Paroxysmal Hypertension Associated With Urination

Case Introduction

Two cases were hospitalized in our hospital at the same period. Case 1 was a 40-year-old woman who presented with a 2-year history of episodes of high blood pressure associated with severe headache, pallor in appearance, and cold sweating. The high blood pressure episodes occurred within 1 to 2 minutes after urination, at which time her blood pressure shot up to 180/120 mm Hg. They only lasted for a few minutes and then relieved spontaneously. However, she complained of a 1-month history of aggressive symptoms before admission. Her father had a history of hypertension. On physical examination, her blood pressure was 130/80 mm Hg, with a heart rate of 70 bpm. Other systemic examinations were normal. The urinalysis, electrocardiography and echocardiography tests were normal.

Case 2 was a 50-year-old man with a 10-year history of episodic hypertension, and his symptoms also appeared 1 to 2 minutes after urination, especially after the first-morning urine. His blood pressure was slightly higher than case 1 at 200–250/100–120 mm Hg, and his symptoms lasted for a few seconds to 5 minutes. However, strikingly, he was very nervous and scared of urination. In terms of physical examination, we found that he was slightly overweight with a blood pressure of 146/68 mm Hg. Echocardiography examination revealed a thickened interventricular septum of 13 mm and left ventricular diastolic dysfunction.

In summary, our patients both had remarkable postmicturition symptoms, including paroxysmal hypertension, severe headache, palpitation, and sweating. However, their symptoms only lasted a few minutes and recovered spontaneously. What possible diagnoses and further examinations would you suggest?

Discussion: Further Examinations

Professor Staessen: I would probably do a bladder endoscopy and echography of the lower urinary tract.

Dr Almustafa: From the presentation, being a primary care physician and a clinical hypertension specialist, I would say it seems that I am facing a case of pheochromocytoma-like symptoms. Let me go further. Are there any complications? Anything else? I may give the patient a monitor for ambulatory blood pressure to take home if the office blood pressure is not that high, just to give me more clarification about this pheochromocytoma. In addition, I would definitely go for a fundus to look for any, what seems to be, masked hypertension. I may see some findings, some early changes of hypertensive fundus changes. In addition, I may go further than the ambulatory blood pressure and fundus examination. I have not heard anything about the electrocardiography findings, which could make it simple for a primary care physician to be suspicious earlier.

Professor Dominiczak: Could I revisit Professor Staessen’s suggestion? With these symptoms, I would be very careful to proceed to cystoscopy since we know that, if our second speaker is right, any anesthesia, procedure or pressing on the source of excessive catecholamines in such a patient could really cause a storm and a very severe situation. So, I would want to first measure things in the laboratory before I proceed to any procedure at all because I have seen tragedy with patients like that.

Associate Professor Staessen: I agree.

Dr Ching: I am also a specialist, so I totally agree with Professor Dominiczak’s suggestion. In addition to assessing for secondary organ damage, I would also like to confirm the diagnosis. Of course, because episodic hypertension together with severe headaches and the adrenergic response suggests pheochromocytoma, I would order 24-hour urinary catecholamines. I would also assess renal function and urinary albumin to assess for secondary organ damage. Since we want to confirm the diagnosis on top of ruling out that this is resistant hypertension, we have to look for secondary organ damage and confirm the diagnosis.

Professor Dominiczak: Okay, so we have similar comments. Any other additional comments that do not confirm the same?

Professor Staessen: One way or another, one has to document increased excretion of catecholamines from 24-hour urinary collections.

Professor Dominiczak: In our center, we would collect 24-hour urinary excretion of every catecholamine we can measure and that would give us a first indication. With this presentation, they would be sky-high, I think.

Biochemical Tests

According to typical symptomatic indications, we suspected the diagnosis of pheochromocytoma or paraganglioma (PPGLs) in these cases. We performed plasma catecholamine examinations 4 times upon symptom attack in case 1. In the latter 2 examinations, we observed slight elevations of norepinephrine and epinephrine. Also, we performed plasma-free metanephrine examinations, but nothing interesting was observed. Nevertheless, the 24-hour urinary fractionated metanephrine examination revealed slightly elevated normetanephrine (Table).

