- Email: [email protected]
Parathyromatosis- Rare cause of recurrent hyperparathyroidism
G Model CMRP 329 No. of Pages 4
Current Medicine Research and Practice xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp
Case report
Parathyromatosis- Rare cause of recurrent hyperparathyroidism Ankita Grover, Seema Rao* Department of Histopathology, Sir Ganga Ram Hospital, New Delhi, India
A R T I C L E I N F O
Article history: Received 17 April 2017 Accepted 6 March 2018 Available online xxx
A B S T R A C T
Parathyromatosis is a rare cause of recurrent or persistent hyperparathyroidism. It poses great diagnostic and therapeutic challenge for the pathologist as well as the treating clinician. Parathyroid carcinoma remains a close clinical and histological diagnostic pitfall. We present a case of 44 year old woman who presented with persistent hypercalcemia and underwent multiple neck surgeries over a period of six years when she was finally diagnosed as parathyromatosis. There was also an incidental occurrence of papillary carcinoma of thyroid which is only rarely reported in literature. © 2018 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Sir Ganga Ram Hospital.
1. Introduction Parathyromatosis is defined as presence of multiple nodules of benignhyperfunctioningparathyroidtissueinneckandmediastinum. Parathryomatosis is a rare cause of recurrent or persistent hyperparathyroidism.1 Various theories have been put forward to explain pathogenesis of this lesion. One of the theories suggests hyperplasia of embryonic cell rests present in the neck and mediastinum, also describedasparathyromatosistypeI.2 Secondtheorysuggestsspillage of parathyroid tissue following capsular rupture during prior parathyroidectomy surgery, also known as parathyromatosis type II.1 An older theory considers parathyromatosis as a low grade parathyroid malignancy.3 A preoperative diagnosis is a challenge due to inconsistent imaging studies.4 Lack of awareness about this entity may result in failed attempts at control and eradication of the disease. Management and control of parathyromatosis remains challenging, even after 40 years since it was first described. 2. Case report A 44 year old woman presented with complaints of pain in legs, thighs and abdomen along with nausea and vomiting for past 3 weeks. On USG abdomen, she was found to have enlarged edematous pancreas and left renal stone. On CT scan, there was a lytic bony lesion in left iliac crest and lower lumbar vertebra. SestaMIBI scan revealed presence of suspicious right inferior parathyroid adenoma. Serum PTH was 1050.0 pg/mL with serum calcium of 12.80 mg%. She underwent exploration of the right side
* Corresponding author. E-mail addresses: [email protected] (A. Grover), [email protected] (S. Rao).
of neck. There was a nodular bulge in lower medial aspect of the sternocleidomastoid muscle measuring approximately 1.5 cm in diameter. Exploration of the muscle revealed parathyroid tissue. Another tiny parathyroid tissue nodule was seen lying further distally in the thoracic inlet. Both these nodules were removed and submitted for histopathlogical examination. Previously, patient had presented on multiple occasions with similar clinical complaints over a period of 6 years, and have had multiple hospital admissions and prior surgeries in the neck region for complaints of persistent hyperparathyroidism. The detailed past clinical history is illustrated in Table 1. The present neck exploration yielded two nodular pieces of tissue measuring 1.5 1 1 cm and 1 0.5 0.5 cm. Histological examination revealed a lesion composed of multiple non encapsulated, sharply circumscribed nodules in soft tissue and skeletal muscle. The nodules had pushy borders and were composed of hyperplastic chief cells present in solid groups and diffuse sheets with minimal admixed fat. Focal areas also revealed scattered aggregates of clear cells. No normal parathyroid gland was identified. No cellular atypia, mitotic activity, necrosis, irregular infiltrative borders, vascular or capsular invasion, thick capsule or fibrous bands were noted. Histological features were consistent with parathyromatosis. In the light of the present case, the slides of previous surgical specimens were retrieved and reviewed and the revised diagnoses are given in Table 1. In brief, the review revealed an initial parathyroid adenoma. Subsequent episodes over a period of six years showed mulitple nodules of hyperplastic parathyroid tissue present in fibrofatty tissue, as seen in the present case, without any definite sign of malignancy. Thus a revised diagnosis of parathyromatosis was given (Fig. 1). Patient was prescribed Vitamin D supplementation. On follow up, patient is free from muscular and bone pains. Vitamin D and
https://doi.org/10.1016/j.cmrp.2018.03.003 2352-0817/© 2018 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Sir Ganga Ram Hospital.
