Missed diagnosis of lymphoma presenting with humoral hypercalcemia of malignancy due to cessation of oncological workup after negative computed tomography scans

Abstract

Malignancy is the most common cause of hypercalcemia among hospitalised patients and is frequently caused by elevations in parathyroid hormone-related peptide (PTHrP). The most common PTHrP-producing cancers are carcinomas of the head, neck and lung. Hypercalcemia can be the presenting sign of cancer and, in these cases, solid tumours are usually discovered on CT scan. In rare cases, lymphoma may also present with hypercalcemia. CT scan is less sensitive for lymphoma than for most solid tumours and the diagnosis may be missed. We present the case of a 69-year-old woman who presented with hypercalcemia in the setting of severe weight loss and elevated PTHrP. Oncological workup was stopped after unrevealing CT scans and an underlying lymphoma was missed. Our case emphasises the need for a comprehensive oncological workup for patients with unexplained hypercalcemia and elevated PTHrP, even when CT scans are unrevealing.

Background

Hypercalcemia of malignancy is usually caused directly by skeletal metastases or by tumour cell secretion of PTHrP, a process known as humoral hypercalcemia of malignancy (HHM).¹ In non-pathological states, low calcium levels trigger the release of parathyroid hormone (PTH) from the parathyroid glands in a process regulated by negative feedback. PTH increases calcium levels by increasing renal and gut absorption and by promoting bone resorption. Higher calcium levels suppress PTH production. However, malignant production of PTHrP is not sensitive to the negative feedback and can lead to increased calcium levels in an unregulated manner.²

Case presentation

A 69-year-old woman with a medical history of hypertension presented to the emergency department with a 2-week history of confusion and generalised weakness. Eleven days prior to presentation, she had a non-traumatic fall and was taken to another hospital. There she was discharged from the emergency department after intracranial haemorrhage was ruled out. On arrival, the patient was confused and unable to provide history. Her family reported that she never smoked cigarettes, had lost about 50 pounds in the last few months and had become so weak that she had to quit her job as a janitor.

Vital signs were within normal limits and physical exam was notable for generalised weakness. Initial labs were notable for a calcium level of 14.9 (table 1). CT scan of the head was unremarkable. On further lab workup, PTH was 9.0 pg/mL (reference: 12–88 pg/mL), PTHrP was 11.3 pmol/L (reference: 0.0–3.4 pmol/L) and 25-hydroxy vitamin D was 33.41 ng/mL (reference: 20–120 ng/mL). The patient was treated with intravenous fluids, calcitonin and zoledronic acid. Her calcium level normalised over the next 2 days and her confusion resolved. Because of the elevation of PTHrP, the oncology service was consulted. Tumour markers including alpha-fetal protein (AFP), carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) were within normal limits. SPEP and UPEP were unremarkable. CT of the lumbosacral spine, chest, abdomen and pelvis did not show any masses or lytic lesions. The patient was discharged without a diagnosis and missed her outpatient follow-up appointment.

Table 1.

Labs at presentation

Lab	Reference range	Value
WBC	4.0–10.0 thousand/mm3	5.7 thousand/mm3
Haemoglobin	12.0–16.0 g/dL	14.3 g/dL
Hematocrit	35.0%–45.0%	43.2%
Platelet count	150–450 thousand/mm3	262 thousand/mm3
Creatinine	0.38–1.02 mg/dL	1.67 mg/dL
Calcium	8.4–10.2 mg/dL	14.9 mg/dL
Ionised calcium	1.00–1.50 mmol/L	1.62 mmol/L
Albumin	3.5–5.2 g/dL	3.8 g/dL
PTH	12–88 pg/mL	9.0 pg/mL
PTHrP	0.0–3.4 pmol/L	11.3 pmol/L
Alkaline phosphatase	33–133 IU/L	199 IU/L
Vitamin D, 25 hydroxy	20–120 ng/mL	33.41 ng/mL
AFP	0.0–9.0 ng/mL	4.1 ng/mL
CA 19–9	0–35 U/mL	<1 U/mL
CEA	0.0–3.0 ng/mL	1.5 ng/mL
ESR	<20 mm/hour	66 mm/hour
CRP	0.00–5.00 mg/L	19.11 mg/L

AFP, alpha-fetal protein; CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related peptide; WBC, white blood cell.

