Most of catecholamine-producing tumors appear in the adrenal medulla, however, about 10% of those arise from extra-adrenal chromaffin tissue and are called paragangliomas. In decreasing order of frequency, PGLs may develop: (i) in the Zuckerkandl body, a vestigial chromaffin ganglion located at the root of the upper mesenteric artery; (ii) in the sympathetic plexus of the urinary bladder, the kidneys, and the heart; or (iii) in sympathetic ganglia in the mediastinum, the head or the neck. Most head and neck PGL are non-secreting [83], as in our second case report.
PGLs are relative rare in general population, occur mainly in adults and are usually benign; nonetheless the prevalence of malignant forms is about 30–40% [1]. Moreover, these tumors might present multiple localizations (in about 30% of cases), but in less than 5% of non-familial types [1]. PGLs can be classified as functional and non-functional types [83], depending on the capacity to produce different types of catecholamines (e.g. epinephrine, norepinephrine, and dopamine) and their metabolites. A specific parade symptom belongs to epinephrine excess, such as headache, palpitation, diaphoresis, flushing, and paroxysmal and/or sustained hypertension. Conversely, about 1% of catecholamine-secreting tumors result asymptomatic, representing an incidental finding [2].
Pelvic PGLs occur in about 2% of cases [9] and bladder PGL represents less than 1% of all bladder neoplasms [84]. The first documented case of bladder PGL was reported by Zimmerman et al in 1953 [13], and since then, more than one hundred cases have been described worldwide. However, the extreme variability of clinical presentation often can “mime” other pathological conditions and raises the interests of different specialists, i.e. urologists, gynecologists, pediatricians, radiologists, and general practitioners. This might lead to a late or misdiagnosis, and, therefore, to an increased incidence of complications. Moreover,
Clinical Guidelines Committee of the Endocrine Society recommends repeated measurements of plasma-free metanephrines or 24-hour urinary fractionated metanephrines for initial biochemical screening of suspected PHEO and PGL [1]. It is necessary to pinpoint that, unfortunately, these determinations do not reach a 100% of sensitivity and specificity, and they could cause false negative results because catecholamines secretion might be sporadic or even undetectable, mainly in asymptomatic patients [86]. Our two cases well document the absence of detectable 24-h urinary metanephrines and VMA in several measurements, despite the histological confirm of PGL diagnosis.
Basing on these clinical and biochemical issues in the pelvic PGL recognition, which lead relentlessly to a delayed diagnosis and treatment, we decided to perform this short review. Furthermore, according to the literature search, the cases reported concerned two females, referred to our Unit for uncontrolled and paroxysmal hypertension, which represents the more frequent sign of disease, but often not investigated. However, if promptly recognized and treated this disease can lead to a full clinical and biochemical recovery. Our case reports, indeed, confirm the outcomes reported in PGLs and PHEOs literature (Figure 4). In more detail, according to Primary Aldosteronism Surgery Outcome (PASO) criteria [87], used for detection of primary aldosteronism cure after adrenalectomy, we performed a subanalysis to evaluate the effect of surgical treatment of PGLs in terms of clinical and biochemical remission. The group A included patients with clinical and biochemical remission; the group B only biochemical values normalization (e.g. plasma and/or 24-hour catecholamines and/or metanephrines) with symptoms and signs persistence, mostly represented by high BP values. In the group C we included patients with neither biochemical nor clinical recovery, and in the group D patients dead during follow-up. We found that up to 50% of patients had complete clinical and biochemical recovery after surgical tumor excision; 2.3% showed only biochemical remission, with clinical persistence of signs and symptoms, 19.1% had no remission, and 19.1% died because of residual or surgery-related complications (Figure 4). We did not find any difference in terms of age between group A and group D (40.9 ± 18.7 vs. 40.7 ± 19.2 years), but a greater prevalence of metastatic disease at diagnosis was found in the group D compared to A (66.7 vs. 20.8%, p < 0.05). Furthermore, we observed that multi-localized tumors at first diagnosis were strongly associated to a poor prognosis, because for these forms it could not be planned a curative and resolute surgery, and because of the biochemical persistence (e.g. catecholamines secretion) leads to fatal cardiovascular events (i.e. dilatative cardiomyopathy).
In summary, our study improves upon previous reviews, which was dated and focalized mainly on bladder PGL [11–85]. For example, Tsai et al. includes one study dating back to 1911, and then eleven studies between 1989 and 2000 [17], while Beilan et al. [85] included 80 studies between 1980 and 2012; therefore, we offer a more updated view for analysing contemporary outcomes. Our study used a multitude of demographics to depict the disease process of pelvic and bladder PGL, including presenting signs and symptoms, tumor functionality and size, treatment modality, and outcomes. From our literature review, according to previous researches [9, 11–85], it was found that pelvic and bladder PGLs are more frequent in females, rarely metastatic, and even more rarely associated to genetic mutations. Therefore, the multi-localized forms are characterized by worst prognosis and higher risk of death for cardiovascular complications, possibly associated to systemic and persistent effect of catecholamines oversecretion. Pelvic and bladder PGLs manifestations are vary and complex; as reported by our research 54.2% of cases showed a diagnosis of hypertension, while more than 30% presented hematuria and headache, and micturition attacks were reported in only 30 cases. Furthermore, pelvic and bladder PGLs, probably because of their unusual localization, are often undiagnosed until later in life, when flank pain and hematuria occurred. The clinical evidences suggest that some patients could underestimate and could not be worried about adrenergic and noradrenergic symptoms, such as paroxysmal headache or palpitations or high BP values, because no specific. These aspects could prolong investigations, just as it happened, in our first patient, which even got a psychiatric consult before a proper diagnosis. Physicians must be careful and cautious to patients with unexplained hypertension, headache, palpitations, and anxiety, associated to “compression-effect” symptoms (i.e. hematuria and/or recurrent cystitis). Moreover, cases of multiple and metastatic lesions are more aggressive and characterized by a worst prognosis; in these situations proper follow-up and treatment is mandatory to avoid the onset of complications. Actually, postoperative follow-up of these patients remains controversial at best, with no established guidelines or algorithms on appropriate management of PGLs. In the diagnosis of multi-localized and malignant PGLs, could be suggested a close follow-up with monthly catecholamines and metanephrines levels and imaging every 6 months—1 year.