In case 2, during the 4 examinations, we found remarkably elevated norepinephrine and epinephrine. We also found around 4- to 7-fold elevation of plasma-free normetanephrine. Additionally, the 24-hour urinary fractionated metanephrine examination revealed dramatically elevated normetanephrine and nearly 1.5-fold elevated metanephrine (Table).

Since biochemical tests of PPGLs were positive, what next step would you suggest? As we all know, the pheochromocytomas are derived from the adrenal gland, and the paragangliomas are derived from extra-adrenal chromaffin cells.^1,2 What would you suggest to find the tumor?

Discussion: Finding the Tumor

Dr Almustafa: I guess once the biochemical tests of PPGLs are positive, I would go for a computed tomography (CT) of the abdomen to clarify whether there is something, before performing further examination. Maybe the CT would be the next step I would do.

Professor Dominiczak: So, what is your first test?

Dr Almustafa: I would go for a CT of the abdomen.

Professor Dominiczak: CT of the abdomen?

Dr Qi: I think the symptoms were induced by micturition. So, I think the bladder should be checked first. I think the first test should be ultrasonography, then CT, and finally, maybe, endoscopy.

Associate Professor Ching: We should consider noninvasive and invasive ways of testing. So, noninvasively, we of course have to make sure that these manifestations are really related to urination. I would like to measure blood pressure before and after urination. And after that, of course, a CT of the abdomen would be first because I think that in the presentation, the ultrasound was normal. So, I think a CT of the abdomen would be my first line. But, of course, from there, I could identify the location and then decide later whether I want to perform the invasive tests.

Professor Persu: I agree with the CT angiography proposal, but in parallel, or immediately after, I would go for some sort of scintigraphy, such as metaiodobenzylguanidine scintigraphy. This is because first, it could be a very small tumor that is difficult to detect by CT, and second, it would allow for detection of additional associated paraganglioma elsewhere, maybe.

Ultrasound Results

Since the symptoms were related to micturition, we thought the tumor could be close to the urinary bladder. We chose ultrasound first because this is the easiest and most economical modality. For case 1, the result of the abdominal and pelvic ultrasound was negative. But, in case 2, we found a 35×20 mm-sized mass located in the anterior part of the urinary bladder.

For case 1, we had to ask ourselves: are we in the correct direction of diagnosis? Case 1 was a middle-aged female patient with episodic hypertension, palpitation, headache, and sweating, but only slightly elevated metanephrines levels were observed. Furthermore, pelvic ultrasound was normal. Is it possible that this patient just has some kind of psychosomatic disorder, such as anxiety or panic attacks, which can be common in middle-aged female patients?

Discussion: Directions for Diagnosis

Dr Almustafa: Ambulatory blood pressure would clarify the issue, and I cannot really imagine that a panic attack may account for such dramatic symptoms after micturition. And, if it is so, it means that I am dealing with a urologic problem that I need to solve very urgently, which will also necessitate a CT of the abdomen and pelvis. I do agree with ultrasound to begin with, but this will not answer the issue. Ultrasound has to be done just for a quick answer, but it will not tell me whether to do CT or not. I am going to do CT, whatever the results of the ultrasound.

Dr Bursztyn: I have a comment about the slightly elevated metanephrine. When testing for catecholamines and metanephrines, preanalytical procedures are of extreme importance. Was the patient sitting or lying down? Was the temperature cold, or was it pleasant? Was it a noisy place? Catecholamines and metanephrines are quite sensitive to preanalytical procedures, which unfortunately is sometimes forgotten.

Professor Dominiczak: Another consideration is drug treatment and whether the patient is on any drug treatment that could interfere with the measurements.

Dr Li: I agree with the presenting doctors that it is possible this female patient had a panic attack. However, even if the ultrasound examination is negative, we still need more accurate imaging to exclude the possibility of pheochromocytoma.

Images of CT scans

We performed CT scans in these 2 patients (Figure 1) according to the recommendation that CT, rather than magnetic resonance imaging, is the first-choice imaging study for thorax, abdomen, and pelvic PPGLs from the Guidelines.^3,4 The adrenal CT scan revealed nothing special. But, in case 1, the pelvic CT scan disclosed an 8.2×10.5 mm mass located in the right back wall of the bladder, with an increase in density after iodine injection.

