Summary.

Paraganglioma and the variant gangliocytic paraganglioma are rare gastrointestinal tumors. We present the first reported case of an esophageal paraganglioma and a review of the literature. From this review it seems that these tumors can occur at any age and usually present with acute or chronic bleeding with or without abdominal pain. The majority of reported cases originated in the foregut, most commonly the second part of the duodenum. Macroscopically the tumor may be pedunculated, sessile or ulcerated and have been described up to 10 cm in size. There are no reported cases of gut paragangliomas shown to be producing clinically significant amounts of catecholamines. The majority of reported tumors have been benign, only 7% malignant at presentation and all with lymph node metastases. One case developed bone metastases 3 years after excision and another recurred locally. There has been no benefit seen from radiotherapy or chemotherapy to date and it is recommended that all of these tumors are widely excised together with a lymph node resection if possible.

Introduction

Paraganglioma is a rare tumor of the gastrointestinal tract (GIT). We believe this to be the first reported case arising within the esophagus. We have reviewed other cases of paraganglioma including the variant gangliocytic paraganglioma reported in the alimentary tract and provide a summary of the presentation, treatment and outcome of this pathology.

Case Report

A 31-year-old woman presented to her general practitioner with a 5-year history of intermittent hematemesis and a 6-month history of dysphagia. A barium swallow revealed a ‘lobulated mass’ in the upper esophagus. The patient underwent open access endoscopy where the presence of a 2-cm polypoid lesion in the esophagus (22 cm from the incisors) was confirmed (Fig. 1). Biopsies were unhelpful and as there was no clinical suspicion, no analysis was performed for 5 hydroxy indole acetic acid (HIAA) or vanillyl mandelic acid (VMA). Endoscopic ultrasound suggested that this was indeed a superficial polyp with no extension into the deeper layers (Fig. 2).

Figure 1

Endoscopic appearance of the esophageal polyp.

Figure 1

Endoscopic appearance of the esophageal polyp.

Figure 2

Endoscopic ultrasound image of the tumor involving the submucosa but not penetrating the muscularis propria (T, ultrasound transducer; Tu, tumor; MP, muscularis propria; Sp, spine).

Figure 2

Endoscopic ultrasound image of the tumor involving the submucosa but not penetrating the muscularis propria (T, ultrasound transducer; Tu, tumor; MP, muscularis propria; Sp, spine).

Under a general anesthetic the lesion was endoscopically snared and removed. The patient made a full recovery. Histologically the lesion consisted of nests of polygonal cells with pale eosinophilic cytoplasm and centrally placed vesicular nuclei separated by a richly vascularized stroma. No mitotic activity or vascular invasion was seen. Immunostains revealed strong cytoplasmic positivity with chromogranin stain. S-100 stain highlighted the sustentacular cells. Cytokeratin stain was negative. In summary, the lesion had the features characteristic of a paraganglioma arising from the submucosa of the esophagus (Fig. 3).

Figure 3

(a) The tumor is composed of nests of polygonal cells; (b) showing strong, granular cytoplasmic positivity with chromagranin stain; (c) S-100 stain highlights the sustentacular cells.

Figure 3

(a) The tumor is composed of nests of polygonal cells; (b) showing strong, granular cytoplasmic positivity with chromagranin stain; (c) S-100 stain highlights the sustentacular cells.

Six months after excision the patient remains asymptomatic with no abnormality on endoscopy.

Literature Review

We have performed a Medline search for gastrointestinal paraganglioma and gangliocytic paraganglioma. There is considerable difficulty in accurately assessing the number of paraganglioma and particularly gangliocytic paraganglioma from the reported cases because of the confusion surrounding the origin of these tumors, the difficulty with classification and the different terms occasionally used, particularly in the less recent publications.

These limitations aside, there are currently 110 cases reported within the alimentary tract. The average age at presentation was 51 years with a wide range of 5–85 years. The distribution of paragangliomas and gangliocytic paragangliomas, and the number of malignant cases are shown in Table 1.1–31,38–41

Table 1

Distribution of paragangliomas and gangliocytic paragangliomas, and the number of malignant cases

 Total Gangliocytic paraganglioma Paraganglioma Malignant 
Mouth  1  0 
Pharynx  1  0 
Stomach  7  1 
Duodenum 81 79† 2† 
Biliary tract  7  0 
Pancreas  9  0 
Jejunum  2  2 
Appendix  2  2 
 Total Gangliocytic paraganglioma Paraganglioma Malignant 
Mouth  1  0 
Pharynx  1  0 
Stomach  7  1 
Duodenum 81 79† 2† 
Biliary tract  7  0 
Pancreas  9  0 
Jejunum  2  2 
Appendix  2  2 

It is not possible from the literature review to be entirely certain as to the number of paraganglioma and gangliocytic paraganglioma within the duodenum, however, the majority are gangliocytic paragangliomas.

