超声则分别检出33枚(84.6%)和27枚(69.2%),两者比较差异无统计学意义(P＞0.05);5例原发性HPT合并TC患者均为单发病灶,⁹⁹Tc^m-MIBI SPECT/CT显像检出5枚,超声检出2枚、漏检3枚。15例患者术中检出并经术后病理证实的TC病灶共16枚,其中单发14例、多发1例(2枚),⁹⁹Tc^m-MIBI SPECT/CT显像对TC病灶的检出率为5/16低于超声的12/16,两者比较差异有统计学意义(P＜0.05)。结论 ⁹⁹Tc^m-MIBI SPECT/CT显像对HPT合并TC的甲状旁腺病灶的检出率优于超声,而超声对合并的TC诊断优于⁹⁹Tc^m-MIBI SPECT/CT显像,两者联合应用有助于HPT合并TC的诊断。     

Fine needle aspiration of osteitis fibrosa cystica

The cytology findings of a fine needle aspiration biopsy from osteitis fibrosa cystica (brown tumor) of the rib in a patient with primary hyperparathyroidism due to parathyroid carcinoma are discussed. Many multinucleated osteoclast-type giant cells, characteristic of either osteitis fibrosa cystica or benign giant cell tumor of bone, were noted. There were also spindly or fibrillary cells with single, ovoid nuclei, probably of stromal origin.     

Localisation of X linked recessive idiopathic hypoparathyroidism to a 1.5 Mb region on Xq26-q27.

X linked recessive idiopathic hypoparathyroidism (HPT) has been observed in two kindreds from Missouri, USA. Affected subjects, who are males, suffer from infantile onset of epilepsy and hypocalcaemia, which appears to be the result of an isolated congenital defect of parathyroid gland development; females are not affected and are normocalcaemic. The gene causing HPT has been previously mapped to a 7 cM interval, flanked centromerically by F9 and telomerically by DXS98, in Xq26-q27, and an analysis of mitochondrial DNA has established a common ancestry for these two kindreds. In order to define further the map location of HPT and thereby facilitate its isolation, we have undertaken linkage studies using polymorphic loci whose order has been established as Xcen - DXS1001 - DXS294 - DXS102 - F9 - DXS1232 - DXS984 - CDR1 - DXS105 - DXS1205 - DXS1227 - DXS98 - DXS52 - Xqter, within this region. Our results established linkage (lod score > 3) between HPT and eight of these 12 loci and indicated that the most likely location of HPT was within a 1.5 Mb interval flanked centromerically by F9 and telomerically by DXS984. Thus, the results of this study have helped to refine the map location of HPT, and this will facilitate the identification of this putative developmental gene and its role in the embryological formation of the parathyroids.     

Tumors of the parathyroid gland and circulating parathyroid hormone-related protein associated with persistent hypercalcemia

Neoplasms of the parathyroid glands are uncommon in all species of laboratory and domestic animals, but occur in low incidence in rats, Syrian hamsters, and dogs and rarely in mice. Proliferative lesions of the parathyroid gland include hyperplasia (diffuse and focal), adenomas, and carcinomas. The tumors may be functional or nonfunctional. Trophic atrophy of remaining parathyroid tissue is present around functional tumors. Humoral hypercalcemia of malignancy (HHM) is a syndrome that occurs in human and animal patients with certain malignant neoplasms and is characterized by hypercalcemia, hypophosphatemia, and increased osteoclastic bone resorption. The syndrome is thought to be due to the release of parathyroid hormone (PTH)-like factors by the tumor cells which bind to PTH receptors in bone and kidney and result in the clinical manifestations of HHM. Parathyroid hormone-related protein (PTHrP) is a newly purified and sequenced protein which originated from human tumors associated with HHM. PTHrP has been shown to stimulate in vitro and in vivo effects similar to PTH-like proteins isolated from tumors associated with HHM. Well characterized animal models of HHM include a rat Leydig cell tumor line (Rice-500), the rat Walker mammary carcinosarcoma, and the canine apocrine adenocarcinoma. All 3 models have been found to contain 3 biologic activities which are thought to be important in the pathogenesis of HHM, viz., in vitro bone resorbing activity, adenylate cyclase-stimulating activity of bone and kidney cells, and transforming growth factor activity. The first 2 activities are due to PTH-like proteins which are able to compete for binding to the PTH receptor. The complete spectrum of functional disturbances in patients with HHM may be the result of the combined effects of a PTH-like protein (i.e., PTHrP) and transforming growth factors.     

Bone histology at autopsy and matched bone scintigraphy findings in patients with hormone refractory prostate cancer: the effect of bisphosphonate therapy on bone scintigraphy results

Bisphosphonates (BisP) are non-metabolized compounds with high bone affinity used in bone metastasis diagnosis and treatment. Currently, BisP are used to treat hypercalcemia of malignancy as well as to prevent, minimize, or delay skeletal morbidity. These compounds have a long half-life in bone. Thus long-term BisP treatment might saturate bone and interfere with a single-dose scanning agent used for bone scintigraphy when visualizing bone metastases. In an effort to answer this question, this study evaluated the concordance of histology and Technetium⁹⁹ methylene diophosphonate (Tc⁹⁹ MDP) bone scintigraphy in the diagnosis of bone metastases in prostate cancer patients. We assessed the concordance of findings between bone scintigraphy and histology using 188 bone biopsies from 11 autopsied patients who died with metastatic prostate cancer, 5 of whom were treated with pamidronate for 2 to 13 months before death. Overall agreement between histology and bone scintigraphy was 84%, 86% in non-pamidronate-treated patients and 82% in pamidronate-treated patients. Scintigraphic bone metastases without histological metastasis (false negatives = 12.7%) were observed in 24 anatomic locations; half of these were in one patient who had been treated with pamidronate and had no histological bone response to the carcinoma. There were only 4 sites where a positive bone scan was not associated with histologic metastasis (false positives = 2.21%). There was no statistical difference between the treated and non-treated group for concordance, specificity, sensitivity, positive and negative predictive values of bone scintigraphy and prevalence of histological abnormality. Long-term pamidronate treatment of prostate cancer bone metastases does not generally affect the ability to detect bone metastases with Tc⁹⁹ MDP bone scintigraphy. This revised version was published online in July 2006 with corrections to the Cover Date.     

Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11

Familial multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroid glands, the pancreas, and the pituitary gland. Pancreatic tumors have previously been shown to be associated with the loss of alleles on chromosome 11; we therefore looked for similar genetic alterations in specimens of parathyroid tumors, which are the most common feature of MEN-1. We obtained parathyroid tumors and peripheral-blood leukocytes from six patients with MEN-1; 18 cloned human DNA sequences from chromosome 11 were then used to identify restriction-fragment-length polymorphisms. A loss of heterozygosity was detected in parathyroid tumors from three of the six patients with MEN-1; this finding demonstrated that allelic deletions on chromosome 11 are involved in the monoclonal development of parathyroid tumors in patients with MEN-1. In addition, studies of three affected families (with 17 affected members and 51 unaffected members) established linkage with the oncogene INT2 (peak lod score, 3.30, at 0 percent recombination); the MEN-1 gene was thus mapped to the pericentromeric region of the long arm of chromosome 11 (11q13). Our location of the MEN-1 gene at 11q13 is close to the location previously reported. We conclude that a single inherited locus on chromosome 11, band q13, causes MEN-1 and that the monoclonal development of parathyroid and pancreatic tumors in patients with MEN-1 involves similar allelic deletions on chromosome 11.     

Technetium-99m MDP bone scintigraphic findings of hypercalcemia in accelerated phase of chronic myelogenous leukemia

Hypercalcemia in accelerated phase of chronic myelogenous leukemia (CML) is very rare. Its pathogenesis is considered humoral hypercalcemia of malignancies mediated by parathyroid hormone-related protein (PTHrP). In severe hypercalcemia, calcifications in kidneys, skin, vessels, heart, and stomach may occur. Our two cases were admitted because of severe hypercalcemia in accelerated phase of CML. On Tc-99m methylene diphosphonate (MDP) bone scintigraphies, a marked tracer accumulation was seen in the lung, heart, stomach and kidney. We report increased tracer accumulation of multiple organs on Tc-99m MDP bone scintigraphy in two rare hypercalcemic patients with CML.     

Huge juxtacortical brown tumor in two patients with secondary hyper-parathyroidism due to chronic renal failure

The brown tumor of the skeletal system is mainly caused by hyperparathyroidism (HPT), and HPT is divided into three categories according to its causes: primary, secondary and tertiary HPT. The secondary HPT patients with brown tumor caused by chronic renal insufficiency are rarely reported. The tumor occurs mostly in the bones such as metacarpals, phalanges, skull, pelvis, clavicle, ribs, femur and spine. We reported two cases of juxtacortical brown tumor in patients with HPT secondary to chronic renal insufficiency which has never been reported previously.     

Tuberculous granulomatous inflammation associated with adenoma of parathyroid gland manifesting as primary hyperparathyroidism

A 36-year-old female presented with generalized bone pain, muscular weakness, and enlarged cervical lymph nodes. The biochemical findings and skeletal survey were suggestive of primary hyperparathyroidism (PHPT). CT of neck and thorax showed enlarged multiple lymph nodes in the cervical and superior mediastinal region. With a diagnosis of PHPT, she underwent cervical exploration and excision of enlarged right inferior parathyroid gland, along with biopsy of nodes. Histopathology revealed the features of parathyroid adenoma with a few foci of epithelioid granuloma and granulomatous lymphoadenitis. Smear and culture were negative for AFB. A positive PCR for Mycobacterium tuberculosis of the homogenates of parathyroid tumor confirmed tuberculous inflammation within the parathyroid adenoma. To the best of our knowledge, this is the first reported case of parathyroid adenoma associated with tuberculous pathology in a case of PHPT.     

Recurrence in Parathyroid Hyperplasias Owing to Secondary Hyperparathyroidism is Predicted by Morphological Patterns and Proliferative Activity Values

The histological pattern and the cell proliferative activity (as detected by Ki-67 immunostaining) of a series of 50 parathyroid hyperplasias (PTHs) secondary to renal failure were studied to assess their value in predicting recurrence of hyperparathyroidism (HPT). On account of their clinical evolution, these cases were divided into two groups: recurrent HPT (23 cases) and nonrecurrent HPT (27 cases). A nodular growth pattern (as opposed to diffuse) was the prevalent one and was observed in 20 (74%) cases of nonrecurrent HPT and in 22 (95.6%) cases of recurrent HPT, a statistically significant difference (p<0.05). The Ki-67 proliferative fraction was 1.9% in recurrent HPT cases, as compared with 0.81% in nonrecurrent HPT, a difference which was statistically significant (p=0.001). We conclude that a nodular pattern of growth and an elevated Ki-67 proliferative fraction (>1.5%) in PTH are both associated with a higher risk of recurrence (4.30) of HPT.