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
G Model CMRP 329 No. of Pages 4
2
A. Grover, S. Rao / Current Medicine Research and Practice xxx (2018) xxx–xxx
Table 1 Laboratory, radiological, and operative findings at various time points in the described case report. Time
Ca (mg/dL) Serum
PTH (pg/mL)
25OHD (ng/dL)
BMD
Localization studies
Surgery done
Pathological Diagnosis
Revised diagnosis
PTHadenoma NA NA
PTHadenoma NA NA
PO4 (mg/dL) 2010
11.0
724.02
NA
NA
PET- CT(+)
Rt inf.PTX
1 day later 2mth later 8mths later 2011
NA NA
48.43 135.20
NA NA
NA NA
NA NA
NA NA
NA NA
687.1 853.00
NA 11.8
NA NA
NA USG(+)
NA Parathyroid carcinoma
NA PTHsis
4 days later 1 week later 1 mth later 2 mth later
NA NA 9.6 NA
NA 747.04 653.7 567.2
NA NA NA NA
NA NA NA – 1.9: vertebra – 2.8:humerus – 2.8:femur
NA NA NA Parathyroid scannormal
NA Removal of suspicious tissue Right hemiTX NA NA NA
PTC NA NA NA
PTC NA NA NA
6 mths later
NA
240
58.1
– 1.6:vertebra – 0.3:rt arm – 2.4:femur
Parathyroid scannormal
NA
NA
NA
2013
12.36 1.56
648.7
7.77
NA
NA
NA
NA
2014
NA
NA
NA
NA
CECT( ) sestaMIBI( ) PET-CT ( ) NA
Left HemiTX, parathyroidTX
2016
12.80
1050.0
NA
NA
Lythyroiditis, PTG- N PTHsis
Lythyroiditis, PTG-N NA
2 days later 10 days later 3 weeks later 1 mth later
10.10 9.8 10.38 10.25
NA NA NA 250.8
8.03 NA NA 55.7
NA NA NA NA
NA NA NA NA
NA NA NA NA
sestaMIBI suspicious of Resection of rt inf PTH adenoma parathyroid tissue NA NA NA NA NA NA NA NA
Abbreviations: 25OHD, 25-hydroxyvitamin D; Ca, calcium;PO4, phosphate, PTG, parathyroid gland, PTC, papillary thyroid carcinoma. Reference range: Ca, 8.5-10.5 mg/dL; PO4, 2.7-4.8 mg/dL; PTH, 15–76 pg/mL, mth-month, PTH- parathyroid, PTHsis-parathyromatosis, NA- not available, Ly-lymphocytic. TXthyroidectomy, PTX-parathyroidectomy.
