African Girl's Symptoms Suggest One Diagnosis, Scans Point to Another

A 10-year old African girl presents to the hospital following referral by her primary care center, due to failure to recover after repeated efforts to manage her presumed malaria. She has a 6-month history of anorexia, weight loss, and easy fatigability. She has also had recurrent headaches and sweating for the past year.

Assessment at the time of presentation determines that her headaches are severe and throbbing, particularly affecting the right temporal area. They have not caused nausea or vomiting, but are associated with excessive sweating and palpitations.

The patient notes that she sweats throughout the day, regardless of her level of activity. It worsens gradually but progressively in the evening, but she has no fever or chills. Similarly, the palpitations are fast, regular, and also begin insidiously. Their intensity gradually increases until they reach a crescendo, then gradually decrease; they usually resolve spontaneously.

Physical examination

The patient is lean and underweight, with a body mass index (BMI) of 12.8 (less than the first percentile for her age). Her weight is 23 kg (71% of expected) and height is 134 cm (23rd percentile, normal stature).

Her pulse rate is 100 bpm, with normal volume, regular, symmetrical, and other peripheral pulses are normal. Blood pressure (BP) ranges from 180/120 to 200/120 mm Hg, and similar when measured on either arm.

Cardiac apex beat is located at the 5th left intercostal space mid-clavicular line, and cardiovascular system and other body systems are otherwise unremarkable.

Her high blood pressure does not respond to treatment with labetalol, captopril, and hydrochlorothiazide.

The patient has no features suggestive of Cushing's syndrome, MEN's syndrome, or skin lesions indicating neurofibromatosis or tuberous sclerosis.

The cardiology team begins treatment with hydrochlorothiazide, carvedilol, and valsartan, and a single dose of intravenous labetalol. Within 5 days, this regimen controls her blood pressure at 92/68 mm Hg.

Laboratory tests including urinalysis, full blood count, blood electrolytes, urea, and creatinine levels return normal results. Chest x-ray (PA) reveals a prominent aortic knuckle, but is otherwise normal.

Abdominal ultrasonography (US) identifies a right kidney with a well circumscribed lower pole mass with internal echoes, compressing the pelvicalyceal system, measuring 3.6 × 3.5 cm. Other abdominal structures are normal.

Computed tomography (CT) scan of the abdomen shows a huge, circumscribed, expansile, isodense mass (HU=37) arising from the renal cortex involving the middle third and lower pole of the right kidney, measuring 4.4 × 3.7 × 4.5 cm, with an estimated volume of 38.1 cc.

With contrast, the scan shows heterogeneous enhancement with prominent vessels coursing through the mass, but no fat density. There is an associated mass effect evidenced by compression of the middle pole of the right kidney.

Scan findings suggest a filling defect within the proximal portion of the right renal vein (extension into the renal vein). The inferior vena cava is within normal limits.

Maximum intensity projection images reveal compression of the right renal artery by the aforementioned mass.

Intravenous administration of a contrast medium shows that the left kidney has prompt and satisfactory excretion. Contrast is not seen in the right ureter, but excretion into the upper pole calyces is noted.

Treatment and Outcome

Surgical findings include a mass seen at the lower pole of the right kidney, infiltrating into the renal parenchyma and extending into the renal vein, compressing on the ureter and right renal artery, but no extension to the inferior vena cava. Lymph nodes are essentially normal. The left kidney is grossly normal.

Two hours following surgery, the patient's blood pressure falls to 60/40 mm Hg, and clinicians discontinued her anti-hypertensive medications.

Case Follow-up

Subsequently, the patient's BP has returned to normal values without anti-hypertensive drugs. All symptoms are resolved, and 5 days later, she is discharged with a BP of 102/60 mm Hg. The histology report leads to a diagnosis of renal cell carcinoma (chromophobe type). Follow-up by the clinic finds that the patient remains well.

Discussion

Clinicians report this case of renal cell carcinoma misdiagnosed as malaria, in a child with nonspecific symptoms and resistant high blood pressure but no sign of an underlying RCC. That her symptoms resolve after nephrectomy makes the case unique in that complete resection confirms RCC as the cause of the symptoms, the case authors suggest.