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Similarly, in case 2, pelvic CT showed a large mass located at the anterior wall of the bladder.

Finally, the CT scan helped us find the tumor in the female patient. The extremely small size and hidden location of the tumor might explain why we could not find it easily. The next question is is that enough for these 2 patients? What kind of other examination do you think they should undergo next?

Discussion: Next Steps

Professor Persu: Now it is time to perform scintigraphy—for example, MIBG scintigraphy—to confirm the diagnosis but also to be sure there are no additional lesions.

Functional Imaging Examinations

Functional imaging examinations are very important for the diagnosis of PPGLs, are complementary to anatomic imaging, and provide functional characterization of tumors. Also, functional imaging examination is a whole-body exploration and is particularly useful for the evaluation of multifocality or for detection of metastatic disease. Functional imaging examinations include MIBG, octreotide scintigraphy, and positron emission tomography.^4–6

We performed octreotide scintigraphy and iodine-131-MIBG scintigraphy (Figure 2) and found no focal area of increased tracer uptake in the whole-body survey of case 1. But, in case 2, we found an increased ¹³¹I-MIBG uptake of the 27×30-mm sized mass in the anterior wall of the bladder.

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Why is the octreotide scintigraphy negative in both patients?

Discussion: Diagnostic Accuracy of Scintigraphy

Professor Persu: I think octreotide scintigraphy performs better in the nonsecreting head and neck paraganglioma, while MIBG is more for adrenal or, maybe, extra-adrenal pheochromocytoma with catecholamine secretion. However, you had to perform both because it may vary from case to case.

Dr Lou: As we all know, octreotide scintigraphy is a somatostatin receptor scintigraphy, and somatostatin receptors are expressed in many kinds of neuroendocrine tumors. The sensitivity of the octreotide scintigraphy is highly body-region dependent. A previous study analyzed SDHx gene-related PPGLs in patients, finding the highest octreotide sensitivity in head and neck paragangliomas and the lowest sensitivity in abdomen paragangliomas and pheochromocytomas.⁷ Given the limited study population, determining the sensitivity and specificity of octreotide scintigraphy requires more large-scale clinical studies. The next question is how to explain the difference of the MIBG results in these 2 patients.

Dr Bursztyn: Usually, there is quite good correlation between the level of secretory potential of the tumor and its uptake. So, I think in case 1, the minimally elevated catecholamines and the small size of the tumor would be the causes, if it was negative.

Dr Lou: For case 1, a smaller tumor always leads to less function, so it may lead to a false-negative in MIBG scintigraphy. Also, the sensitivity of MIBG scintigraphy ranges from 56% to 75% for paragangliomas, which means almost one-third of patients are MIBG-negative.⁴

Case Resolution and Prognosis

The diagnosis of these 2 patients is urinary bladder paraganglioma and the therapeutic strategy is surgery after appropriate medical preparation.

Case 1 underwent transurethral resection of the bladder tumor after orally taking an alpha-blocker, phentolamine, for 4 weeks. We also performed postoperative histological examination (Figure 3), and we found that the tumor tissue was composed of spindle-shaped, slightly metatypical cells and was positive for chromogranin. The immunohistochemical results (CgA[+], Syn[+], CD56[+], S-100[+], and Ki-67[<5%+]) also confirmed the diagnosis of bladder paraganglioma.

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Case 2 also experienced resection of the bladder tumor and partial bladder resection after taking alpha-blockers orally for 4 weeks. The typical Zellballen growth pattern of the tumor cells was observed in the postoperative histological examination, as well as positive immunohistochemical results (CgA[+], Syn[+], CD56[+], S-100[+], and Ki-67[<5%+]), which were consistent with the diagnosis of bladder paraganglioma (Figure 3).

We followed up these 2 patients for 2 years, and no paroxysmal hypertensive symptoms reappeared.

Now it seems to be a story with a happy ending, but genetic testing should not be forgotten as it is strongly recommended by current guidelines.^3,4 We performed genetic testing only in case 2 as it was refused by case 1 The peripheral blood test showed no germinal mutation of PPGL-related genes, including RET, NF, VHL, SDHB, and other related genes.^4,8 But, for the tumor tissue test, we found a RET gene 341 site G to A mutation. Can we state that there is no germline mutation, but a somatic mutation exists? What do you think of the genetic test results?