serum calcium levels have normalised, however, parathormone (PTH) is still raised. 3. Discussion Parathyromatosis is defined as multiple foci of benign parathyroid hyperfunctioning tissue in neck and mediastinum resulting in recurrent or persistent hyperparathyroidism.1 Recurrence is defined as recurrent hypercalcemia with high serum PTH levels following a normocalcemic period of atleast 6 months. Persistent disease is defined as evidence of disease recurrence within 6 months of the first parathyroid surgery.5 Palmer et al. described the first case of parathyromatosis in 1975.1 Later in 1977, Reddick classified parathyromatosis as a disease entity.2 This was followed by sporadic case reports and small series describing approximately 40 cases over last four decades. Parathyromatosis most commonly occurs in patients following a prior neck surgery. The parathyroid tissue which spills in the neck and mediastinum during surgical handling of parathyroid adenoma or hyperplastic gland may lead to hyperplasia of these tissue implants as a consequence to hypocalcemia, hypophosphatemia and hypovitaminosis D secondary to chronic renal failure.6 Less commomly, it may develop primarily from embryonic cell rests of parathyroid tissue.2 Parathyromatosis shows a median age of presentation at 47 years (range 18–75 years) with slight female predilection. It occurs most frequently after previous parathyroid surgery in patients with secondary hyperparathyroidism due to chronic renal failure (63%), also in otherwise healthy patients (34%) and uncommonly in
patients with familial primary hyperparathyroidism, MEN1 and 2A (3%).7 Symptoms manifested in the patients include fatigue, weakness, polydipsia, polyuria, bone pain, back pain, constipation, depression, loss of appetite, weight loss, bone fracture and swollen joint.8 Clinically, it presents as recurrent or persistent hypercalcemic state with serum calcium levels not exceeding 14 mg/dl.5 Serum PTH levels show recurrent or persistent increase following surgery. Hypophosphatemia, elevated alkaline phophatase levels may be noted.8 As a rule, preoperative diagnosis is elusive. The diagnosis is suspected in context of previous parathyroid surgeries and recurrent or persistent clinical and biochemical profile. Time and again, diagnosis at the initial surgery is benign parathyroid lesion which may be erroneously reported on repeated surgeries as nodular hyperplasia, adenoma or ectopic parathyroid gland as illustrated in a study by Hage et al.7 Local recurrences following parathyroidectomy surgery raises the suspicion of parathyroid carcinoma. Pathological distinction from parathryoid carcinoma is imperative for the therapy related decisions. Intraoperatively, parathyromatosis presents as multiple small grey tan nodules while parathyroid carcinoma forms a solitary large hard white nodule with infiltrative borders. Both lesions are surrounded by adherent fibrous tissue. Histological features associated with malignacy include capsular invasion, vascular invasion, mitoses 5/10 HPF, trabecular growth pattern, broad intratumoral fibrous band, coagulative tumor necrosis and diffuse cellular atypia with macronucleoli.5 Fernandez-Ranvier GG et al. have reported occurrence of some of these features in cases of parathyromatosis as well.5 Thus, these histological features are not absolutely
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
G Model CMRP 329 No. of Pages 4
A. Grover, S. Rao / Current Medicine Research and Practice xxx (2018) xxx–xxx
3
Fig. 1. 1a, Parathyromatosis, multiple nodules of hyperplastic parathyroid tissue present in fibrofatty tissue. 1b, Review of slides from initial surgical specimen revealing parathyroid adenoma. 1c, presence of parathyroid tissue presenting as infiltrating nodules. 1d, Papillary carcinoma thyroid.