The variable nature of the clinical manifestations seen in this case demonstrates the importance of routine hypertension screening in children, case authors write. The complex causes of hypertension (HTN) often make it difficult to identify the mechanism underlying high blood pressure in a particular patient. This is why treatment is often designed to affect regulatory factors rather than the cause of the disease, authors note.

Renal cell carcinoma (RCC) is the most common renal tumor in adolescents; the average age at presentation is approximately 10–11 years. Children ages 0–14 years are affected at a 0.3% age-adjusted incident rate across all races and both sexes; it accounts for 3.8% of all renal tumors.

The clinical manifestations of RCC are protean in nature, and only rarely is it a cause of secondary hypertension in children. In fact, authors note that RCC is known as a "tumor of internal medicine" because it is often associated with a constellation of signs, symptoms, and laboratory data abnormalities not related to tumor local effect or its metastases.

Renal cell carcinoma can cause high blood pressure via a range of possible mechanisms, including increased renin secretion, parenchymal or ureteral compression, polycythemia, venous fistula, ischemia, and tumor from juxtaglomerular apparatus (JGA).

Importantly, hypertension is becoming a common finding in the pediatric population, and can have significant long- and short-term health risks to children.

However, the true incidence of hypertension in children is not known, as a result of its arbitrary definition and incomplete BP screening during routine pediatric clinical visits. The fourth report of the Task Force on BP Control in Children, commissioned by the National Heart, Lung, and Blood Institute considers BP normal when the systolic and diastolic values are less than the 90th percentile for the child's age, sex, and height.

Case authors suggest that this may explain the failure of the referral center to check this patient's blood pressure, which ranged from 180/120 mm Hg to 200/120 mm Hg; thus her hypertension was severe, given that 118/76 mm Hg is the recommended value for girls by age and height percentile.

In general, case authors write, the younger the child and the higher the BP, the greater the likelihood that HTN is secondary to an identifiable cause. A secondary cause such as renal parenchymal abnormality is also more commonly found before rather than after puberty, when it is more likely to be essential HTN. Thus, the profile of presentation in this patient suggested renal causes of hypertension.

In children, RCC increases with age, commonly presenting from ages 9 to 15, as in our patient, authors write. However, typical signs such as macroscopic hematuria and abdominal or flank pain were not seen in this patient.

Case authors note that their patient's history might easily have been missed, since her weight loss could be explained by anorexia. The presence of easy fatigability in addition to these symptoms could easily be linked to possible hypertensive heart failure.

While in adults, the RCC tumor predominates in males, there is no sex predominance for RCC in children. In children, only 2% to 3% of malignant renal tumors are proved to be RCC.

According to a survey by the Japanese Society of Pediatric Surgeons, RCC accounts for 1.4% of all renal tumors in patients ages 5 to 9 years and 52.6% in patients ages 10 to 15 years. The incidence of HTN among age-matched controls is close to 20%, and almost 40% of those with RCC experience HTN.

Case authors note that RCC is a unique and challenging tumor because of the frequent occurrence of paraneoplastic syndromes, including hypertension. Therefore, the mechanisms of hypertension in this patient may be multiple, one of which may be a consequence of impeding blood flow to the right kidney or to the intrarenal segments, a mass effect that was confirmed intraoperatively.

Another mechanism may be the local renal parenchymal compression from the large tumor. This may lead to intrarenal ischemia and further increase in renin secretion by the JGA. Ureteral obstruction can cause renin secretion by a similar mechanism.

As well, immunohistochemical studies on RCC tissues suggest that neoplastic proximal tubular cells themselves may secrete renin. That their center was not equipped to perform an immunochemistry study to identify the specific renal tissue involved is a limitation of the case study, case authors note.

About 70% of RCC tumors are radiographically hypervascular; HTN in these cases may be due to increased cardiac output. In certain cases, as seen in this patient, 85% of those with HTN secondary to RCC are normotensive following tumor resection.

Case authors conclude that their findings further confirm the importance of previous recommendations on BP screening in children. Specifically, they reiterate, children over the age of 3 years should have their BP assessed at least once during every health care visit, and in special circumstances, those under age 3 should also be checked.

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