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PTHRP MALIGNANCY-ASSOCIATED HYPERCALCEMIA
Authored By: Keith Fischer and Livnat Uliel.
Patient: 47 year old male
History:

47 year-old man with cholangiocarcinoma and progressive generalized weakness admitted with altered mental status. The patient's left kidney was surgically resected (no additional information available).

The following study was requested to evaluate metastatic disease. Describe the findings. What additional clinical information will be relevant for the interpretation of this study.

Presented whole body bone scintigraphy study (Figure 1 and Figure 2).

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Fig. 1
Figure 1

Fig. 2
Figure 2

Fig. 3
Figure 3

Fig. 4
Figure 4
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Findings:

22.1 mCi Tc-99m MDP was administered i.v.

The images demonstrate marked increased tracer uptake throughout the axial and appendicular skeleton with pronounced symetric uptake in the periarticular regions of the elbows, wrists, knees and ankles. There is no obvious evidence of osseous metastatic lesions. The hazy activity in the abdomen is related to ascites (Figure 3). There is compensatory hypertrophy of the remaining right kidney.

Delineate your differential diagnosis.

DDx:

Diffuse tracer uptake in the axial and appendicular skeleton can be seen with diffuse metastases (if little or no activity is seen in the soft tissues or urinary tract often referred as a "super scan") and in metabolic bone disease.

The uptake in metabolic bone disease, such as hyperthyroidism, is more uniform in appearance and extends into the distal appendicular skeleton. Intense calvarial uptake that is disproportionate to that in the remainder of the skeleton is another feature of a metabolic etiology (not prominent in our case).

Additional clinical information is provided (Figure 4) to narrow the differential diagnosis: Calcium level 14.9 mg/dL (normal range 8.6-10.3), Phosphorus 1.7 mg/dL (2.3-4.3 mg/dL), PTH 4 pg/mL (normal range 14-72), PTH related protein 5.5 pmol/L (normal <2.0), ALKP 524 Units/L (38-126).

The laboratory results demonstrate moderate hypercalcemia with suppressed TSH. The differential diagnosis includes hypercalcemia associated with cancer, hyperthyroidism, adrenal insufficiency and acromegaly (if malignancy work-up is negative). Hypercalcemia associated with cancer also known as malignant hypercalcemia or humoral hypercalcemia of malignancy, is associated with elevated alkaline phosphatase and elevated PTH related protein as in our case.

Diagnosis: PTHrP Malignancy-Associated Hypercalcemia
General Discussion:

Malignancy-associated hypercalcemia (MAH) is the term used to describe increased levels of calcium found in patients with primary or metastatic cancer. The prevalence of this condition is around 3 to 30% of all cancer patients  not always in correlation of overt bone metastases

 Three main pathogenetic mechanisms may sustain MAH:

1. Release of parathyroid hormone-related protein (PTHrP, as in our case) and, rarely, parathyroid hormone (PTH) itself, with activity on bone and kidney.

2. Ectopic activation of vitamin D to 1,25-dihydroxyvitamin D, which increases bowel calcium absorption with moderate effects on bone and kidney;

3. Direct bone degradation promoted by cancer cells invading the bone stroma and releasing new proteolytic enzymes or those entrapped in the bone-matrix.

 

PTHrP dependent hypercalcemia is usually called “humoral” MAH because it does not require direct bone involvement by tumor cells. The PTHrP has similar PTH effects on the bone and kidney which may be reflected as diffuse increased uptake on bone scintigraphy. However, production of PTHrP and bone lysis often coexist in the same patient with MAH, and therefore the extent of bone involvement seen on bone scintigraphy may not be correlated with the severity of hypercalcemia. PTHrP has been found almost in 100% of blood samples of patients who developed MAH in the absence of bone involvement. High PTHrP levels have been associated with more extended tumor burden as well as with reduced response to bisphosphonates since the pathogenetic contribution of the kidney is not counteracted, thus explaining a poorer prognosis of those patients.

This case is an example of abnormally diffuse increased Tc-99m MDP uptake related to PTHrP induced hypercalcemia in a patient with advanced cholangiocarcinoma with no osseous metastatic lesions.

 

 

References:

Basso U. et al; Malignant Hypercalcemia, Current Medicinal Chemistry 2011;18:3462-3467

A.F. Stewart; Hypercalcemia Associated with Cancer, NEJM 2005;352:373-9

C. Love et al; Radionuclide Bone Imaging: An Illustrative Review, RadioGraphics 2003;23:341-358

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Additional Details:

Case Number: 385072Owner(s): Keith Fischer and Livnat UlielLast Updated: 02-07-2013
Anatomy: Skeletal System   Pathology: Metabolic
Modality: CT, Nuc Med, OtherAccess Level: Readable by all users, writable by NucMed Certifiers
Keywords: hypercalcemia, bone scan

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Certified by Keith Fischer on 01-23-2013

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