Discussion: Genetic Tests

Professor Persu: First, I agree it was important to look for a germinal mutation in SDHB because it is associated with an increased risk of malignancy. But still, in some cases, you may identify an SDHD or even SDHC mutation. Did you look for mutations in these genes?

Dr Lou: Yes, all the SDHx series genes were screened.

Professor Persu: Then, my second question is about the somatic mutation. Was this mutation already described in the past as a germinal mutation?

Dr Wang: Was this a new mutation or one already reported previously?

Dr Lou: It is not a new mutation. It has been reported.^3,9

Professor Persu: Was it associated with a syndromic form of pheochromocytoma in the literature as a germinal mutation?

Dr Lou: Yes.¹⁰

Professor Persu: Thank you. This is interesting. Nevertheless, I would like to provide a reminder that the current recommendation is to screen for germinal mutations in patients with PPGL. Searching for somatic mutations is, in principle, reserved for research, and in the present case, I do not think identification of a somatic RET mutation will change the follow-up.

Professor Dominiczak: Have you inquired more as to why case 1 refused genetic testing? People normally want to know. Was there something in her family history that made her afraid of genetic testing? Maybe there was a similar case; maybe she remembered something about her parents? Have you tried to understand this refusal?

Dr Lou: In our hospital, we have a commercial panel for hypertension-related genes.

Professor Dominiczak: That is an easy explanation. I come from a country where every test is free at the point of delivery, so I would not understand.

Dr Wang: Well, actually, in China, we also have the same problems you have. Some family members are afraid of this kind of testing because they just do not like it. Recently, we had a Gitelman syndrome family, but the family members refused to provide blood for genetic testing because they do not have any symptoms. They said they would not do any genetic testing for that. The same thing happens in China. Even if we provide free testing, they may still refuse.

Overview of Urinary Bladder Paragangliomas

Urinary bladder paraganglioma is very rare, as it represents around 9.8% of all extra-adrenal paragangliomas and only 0.06% of all primary urinary bladder tumors.^2,11 Typical manifestations of urinary bladder paragangliomas include hematuria, hypertension, headache, sweating, and tachycardia or palpitation, provoked by micturition or overdistension of the bladder.^12,13 Remarkably, early diagnosis of urinary bladder paraganglioma is necessary because delayed diagnosis can lead to target organ damage involving heart, kidney, brain, and the fundus of eyes. For instance, severe morbidities such as hypertensive crisis and catecholamine cardiomyopathy can occur due to undiagnosed and uncontrolled paragangliomas. Most importantly, after the correct diagnosis and surgery, hypertension secondary to paraganglioma is curable in nearly all patients.^12,13

How do we diagnose urinary bladder paraganglioma? We need biochemical tests including plasma and urine metanephrines; imaging studies including ultrasound examination, CT scan, and magnetic resonance imaging; and functional imaging studies including MIBG scintigraphy, positron emission tomography, and octreotide scintigraphy.⁴

In terms of treatment, all patients with urinary bladder paragangliomas should undergo surgery as soon as possible. However, preoperative medical management, including prescription of alpha-blockers for at least 7 to 14 days before surgery, is very important for blockading alpha-receptors. Beta-blockers should only be added to control tachycardia after the administration of alpha-blockers. Also, a high-sodium diet and fluid intake should not be forgotten to prevent hypotension during operation. Surgical strategies include transurethral resection or open resection, depending on the location and size of the tumors.^4,9

Regarding prognosis and follow-up, urinary bladder paragangliomas are usually benign, so the prognosis is usually good.^14–16 Unfortunately, there are no specific pathological criteria for predicting malignancy, and reliable indicators of malignancy are limited to invasion of adjacent tissue or metastatic spreading.¹⁷ Long-term follow-up is needed to investigate reoccurrence.

In conclusion, urinary bladder paraganglioma is rare and challenging to identify because of the various clinical, imaging, and pathological appearances. Early recognition, diagnosis, and treatment result in improved outcomes. Long-term follow-up is needed.

