Pigmented Renal Paraganglioma: A Case Report and Review of the Literature

Paraganglia is a structure of neural crest origin, which acts as a chemoreceptor and is specialized from neurosecretory cells [1]. Paragangliomas are rare non-epithelial tumors originating from paraganglia cells in various anatomical regions [2-3]. 80-85% of all paraganglia tumors are adrenal gland-borne pheochromocytomas. The remaining 15-20% is of extra-adrenal origin [4]. Most of the extra-adrenal paragangliomas are head and neck paragangliomas. Up to this point, paragangliomas have been reported in very rare localizations such as uterus [5], kidney [3-6-7], prostate [8]. Pigmented extra-adrenal paragangliomas are more rare. Reported cases are localized in the uterus [5], retroperitoneum, bladder, vertebra, mediastinum [9], orbit [10], heart [11-12-13]. To this day, only one pigmented renal paraganglioma has been reported [3]. We present the second reported case of Abstract


Introduction
Paraganglia is a structure of neural crest origin, which acts as a chemoreceptor and is specialized from neurosecretory cells [1]. Paragangliomas are rare non-epithelial tumors originating from paraganglia cells in various anatomical regions [2][3]. 80-85% of all paraganglia tumors are adrenal gland-borne pheochromocytomas. The remaining 15-20% is of extra-adrenal origin [4]. Most of the extra-adrenal paragangliomas are head and neck paragangliomas. Up to this point, paragangliomas have been reported in very rare localizations such as uterus [5], kidney [3-6-7], prostate [8]. Pigmented extra-adrenal paragangliomas are more rare. Reported cases are localized in the uterus [5], retroperitoneum, bladder, vertebra, mediastinum [9], orbit [10], heart [11-12-13]. To this day, only one pigmented renal paraganglioma has been reported [3]. We present the second reported case of  between kidney middle pol and vena cava inferior was separated from the surrounding tissues. Both adrenal glands were normal in surgical inspections.

Results
Macroscopically, the mass was 60x45x40 mm in size, with a smooth surface, round contours, and a dark brown color. The section surface was completely dark brownblack and spongy in appearance ( Figure 1).
In the sections prepared from the lesion, there were organoid patterned cell islands separated by fibrovascular septa. The islands consisted of oval and polygonal cells with a hyperchromatic nuclei and granular cytoplasm ( Figure 2A). Brown pigment was evident in most of the tumor cells ( Figure 2B).
Histochemically, the pigment was not stained with Prussian blue but significant staining was observed with Masson Fontana. Immunohistochemically, tumor cells expressed synaptophysin, chromogranine, NSE. In tumor cells, Mart1 and HMB45 were negative. Sustentacular cells were stained with S100. Ki67 proliferation index was below 5%. Necrosis or mitotic figure was not observed in any area. In the light of all these findings, the case was diagnosed as 'pigmented paraganglioma'.

Discussion and Review of the Literature
As a result of the literature review, 21 non-adrenal pigmented paraganglioma cases were detected between 1986-2020 (Table 1).
According to the cases reported in the literature, the age range is from 17 to 70, with an average age of 48.3 years. There was a clear female dominance (15 females, 6 males). Tumor sizes range from 3mm to 130mm. Our case is a 44-year-old female patient with a 60 mm tumor.
Extra-adrenal paragangliomas are very rare. The most common localizations are carotid body, vagal body, middle ear, Zuckerkandl organ, mediastinum and retroperitoneum. They have also been reported in several rare localizations. as palpitation, sweating, and headache related to hormone secretion [14].
The most important finding in these lesions is the existence of abundant pigment. According to histochemical studies and electron microscopic findings, this pigment is neuromelanin, lipofuskin or true melanin [3]. Neuromelanin has been reported in some pigmented paraganglioma cases [12][13][14][15][16][17][18]. Melanin was reported in an article published by Tavassoli in 1986 [5]. Lipofuskin has been reported in retroperitoneal paraganglioma [19]. These pigments accumulating in the tumor are thought to originate from chromaffin cells, chief cells and melanocytes of neural crest origin. Due to the accumulating pigment, the differential diagnosis of pigmented paragangliomas from primary or metastatic malignant melanomas has to be made [20]. Paragangliomas have a growth pattern in the form of classic islands and HMB45 is negative. On the other hand there are pleomorphic cell groups in malignant melanomas, mitotic figures are increased and HMB45 positivity is present [3].
In conclusion, to date, tumors in various spectra such as adrenal cortical adenomas, schwannomas, ganglioneuroblastomas, carcinoid tumors, medullary thyroid carcinomas, dermatofibrosarcoma protuberans have been reported as melanotic or pigmented [20]. Pigmented paragangliomas are very rare. By presenting the second kidney-derived pigmented paraganglioma reported in the literature, we emphasize that the morphological and geographic spectra of these rare tumors may be large.
There are 12 cases of intrarenal paraganglioma reported in the literature [14]. Pigmented paraganglioma originating from the kidney has been reported only once [3]. Our case is the second known case of pigmented paraganglioma of kidney origin.
It is not known exactly how paraganglioma develops in the kidney, but it is thought to be developed from ectopic adrenal tissues or adrenal residues in the kidney. Another possibility is that neuroendocrine progenitor cells migrating from the neural crest during embryogenesis lead to the development of paraganglioma [3]. Another view regarding intrarenal paragangliomas is renal-adrenal fusion [15]. The renal-adrenal fusion theory was first described by Rokitansky [16]. According to this view, if a capsule formation cannot be achieved as a result of an error in the retroperitoneal mesenchyma during development, fusion develops between these two organs. This is an important problem for radiologists as well as for pathologists. Adrenal adherent to the kidney can be mixed radiologically with renal masses, causing unnecessary resections. Likewise, a pseudocyst resulting from renal-adrenal fusion may be mistakenly confused with a cystic renal tumor [15]. In our case, both adrenal glands can be clearly demonstrated radiologically.
Renal paragangliomas have been defined in kidney upper pol, hilum and lower pol so far [14]. In our case, the tumor was located in the kidney lower pol and adjacent to the hilum. While paragangliomas of renal pelvis / hilum origin are related to hypertension, paragangliomas with peripheral location are generally not associated with hypertension as in our case [17]. Reported tumor diameters range from 3 to 18 cm. Small lesions can be detected in the early period if they cause symptoms such