Five weeks later, the patient returned to the hospital with worsening fatigue, weakness, poor appetite and 25 additional pounds of weight loss.

Investigations

Repeat CT scan of the abdomen showed a heterogeneous liver lesion that had not been seen on prior imaging studies (figure 1). Liver biopsy was performed and demonstrated aggressive diffuse large B-cell lymphoma (DLBCL) with a Ki67 index of 90% and overexpression of c-MYC and BCL-2.

Figure 1.

Liver biopsy demonstrating diffuse dense lymphoid infiltrate composed of intermediate to large cells with vesicular chromatin, inconspicuous nucleoli and scant cytoplasm. Frequent apoptotic figures are seen. These findings were considered to be consistent with an aggressive B-cell lymphoma with germinal centre type (CD10 + and BCL-6+) with high Ki67 index (90%) and overexpression of c-MYC and BCL-2 (double expressor) and also MUM-1 expression.

Treatment

Chemotherapy was initiated with rituximab, etoposide, prednisone, vincristine, cyclophosphamide and hydroxydaunorubicin with intrathecal methotrexate.

Outcome and follow-up

The following week, after her initial return visit in which the aforementioned findings were seen and treatment was begun, the patient returned to the hospital in septic shock. Blood cultures demonstrated group-B Streptococci, methicillin-sensitive Staphylococcus aureus, Klebsiella and Candida albicans in all samples. Despite aggressive measures, the patient developed multi-organ failure and died. The patient’s death came 22 days after her diagnosis with DLBCL and 76 days after her initial presentation to the emergency department with confusion.

Discussion

Malignancy is commonly associated with hypercalcemia and is the most common cause of hypercalcemia among hospitalised patients.² Hypercalcemia of malignancy may be caused by skeletal metastases or by tumour cell secretion of PTHrP, a process known as HHM.¹ Hypercalcemia of malignancy can also be caused by osteolytic metastases or cancerous production of 1,25-dihydroxy vitamin D.³ Although malignancy is usually already diagnosed or grossly apparent by the time hypercalcemia develops, hypercalcemia can be the presenting sign of cancer.² This was the case in our patient. Symptoms of hypercalcemia include polyuria, polydipsia, confusion, nausea, constipation, weakness and headaches. Prognosis associated with hypercalcemia of malignancy is extremely poor; in one study, median survival was just 55 days.⁴

The differential diagnosis of hypercalcemia is short and the diagnostic approach is relatively simple.⁵ More than 90% of cases of hypercalcemia are caused by hyperparathyroidism and malignancy.⁵ Other causes are easy to exclude with history and basic laboratory work; these include vitamin D intoxication, granulomatous disease, medications such as thiazide diuretics, lithium and theophylline, as well as prolonged immobilisation, hyperthyroidism and milk-alkali syndrome.⁵ Once elevated calcium has been confirmed with an ionised calcium level, PTH should be measured.⁵ Elevations in PTH are diagnostic of primary hyperparathyroidism.⁶ When PTH levels are low, as was the case for our patient, PTHrP should be measured.⁶ Although malignancy may be present in the absence of elevated PTHrP (if hypercalcemia is being caused by lytic lesions or malignant vitamin D production), an elevated PTHrP is highly specific for malignancy.⁶ When PTHrP is elevated, subsequent tests should be aimed at identifying the malignancy, usually via CT scan. The most common causes of HHM are squamous cell carcinomas of the head, neck and lung, as well as breast, renal, ovarian and endometrial cancers.⁷

Lymphoma can also present with hypercalcemia and, as was the case for our patient, may not have obvious findings on CT scan. Our patient had low PTH, elevated PTHrP and significant recent weight loss, making malignancy by far the most likely diagnosis. Unfortunately, oncological workup was stopped after unrevealing CT scans. Although CT can usually detect the more common malignancies causing HHM, its sensitivity for lymphoma may be as low as 70%.⁸

When severe hypercalcemia, suppressed PTH and elevated PTHrP are present, malignancy is overwhelmingly likely and using CT alone to rule cancer runs the risk of missing a malignancy. At least three other case reports have described patients with HHM in which CT scan failed to reveal a malignancy and lymphoma was later discovered (table 2).