Table 2 Distinguishing parathyromatosis from parathyroid carcinoma. Features
Parathyromatosis
Parathyroid carcinoma
14 mg/dl. 14 mg/dl Blood calcium level Associated with secondary hyperparathyroidism primary hyperparathyroidism Capsule Absence of real capsule, well circumscribed nodule Encapsulated nodule with capsular invasion and/or infiltrative margins Infiltration into surrounding structures Absent Present (thyroid, esophagus, nerves or soft tissue) Distant metastasis Absent Present
reliable for the distinction between the two entities and therefore should be used with caution. Table 2 highlights the differences between parathyromatosis and parathyroid carcinoma. Use of some immunohistochemical markers has been suggested for distinction of parathyromatosis from parathyroid carcinoma. Rbretinoblastoma expression, loss of parafibromin and overexpression of galectin-3 are seen in the latter.9 Galectin 3 overexpression has been reported in benign parathyroid lesions also.10 Distinguishing parathyromatosis from parathyroid adenoma is easier as it lacks the encapsulation and classical features of the latter. Management of parathyromatosis remains a challenge. Surgical management aimed at removal of all the disseminated nodules is rarely successful, which is complicated by scarring of surgical field.7 Medical management forms the cornerstone of therapy. Vit D replenishing helps in reducing PTH level and bone turnover.11 Cinacalcet, an oral calcimimetic that binds to calcium sensing receptor resulting in decreased PTH secretion, has been used especially in chronic renal failure patients with some success.12
Bisphosphonates are another group of drug which have shown inconsistent results in cases associated with primary hyperparathyroidism.13 Data on their use in chronic renal failure patients is lacking. Parathyromatosis remains a difficult condition to treat. Repeated recurrences occur despite surgical and medical options during the usual course of the disease with associated morbidity and mortality. Another exclusive observation in this case is incidental coexistence of papillary carcinoma of thyroid with parathyromatosis. Association of papillary carcinoma of thyroid with parathyromatosis has earlier been reported only in one case report.14 4. Conclusion Parathyromatosis is a rare cause of recurrent and persistent hyperparathyroidism which must be differentiated from parathyroid carcinoma. Careful surgical practice and avoiding capsular rupture during parathyroid surgery can prevent occurrence of parathyromatosis. Awareness about this rare entity can prevent
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
G Model CMRP 329 No. of Pages 4
4
A. Grover, S. Rao / Current Medicine Research and Practice xxx (2018) xxx–xxx
unwarranted surgeries in patients with recurrent hyperparathyroidism which are often met with failure. Conflict of interest None. References 1. Palmer JA, Brown WA, Kerr WH, Rosen IB, Watters NA. The surgical aspects of hyperparathyroidism. Arch Surg. 1975;110:1004–1007. 2. Reddick RL, Costa JC, Marx SJ. Parathyroid hyperplasia and parathyromatosis. Lancet. 1977;1:549. 3. Barnes BA, Cope O. Carcinoma of the parathyroid glands: report of 10 cases with endocrine function. JAMA. 1961;178:556–559. 4. Matsuoka S, Tominaga Y, Sato T, et al. Recurrent renal hyperparathyroidism caused by parathyromatosis. World J Surg. 2007;31:299–305. 5. Fernandez-Ranvier GG, Khanafshar E, Jensen K, et al. Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis. Cancer. 2007;110:255–264.
6. Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone. 1997;20:303–309. 7. Hage MP, Salti I, El-Hajj Fuleihan G. Parathyromatosis: a rare yet problematic etiology of recurrent and persistent hyperparathyroidism. Metabolism. 2012;61:762–775. 8. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a casecontrol study. Ann Surg. 1995;222:402–414. 9. Fernandez-Ranvier GG, Khanafshar E, Tacha D, et al. Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer. 2009;115:334–344. 10. Saggiorato E, Bergero N, Volante M, et al. Galectin-3 and Ki-67 expression in multiglandular parathyroid lesions. Am J Clin Pathol. 2006;126:59–66. 11. Rolighed L, Bollerslev J, Mosekilde L. Vitamin D treatment in primary hyperparathyroidism. Curr Drug Saf. 2011;6(April (2)):100–107. 12. Unbehaun R, Lauerwald W. Successful use of cinacalcetHCl in a patient with end-stage renal failure and refractory secondary hyperparathyroidism due to parathyromatosis. Clin Nephrol. 2007;67:188–192. 13. Miller PD. The kidney and bisphosphonates. Bone. 2011;49:77–81. 14. Diaconescu MR, Glod M, Mirela G, Smaranda S. Parathyromatosis coexisting with papillary thyroid microcarcinoma. Chirurgia (Bucur). 2011;106:669–672.