Final Discussion

Dr Almustafa: What was the early presentation of these 2 cases to the health facility? How did they present? You are presenting final symptoms. I need a record of early symptom presentation investigation. It is not all of a sudden that they developed such symptoms.

Dr Wang: It is better to tell us what happened before they were admitted into your care.

Professor Dominiczak: Before they were with their primary care physician, what was their first presentation?

Dr Fan: They had visited other hospitals before but had no diagnosis. So, they were finally transferred to our clinic. After we took the history of their symptoms, we thought there might be a suspicion of PPGLs.

Dr Wang: And why did they originally go to the doctor?

Dr Fan: Because they were scared of urination. After urination, they were scared of the paroxysmal hypertension, headaches, and severe palpitations, so they came to the hospital.

Dr Almustafa: How did they know that they had high blood pressure?

Dr Wang: Yes, how did they identify high blood pressure after they urinated?

Dr Fan: Because they had headache and palpitation symptoms associated with hypertension.

Associate Professor Ching: In your slide, you mentioned that typical presentation would be hematuria. In this patient, I think this symptom was not present. Would you like to give some information from the literature? How many of them actually have absence of hematuria? Because in the presence of hematuria, I think the diagnosis is very easy.

Dr Fan: The literature about bladder paraganglioma is very scarce. We searched and found 2 studies about this condition. Only nearly 50% of patients have very typical postmicturition symptoms. The other 50% might just have a headache or hypertension.^12,15

Associate Professor Ching: I feel that it is not a typical presentation; rather, it is an atypical presentation of the paraganglioma of the bladder.

Professor Dominiczak: You said that you frequently administer alpha-blockers first and when the patient is completely alpha-blocked, you then add beta-blocker, which is the standard. You did not do it in these cases. If I understand correctly, you stayed with alpha-blockers alone for both cases. Why?

Dr Fan: Our first choice is alpha-blockers. Only when the patients have tachycardia, do we use beta-blockers.

Professor Dominiczak: Only with tachycardia?

Dr Fan: Yes, with tachycardia. The first choice is alpha-blockers for catecholamine crisis after surgery.

Professor Dominiczak: The belief in some centers is that you block everything you can block. The ambition in our center has always been that the physician goes to the operating theater, and whether it is cystoscopy or open surgery, the blood pressure should not move an iota during surgery, meaning you blocked properly.

Dr Bursztyn: Absence of tachycardia suggests that there was not enough alpha-blockade.

Professor Dominiczak: Precisely.

Dr Wang: Actually, in China, the current practice is that you start with an alpha-blockade. If there is, as Dr Fan said, tachycardia, then we use beta-blockers. Otherwise, we do not. That is the current practice. We would probably consider a trial comparing surgery with or without beta-blockers. For instance, in the absence of tachycardia, it could determine whether beta-blockade would help clinical outcomes of an operation.

Professor Dominiczak: I think the patient is more stable if everything is blocked. Alpha first, then add beta. Then you have everything blocked, and the patient is stable during the procedure.

Summary

We herein reported 2 rare cases of urinary bladder paraganglioma presenting with severe postmicturition syndrome and paroxysmal hypertension, in the absence of hematuria. Biochemical tests of plasma catecholamines after symptoms’ onset and determinations of metanephrines in plasma or urine can assist in screening for paragangliomas but can also be falsely negative due to multiple factors such as small tumor size, preanalytical procedures, and concomitant medications. Imaging tests are required to identify the location and size of the tumor, with thorax, abdomen, and pelvis CT scans recommended. Functional imaging examinations including MIBG, octreotide scintigraphy, and positron emission tomography are needed to identify additional lesions and their function via whole-body exploration. Diagnostic accuracy of different functional imaging examinations highly depends on the type and location of tumors and requires further investigation. Genetic tests are valuable for prediction of increased risk of malignancy in affected individuals and their relatives. Surgery after sufficient adrenergic blockage remains the mainstream treatment for localized tumors with generally optimistic outcomes. Long-term follow-up is necessary to monitor tumor recurrence.

Acknowledgments

We are grateful to the following session audience members for contributing to the discussion: Lixing Qi and Yan Li.

Footnotes