Lesions in the mouth and pharynx were included for completion but they would probably best be considered as part of the head and neck where paragangliomas are more commonly reported.1,2 Considering the remaining GIT the vast majority of these tumors develop within the second part of the duodenum, in particular the medial wall. Most of these arise from the submucosa. Most cases within the duodenum are gangliocytic paragangliomas. Of the remainder, all except the two cases of gangliocytic paraganglioma reported in the appendix and the two cases in the jejunum, arose within foregut structures. In the cases arising in the duodenum and pancreas it is worth noting that it can be difficult to differentiate whether the lesion arises within these structures or from the retroperitoneum. The retroperitoneum is well recognized as a site for paragangliomas.32

Clinical presentation of gut paragangliomas, like other GIT neoplasms is dependant upon the site of the tumor. Approximately 50% of the 110 patients presented with gastrointestinal hemorrhage (melena and hematemesis). Only a minority of these suffered hemorrhage significant enough to warrant emergency surgery. Many other cases were found to be anemic, suggesting chronic blood loss. Another frequent presenting symptom was epigastric or right upper quadrant pain (40% of cases). One patient presented with gastric outlet obstruction. Despite the propensity for the periampullary site within the duodenum, jaundice was an uncommon finding within the group with duodenal tumors (4% of patients at presentation). Of the seven patients with biliary lesions, three were reported within the extrahepatic biliary system, two in the hepatic duct and one in the common bile duct. Two of those with biliary lesions presented with obstructive jaundice, the other, in common with the four patients with paragangliomas of the gallbladder presented with right upper quadrant pain. Patients with gall bladder paragangliomas were believed preoperatively to be suffering with cholelithiasis, the tumor being discovered at the time of surgery and confirmed histologically. One of the patients with a paraganglioma of the gall bladder had a cholecystoduodenal fistula. Two patients with tumors of the appendix presented as acute appendicitis. Of the pancreatic lesions two were incidental findings; pain was the predominant complaint in three patients and a mass was the presenting feature in the three other cases (no comment on presentation was made in one case). In all 110 patients, only five presented with a palpable mass.

In most cases endoscopy was the most important investigative tool, with ultrasound and computerized tomography also frequently employed. No case, as far as we are aware, was identified histologically prior to excision of the lesion however, endoscopic biopsy usually being unhelpful. It has been noted that the lesions morphologically may be pedunculated, sessile or ulcerated and have reached sizes of up to 10 cm. We can find no case of gut paraganglioma shown to be producing clinically significant amounts of excessive catecholamines. Among the possible differential diagnoses of a gut paraganglioma are carcinoid tumor, glomus tumor, metastatic phaeochromocytoma and epithelioid leiomyoblastoma.

Most lesions were excised locally, largely because of the site of origin. The majority of lesions were believed to be benign. Histological assessment however, is not straightforward. Cell pleomorphism is not a reliable criterion in predicting malignancy, whereas mitotic activity and vascular invasion should be considered as signs of potential malignancy.21 Evidence of local invasion or metastasis may ultimately be the only accurate indicator of malignancy.33 We have discovered two reported cases of malignant paragangliomas in the stomach, and six cases of malignant gangliocytic paragangliomas in the duodenum (7% of total GIT tumors). In all cases there were lymph node metastases at presentation. In the majority of the malignant gangliocytic paragangliomas the lymph nodes involved have only shown evidence of the epithelioid component of the tumor. There is one reported case of distant hematological metastases to bone occurring 3 years after resection.19 In general, paragangliomas are known to predominantly metastasize to lungs and bone. Lymph nodes are also recognized as a possible metastatic site along with the liver, heart and kidneys.33 Interestingly of the 110 cases of GIT paragangliomas only one had evidence of recurrence and this was 2 years after primary resection. The recurrence rates for tumors arising from outside the GIT has been reported to be much higher.21,42

Evaluation of the possible benefits of adjuvant therapy has been hampered by the rarity of the tumor. Some reduction in vascularity has been seen after radiotherapy but other tumors have been found to be radio-resistant. Chemotherapy has proven to be of little use to date.33