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
Current Medicine Research and Practice xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Current Medicine Research and Practice journal homepage: www.elsevier.com/locate/cmrp
Case report
Parathyromatosis- Rare cause of recurrent hyperparathyroidism Ankita Grover, Seema Rao* Department of Histopathology, Sir Ganga Ram Hospital, New Delhi, India
A R T I C L E I N F O
Article history: Received 17 April 2017 Accepted 6 March 2018 Available online xxx
A B S T R A C T
Parathyromatosis is a rare cause of recurrent or persistent hyperparathyroidism. It poses great diagnostic and therapeutic challenge for the pathologist as well as the treating clinician. Parathyroid carcinoma remains a close clinical and histological diagnostic pitfall. We present a case of 44 year old woman who presented with persistent hypercalcemia and underwent multiple neck surgeries over a period of six years when she was finally diagnosed as parathyromatosis. There was also an incidental occurrence of papillary carcinoma of thyroid which is only rarely reported in literature. © 2018 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Sir Ganga Ram Hospital.
1. Introduction Parathyromatosis is defined as presence of multiple nodules of benignhyperfunctioningparathyroidtissueinneckandmediastinum. Parathryomatosis is a rare cause of recurrent or persistent hyperparathyroidism.1 Various theories have been put forward to explain pathogenesis of this lesion. One of the theories suggests hyperplasia of embryonic cell rests present in the neck and mediastinum, also describedasparathyromatosistypeI.2 Secondtheorysuggestsspillage of parathyroid tissue following capsular rupture during prior parathyroidectomy surgery, also known as parathyromatosis type II.1 An older theory considers parathyromatosis as a low grade parathyroid malignancy.3 A preoperative diagnosis is a challenge due to inconsistent imaging studies.4 Lack of awareness about this entity may result in failed attempts at control and eradication of the disease. Management and control of parathyromatosis remains challenging, even after 40 years since it was first described. 2. Case report A 44 year old woman presented with complaints of pain in legs, thighs and abdomen along with nausea and vomiting for past 3 weeks. On USG abdomen, she was found to have enlarged edematous pancreas and left renal stone. On CT scan, there was a lytic bony lesion in left iliac crest and lower lumbar vertebra. SestaMIBI scan revealed presence of suspicious right inferior parathyroid adenoma. Serum PTH was 1050.0 pg/mL with serum calcium of 12.80 mg%. She underwent exploration of the right side
* Corresponding author. E-mail addresses: [email protected] (A. Grover), [email protected] (S. Rao).
of neck. There was a nodular bulge in lower medial aspect of the sternocleidomastoid muscle measuring approximately 1.5 cm in diameter. Exploration of the muscle revealed parathyroid tissue. Another tiny parathyroid tissue nodule was seen lying further distally in the thoracic inlet. Both these nodules were removed and submitted for histopathlogical examination. Previously, patient had presented on multiple occasions with similar clinical complaints over a period of 6 years, and have had multiple hospital admissions and prior surgeries in the neck region for complaints of persistent hyperparathyroidism. The detailed past clinical history is illustrated in Table 1. The present neck exploration yielded two nodular pieces of tissue measuring 1.5 1 1 cm and 1 0.5 0.5 cm. Histological examination revealed a lesion composed of multiple non encapsulated, sharply circumscribed nodules in soft tissue and skeletal muscle. The nodules had pushy borders and were composed of hyperplastic chief cells present in solid groups and diffuse sheets with minimal admixed fat. Focal areas also revealed scattered aggregates of clear cells. No normal parathyroid gland was identified. No cellular atypia, mitotic activity, necrosis, irregular infiltrative borders, vascular or capsular invasion, thick capsule or fibrous bands were noted. Histological features were consistent with parathyromatosis. In the light of the present case, the slides of previous surgical specimens were retrieved and reviewed and the revised diagnoses are given in Table 1. In brief, the review revealed an initial parathyroid adenoma. Subsequent episodes over a period of six years showed mulitple nodules of hyperplastic parathyroid tissue present in fibrofatty tissue, as seen in the present case, without any definite sign of malignancy. Thus a revised diagnosis of parathyromatosis was given (Fig. 1). Patient was prescribed Vitamin D supplementation. On follow up, patient is free from muscular and bone pains. Vitamin D and
https://doi.org/10.1016/j.cmrp.2018.03.003 2352-0817/© 2018 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Sir Ganga Ram Hospital.