Table 2.

Lymphomas not visible on CT presenting with hypercalcemia

Age, sex	Calcium at diagnosis ref: (8.5–10.5 mg/dL)	PTH (pg/mL) ref: 15–65)	PTHrP (pmol/L) ref:<1.1	25-OH-D (pg/mL)	Non-diagnostic studies	Diagnostic study	Diagnosis	Treatment	Outcome	Citation
69, F	16.1 mg/dL	16.8 pg/mL	3.7 pmol/L	168 pg/mL	CT C/A/P, SPEP. UPEP, PBS, skeletal survey	BMBx	TC/HRBCL	Hyper-CVAD	Complete remission at 1 year	12
74, M	13.9 mg/dL	5.24 pg/mL	4.0 pmol/L	22.3 pg/mL	CT C/A/P, SPEP/UPEP, PET-CT	BMBx	DLBCL	--	--	13
68, M	20.6 mg/dL	0.8 pg/mL	2.7 pmol/L	22 pg/mL	CT H/C/A/P, LP	PET-CT	IVLBCL	R-CHOP	Complete response, alive at 16 months	9
69, F	14.9 mg/dL	9.0 pg/mL	11.3 pmol/L	33.41 pg/mL	CT C/A/P, SPEP, UPEP	Diagnosis missed	DLBCL	R-EPOCH	Died 22 days after diagnosis, (76 days after presentation)	Current case

CT C/A/P, computed tomography of the chest, abdomen and pelvis; CVAD, cyclophosphamide, vincristine, adriamycin, dexamethasone; DLBCL, diffuse large B-cell lymphoma; PTH, parathyroid hormone; PTHrP, PTH-related peptide; RCHOP, rituximab, cyclophosphamide, hydroxydaunomycin, vincristine, prednisone; R-EPOCH, rituximab, etoposide, prednisone, vincristine, cyclophosphamide and hydroxydaunorubicin; SPEP, serum protein electrophoresis; TC/HRBCL, T-cell/histiocyte-rich B-cell lymphoma; UPEP, urine protein electrophoresis.

In the other three cases, the index of suspicion for underlying malignancy in the setting of elevated calcium and PTHrP was high enough that the authors continued diagnostic workup despite negative serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and unrevealing CT scans of the chest, abdomen and pelvis. In one case, PET-CT showed concerning findings in the spleen and bone marrow that biopsy showed to be intravascular large B-cell lymphoma.⁹ In two cases, diagnosis was made on bone marrow biopsy. These cases demonstrate the importance of continuing oncological workup with empiric bone marrow biopsy when all other workup has been negative.¹⁰ Other options for malignant workup include a skeletal survey, which is more sensitive for malignancy than bone scintigraphy, which is limited to detection of osteoblastic activity.¹¹ Unfortunately, further diagnostic workup was not pursued in our patient, and she was diagnosed without a diagnosis. Our case emphasises the need for a comprehensive oncological workup for patients with unexplained hypercalcemia and elevated PTHrP, even when initial CT scans are unrevealing.

Learning points.

• Malignancies frequently cause hypercalcemia. While cancer is often already diagnosed when hypercalcemia arises, hypercalcemia can also be the presenting sign of cancer.

• Hypercalcemia of malignancy is usually caused by elevations in parathyroid hormone-related peptide (PTHrP) and is often a sign of advanced disease.

• The most common PTHrP-producing cancers are carcinomas of the head, neck and lung, as well as breast, renal, ovarian and endometrial cancers. These tumours are usually visible on CT scan. However, lymphoma may also cause hypercalcemia of malignancy and may be missed on CT scan. When PTHrP is normal, skeletal survey should be pursued and 1,25-dihydroxy vitamin D levels should be obtained to rule out skeletal metastases, primary bone cancer and vitamin D-producing tumours.

• When severe hypercalcemia, suppressed parathyroid hormone and elevated PTHrP are present, malignancy should be strongly suspected. Using CT alone to rule out cancer runs the risk of missing a malignancy.

• Our case emphasises the need for a comprehensive oncological workup for patients with unexplained hypercalcemia and labs suggestive of malignancy in the appropriate clinical setting.

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