Discussion

Benign polyps of the esophagus are unusual. Although leiomyomata are occasionally found at postmortem, most are asymptomatic and are rarely polypoid.34 Similarly, granular cell tumors usually arise from submucosa and are therefore not usually pedunculated.35 Polyps that are inflammatory (a result of chronic esophagitis) or adenomatous (which can be sessile or pedunculated) are rarely found but are generally located in the lower esophagus. Even more rarely polypoid lipomata have been described. Squamous papillomas, although polypoid, are usually asymptomatic.36,37 Benign vascular-fibroblastic polyps large enough to cause dysphagia or even regurgitation into the pharynx with airway obstruction have been described in the elderly.

Paraganglia are clusters of neuroendocrine (chromaffin) cells. These cells originate in the embryonic neural crest and migrate widely throughout the body in close association with ganglion cells of the autonomic nervous system. The largest collection of these cells occurs in the adrenal medulla, their function within this gland and the aortic and carotid bodies, is well known. The significance of their presence elsewhere however, is less well understood.

Paraganglionic cell tumors are neuroendocrine and if found in the adrenal medulla are termed phaeochromocytomas, but if found arising from a paraganglion elsewhere then they are termed paragangliomas. Dahl is recognized as identifying the first paraganglioma in 1957, although at the time it was described as a ‘duodenal ganglioneuroma’.5 It is estimated that 10% of tumors occur outside the adrenal gland. Of extra-adrenal tumors, chemodectomas and glomus jugulare tumors account for 90%, but they have been reported at many other sites within the head and neck, as well as the mediastinum, retroperitoneum, cauda equina, urinary and the gastro intestinal tract.3,32

Histologically, paragangliomas are composed of spindle (sustentacular) cells and round or polygonal epithelioid cells arranged in a ‘Zellballen’ pattern. The spindle cells correspond to Schwann cells and are S-100 positive. The tumor may produce ectopic substances such as adrenocorticotrophic hormone (ACTH) and vasointestinal peptide (VIP).

In 1962 Taylor and Helwig described a duodenal variant paraganglioma. Later these tumors came to be known as ‘gangliocytic paragangliomas’. These are most commonly located in the medial wall of the second part of the duodenum, especially at the ampulla of Vater. Other sites reported include the first, third and fourth parts of the duodenum, the jejunum, the stomach and appendix. Histologically, these tumors contain mixtures of three distinct histological patterns; typical neurofibroma (with proliferating neuritis and Schwann cells); ganglion cells mixed with Schwann cells and proliferations of clear epithelioid cells arranged in clusters, or radial patterns resembling carcinoid tumors. There can be significant variation in the proportion of the cell types within a particular lesion and this has resulted in difficulty accurately classifying a particular tumor. Like their close relatives the somatostatinomas, gangliocytic paragangliomas may be associated with neurofibromatosis. Gangliocytic paragangliomas are also known to contain a wide variety of polypeptide hormones including somatostatin, pancreatic polypeptide, serotonin, gastrin, insulin and glucagon, but at levels that are clinically insignificant.

There is debate as to the origin of gangliocytic paragangliomata and currently several theories are propounded. It has been suggested paragangliomata arise from a hamartomatous process derived from the ventral primordium of the pancreas. A second theory based on their resemblance to endodermal-neurectodermal complexes suggest they may originate from stray embryonic cells that recruit nerves, ganglion cells and smooth muscle cells. Finally the lesion may arise from ganglion islet cell complexes. The positivity of islet cells and subductal epithelium for pancreatic polypeptide supports this last theory.

Conclusion

Paraganglioma and the variant gangliocytic paraganglioma are rare gastrointestinal malignancies. From our assessment of the reported cases it would seem that the paragangliomas of the GIT present at any age, usually with symptoms of bleeding (acute or chronic) and occasionally non-specific upper abdominal pain. There are no reported cases of clinically functional endocrine GIT paraganglioma. Local resection of the tumors is usually adequate as most tumors are benign and local recurrence is uncommon. Dependent upon the anatomical site, a regional lymphadenectomy should be considered as nodal metastasis of GIT malignant paragangliomas is described. It is worth remembering that these tumors may be extremely vascular, a property apparent at resection as well as presentation. Although local recurrence and rates of metastases are low in the GIT cases, the rates described in tumors elsewhere are much higher and can occur many years after resection. For this reason and the young age of many patients at presentation, long-term follow-up is probably indicated.

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