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
G Model CMRP 329 No. of Pages 4
2
A. Grover, S. Rao / Current Medicine Research and Practice xxx (2018) xxx–xxx
Table 1 Laboratory, radiological, and operative findings at various time points in the described case report. Time
Ca (mg/dL) Serum
PTH (pg/mL)
25OHD (ng/dL)
BMD
Localization studies
Surgery done
Pathological Diagnosis
Revised diagnosis
PTHadenoma NA NA
PTHadenoma NA NA
PO4 (mg/dL) 2010
11.0
724.02
NA
NA
PET- CT(+)
Rt inf.PTX
1 day later 2mth later 8mths later 2011
NA NA
48.43 135.20
NA NA
NA NA
NA NA
NA NA
NA NA
687.1 853.00
NA 11.8
NA NA
NA USG(+)
NA Parathyroid carcinoma
NA PTHsis
4 days later 1 week later 1 mth later 2 mth later
NA NA 9.6 NA
NA 747.04 653.7 567.2
NA NA NA NA
NA NA NA – 1.9: vertebra – 2.8:humerus – 2.8:femur
NA NA NA Parathyroid scannormal
NA Removal of suspicious tissue Right hemiTX NA NA NA
PTC NA NA NA
PTC NA NA NA
6 mths later
NA
240
58.1
– 1.6:vertebra – 0.3:rt arm – 2.4:femur
Parathyroid scannormal
NA
NA
NA
2013
12.36 1.56
648.7
7.77
NA
NA
NA
NA
2014
NA
NA
NA
NA
CECT( ) sestaMIBI( ) PET-CT ( ) NA
Left HemiTX, parathyroidTX
2016
12.80
1050.0
NA
NA
Lythyroiditis, PTG- N PTHsis
Lythyroiditis, PTG-N NA
2 days later 10 days later 3 weeks later 1 mth later
10.10 9.8 10.38 10.25
NA NA NA 250.8
8.03 NA NA 55.7
NA NA NA NA
NA NA NA NA
NA NA NA NA
sestaMIBI suspicious of Resection of rt inf PTH adenoma parathyroid tissue NA NA NA NA NA NA NA NA
Abbreviations: 25OHD, 25-hydroxyvitamin D; Ca, calcium;PO4, phosphate, PTG, parathyroid gland, PTC, papillary thyroid carcinoma. Reference range: Ca, 8.5-10.5 mg/dL; PO4, 2.7-4.8 mg/dL; PTH, 15–76 pg/mL, mth-month, PTH- parathyroid, PTHsis-parathyromatosis, NA- not available, Ly-lymphocytic. TXthyroidectomy, PTX-parathyroidectomy.
