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, kidneys, and heart; or (iii) in sympathetic ganglia in the mediastinum, head or neck. Most head and neck PGLs are non-secreting , as in our second case report.
PGLs are relative rare in general population, occuring mainly in adults and usually benign; nonetheless the prevalence of malignant forms is about 30-40% . Moreover, these tumors might present multiple localizations (in about 30% of cases), but in less than 5% of non-familial types . PGLs can be classified as functional and non-functional types , 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. Various phenotypical presentation depends on various productions of catecholamine metabolites, such as 3-methoxytyramine, normetanephrine and metanephrine, and eventually a mixed combinations of their secretion . Conversely, about 1% of catecholamine-secreting tumors result asymptomatic, representing an incidental finding .
Pelvic PGLs occur in about 2% of cases  and bladder PGL represents less than 1% of all bladder neoplasms . The first documented case of bladder PGL was reported by Zimmerman et al in 1953 , 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, raising the interests of different specialists (urologists, gynecologists, pediatricians, radiologists, and general practitioners). This might lead to delay or lack of diagnosis, 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 .
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 . Our two cases well document the absence of detectable 24-h urinary metanephrines and VMA in repeated measurements, despite the histological confirm of PGL diagnosis. An extra-adrenal localization of PGL results in a clinical displacement between dopaminergic or noradrenergic over-production; an enhanced turnover of those metabolites could moreover aggravate clinical diagnosis because of repeated false-negative metanephrines determination. Furthermore, MIBG Scintigraphy has limited use in these cases because of sub-optimal sensitivity, especially in metastatic PGLs and those carrying succinate-dehydrogenase (SDH)x mutations. In particular, Brito et al. had observed that functional imaging in pheochromocytoma had small additive value to morphological imaging such as CT or MR; further research should evaluate impact of functional imaging in specific subgroups such as metastatic or extra-adrenal PGLs .
Atypical clinical presentation and complex management of our two patients has been an hint to elaborate an extended research on international literature on pelvic and bladder PGLs; 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.
According to the case reports in literature, the cases reported concerned two females, evaluated at our Specialized Unit for uncontrolled and paroxysmal hypertension, which represents the more frequent sign of disease, but unfortunately 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 , 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 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 surgical treatment, 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 , while Beilan et al.  included 80 studies between 1980 and 2012; therefore, we offer a more updated view for analyzing 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 are often undiagnosed until later in life, when flank pain and hematuria occurred, probably because of their unusual localization. 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. These aspects could extend investigations, as happened in our first patient, which even got a psychiatric consult before a proper diagnosis. Therefore, catecholamine overproduction could be misdiagnosed in patients who complain of anxiety or moreover depressive behavior disorder. 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). In our experience, as it has been demonstrated in our case reports, it is important to do not underestimate atypical presentation of pelvic and bladder PGLs and to do not neglect latent signs or symptoms. We recommend a detailed anamnesis and physical examination to detect subtle symptoms which are suggestive of cathecolaminergic spill-over. 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. Limitations our study consists that most cases and series reports were extremely eterogeneous, some of them were anecdotal; some manuscripts missed a section with a well established and clear diagnosis, treatment and follow-up of pelvic and bladder PGLs. This reflects, in our opinion, a missing section in guidelines  in proper managing of these neoplasms’ subgroup. There are missing data in further subgroups analysis. Actually a unique systematic register to describe pelvic and bladder PGLs does not exist. More evidences could be discovered if future efforts were directed in a prospective view of the problematique. Furthermore, in our view, 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.
Furthermore, it is important in these patients to consider genetic mutations in patients with multiple and familial PGLs. In particular, physicians may consider SDHA germline mutation in patients with skull base, neck or thoracic, abdominal, and pelvic localization, even if SDHB and SDHA immunohistochemistry on tumoral tissue resulted negative (1).