serum calcium levels have normalised, however, parathormone (PTH) is still raised. 3. Discussion Parathyromatosis is defined as multiple foci of benign parathyroid hyperfunctioning tissue in neck and mediastinum resulting in recurrent or persistent hyperparathyroidism.1 Recurrence is defined as recurrent hypercalcemia with high serum PTH levels following a normocalcemic period of atleast 6 months. Persistent disease is defined as evidence of disease recurrence within 6 months of the first parathyroid surgery.5 Palmer et al. described the first case of parathyromatosis in 1975.1 Later in 1977, Reddick classified parathyromatosis as a disease entity.2 This was followed by sporadic case reports and small series describing approximately 40 cases over last four decades. Parathyromatosis most commonly occurs in patients following a prior neck surgery. The parathyroid tissue which spills in the neck and mediastinum during surgical handling of parathyroid adenoma or hyperplastic gland may lead to hyperplasia of these tissue implants as a consequence to hypocalcemia, hypophosphatemia and hypovitaminosis D secondary to chronic renal failure.6 Less commomly, it may develop primarily from embryonic cell rests of parathyroid tissue.2 Parathyromatosis shows a median age of presentation at 47 years (range 18–75 years) with slight female predilection. It occurs most frequently after previous parathyroid surgery in patients with secondary hyperparathyroidism due to chronic renal failure (63%), also in otherwise healthy patients (34%) and uncommonly in
patients with familial primary hyperparathyroidism, MEN1 and 2A (3%).7 Symptoms manifested in the patients include fatigue, weakness, polydipsia, polyuria, bone pain, back pain, constipation, depression, loss of appetite, weight loss, bone fracture and swollen joint.8 Clinically, it presents as recurrent or persistent hypercalcemic state with serum calcium levels not exceeding 14 mg/dl.5 Serum PTH levels show recurrent or persistent increase following surgery. Hypophosphatemia, elevated alkaline phophatase levels may be noted.8 As a rule, preoperative diagnosis is elusive. The diagnosis is suspected in context of previous parathyroid surgeries and recurrent or persistent clinical and biochemical profile. Time and again, diagnosis at the initial surgery is benign parathyroid lesion which may be erroneously reported on repeated surgeries as nodular hyperplasia, adenoma or ectopic parathyroid gland as illustrated in a study by Hage et al.7 Local recurrences following parathyroidectomy surgery raises the suspicion of parathyroid carcinoma. Pathological distinction from parathryoid carcinoma is imperative for the therapy related decisions. Intraoperatively, parathyromatosis presents as multiple small grey tan nodules while parathyroid carcinoma forms a solitary large hard white nodule with infiltrative borders. Both lesions are surrounded by adherent fibrous tissue. Histological features associated with malignacy include capsular invasion, vascular invasion, mitoses 5/10 HPF, trabecular growth pattern, broad intratumoral fibrous band, coagulative tumor necrosis and diffuse cellular atypia with macronucleoli.5 Fernandez-Ranvier GG et al. have reported occurrence of some of these features in cases of parathyromatosis as well.5 Thus, these histological features are not absolutely
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
G Model CMRP 329 No. of Pages 4
A. Grover, S. Rao / Current Medicine Research and Practice xxx (2018) xxx–xxx
3
Fig. 1. 1a, Parathyromatosis, multiple nodules of hyperplastic parathyroid tissue present in fibrofatty tissue. 1b, Review of slides from initial surgical specimen revealing parathyroid adenoma. 1c, presence of parathyroid tissue presenting as infiltrating nodules. 1d, Papillary carcinoma thyroid.
Table 2 Distinguishing parathyromatosis from parathyroid carcinoma. Features
Parathyromatosis
Parathyroid carcinoma
14 mg/dl. 14 mg/dl Blood calcium level Associated with secondary hyperparathyroidism primary hyperparathyroidism Capsule Absence of real capsule, well circumscribed nodule Encapsulated nodule with capsular invasion and/or infiltrative margins Infiltration into surrounding structures Absent Present (thyroid, esophagus, nerves or soft tissue) Distant metastasis Absent Present
reliable for the distinction between the two entities and therefore should be used with caution. Table 2 highlights the differences between parathyromatosis and parathyroid carcinoma. Use of some immunohistochemical markers has been suggested for distinction of parathyromatosis from parathyroid carcinoma. Rbretinoblastoma expression, loss of parafibromin and overexpression of galectin-3 are seen in the latter.9 Galectin 3 overexpression has been reported in benign parathyroid lesions also.10 Distinguishing parathyromatosis from parathyroid adenoma is easier as it lacks the encapsulation and classical features of the latter. Management of parathyromatosis remains a challenge. Surgical management aimed at removal of all the disseminated nodules is rarely successful, which is complicated by scarring of surgical field.7 Medical management forms the cornerstone of therapy. Vit D replenishing helps in reducing PTH level and bone turnover.11 Cinacalcet, an oral calcimimetic that binds to calcium sensing receptor resulting in decreased PTH secretion, has been used especially in chronic renal failure patients with some success.12
Bisphosphonates are another group of drug which have shown inconsistent results in cases associated with primary hyperparathyroidism.13 Data on their use in chronic renal failure patients is lacking. Parathyromatosis remains a difficult condition to treat. Repeated recurrences occur despite surgical and medical options during the usual course of the disease with associated morbidity and mortality. Another exclusive observation in this case is incidental coexistence of papillary carcinoma of thyroid with parathyromatosis. Association of papillary carcinoma of thyroid with parathyromatosis has earlier been reported only in one case report.14 4. Conclusion Parathyromatosis is a rare cause of recurrent and persistent hyperparathyroidism which must be differentiated from parathyroid carcinoma. Careful surgical practice and avoiding capsular rupture during parathyroid surgery can prevent occurrence of parathyromatosis. Awareness about this rare entity can prevent
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003
G Model CMRP 329 No. of Pages 4
4
A. Grover, S. Rao / Current Medicine Research and Practice xxx (2018) xxx–xxx
unwarranted surgeries in patients with recurrent hyperparathyroidism which are often met with failure. Conflict of interest None. References 1. Palmer JA, Brown WA, Kerr WH, Rosen IB, Watters NA. The surgical aspects of hyperparathyroidism. Arch Surg. 1975;110:1004–1007. 2. Reddick RL, Costa JC, Marx SJ. Parathyroid hyperplasia and parathyromatosis. Lancet. 1977;1:549. 3. Barnes BA, Cope O. Carcinoma of the parathyroid glands: report of 10 cases with endocrine function. JAMA. 1961;178:556–559. 4. Matsuoka S, Tominaga Y, Sato T, et al. Recurrent renal hyperparathyroidism caused by parathyromatosis. World J Surg. 2007;31:299–305. 5. Fernandez-Ranvier GG, Khanafshar E, Jensen K, et al. Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis. Cancer. 2007;110:255–264.
6. Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone. 1997;20:303–309. 7. Hage MP, Salti I, El-Hajj Fuleihan G. Parathyromatosis: a rare yet problematic etiology of recurrent and persistent hyperparathyroidism. Metabolism. 2012;61:762–775. 8. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a casecontrol study. Ann Surg. 1995;222:402–414. 9. Fernandez-Ranvier GG, Khanafshar E, Tacha D, et al. Defining a molecular phenotype for benign and malignant parathyroid tumors. Cancer. 2009;115:334–344. 10. Saggiorato E, Bergero N, Volante M, et al. Galectin-3 and Ki-67 expression in multiglandular parathyroid lesions. Am J Clin Pathol. 2006;126:59–66. 11. Rolighed L, Bollerslev J, Mosekilde L. Vitamin D treatment in primary hyperparathyroidism. Curr Drug Saf. 2011;6(April (2)):100–107. 12. Unbehaun R, Lauerwald W. Successful use of cinacalcetHCl in a patient with end-stage renal failure and refractory secondary hyperparathyroidism due to parathyromatosis. Clin Nephrol. 2007;67:188–192. 13. Miller PD. The kidney and bisphosphonates. Bone. 2011;49:77–81. 14. Diaconescu MR, Glod M, Mirela G, Smaranda S. Parathyromatosis coexisting with papillary thyroid microcarcinoma. Chirurgia (Bucur). 2011;106:669–672.
Please cite this article in press as: A. Grover, S. Rao, Parathyromatosis- Rare cause of recurrent hyperparathyroidism, Curr Med Res Pract. (2018), https://doi.org/10.1016/j.cmrp.2018.03.003