Peripancreatic Head Paraganglioma Versus Neuroendocrine Tumor: A Roller Coaster Diagnostic Dilemma in Fine Needle Aspiration Cytology Requiring a Note That “A Definite Diagnosis Cannot Be Concluded”

Abstract

Cytologic diagnosis of extra-adrenal paraganglioma presenting as a peripancreatic mass is challenging, with a high rate of diagnostic error. We present a case of a peripancreatic mass identified by radiology as a gastrointestinal stromal tumor. Endoscopic ultrasound-guided fine-needle aspiration (FNA) of the mass showed a moderately cellular tumor composed of small-to-medium-sized neoplastic cells with round-to-oval nuclei arranged singly and in loose clusters. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin) and negative for CD117. A diagnosis of neoplasm with a neuroendocrine tumor (NET) was made based on FNA cytology. The subsequent surgical resection of the tumor revealed peripancreatic paraganglioma with immunohistochemistry positive for synaptophysin, chromogranin, and S100. The latter delineated the sustentacular cells. Although paraganglioma is a well-recognized tumor, a detailed comparison of peripancreatic paraganglioma versus pancreatic/gastrointestinal NET is still lacking.

1. Introduction

Paraganglioma is a rare tumor arising from non-epithelial neural clusters from the chief cells. The annual incidence is 2–8 per 1 million people [1]. More than 40% of paragangliomas are associated with germline mutations [2]. Extra adrenal paragangliomas originate from the autonomic nervous system close to the gastric wall. The vast majority of paragangliomas are considered benign, and nearly 6 to 13% of cases are proven to be malignant with distant metastasis. Peripancreatic masses impose a great diagnostic challenge for both clinicians and pathologists. Non-specific symptoms plus endoscopic and radiological findings can result in significant diagnostic errors for these tumors [3]. The peripancreatic lesion imposes many differentials, including lymph node, leiomyoma, gastrointestinal stromal tumor, neuroendocrine tumor, paragangliomas, and carcinomas. Fine needle aspiration of these lesions is always a diagnostic challenge for pathologists. Nearly 50% of cases of paragangliomas are reported as NETs based on fine-needle aspiration (FNA) [4].

2. Case Report

A 44-year-old hypertensive male presented with a complaint of abdominal pain for 3 months. He weighed 102 kilogram with a body mass index of 29 kg/mm². On physical examination, his abdomen was soft, non-tender, and non-distended.

The endoscopic ultrasound (EUS) showed a solid, hypoechoic, mild, vascular lesion with intact borders measuring around 23 × 20 mm close to the gastric wall and anterior to the pancreatic head. A differential diagnosis of gastrointestinal stromal tumor versus neuroendocrine tumor was given.

The patient’s biochemical analysis was within normal limits. The chromogranin A level was 50.98 (normal value is <76.30); the gastrin level was 33.50 (normal range is 13–115 pg/mL); the 5-hydroxy indole acetic acid (5-HIAA) was 4.10 mg/24 h (normal range is 2–8 mg/24 h); and fluid amylase was 47 U/L (normal range is 28–100).

Computed tomography and magnetic resonance imaging scans showed a solid, avidly enhancing nodule 2.2 cm in short axis—likely a lymph node just anterior to the pancreatic head.

The Ga-68 DOTATATE positron emission tomography scan reported that there was increased tracer uptake in the soft tissue nodule anterior to the pancreatic head (2.1 cm, SUV max 10.3) (Figure 1).

EUS fine-needle aspiration cytology (FNAC) showed cellular smears with numerous abnormal cells appearing with a high nuclear–cytoplasmic ratio, salt-and-pepper chromatin with rare nuclear molding, and some markedly enlarged nuclei. Scant lymphocytes were seen in the background (Figure 2). Immunohistochemistry performed on the cell block showed tumor cells positive for CD56 and synaptophysin, and negative for CD117 and CD34. A diagnosis of neuroendocrine tumor was made and a resection was advised.

The patient went through laparoscopic resection and the resected nodule measured 27 × 25 × 20 mm with a homogenous yellow surface. Microscopically, a well-circumscribed tumor arranged in solid sheets and nests in a zellballen pattern with tumor cells showed abundant clear-to-granular cytoplasm, vesicular clumped chromatin, and small nucleoli. Also, spindle cells were seen at the peripheries of tumor nests. Mitoses were scarce (0–1/10 hpf). Immunohistochemistry S100 was positive with diffuse and mild cytoplasmic staining in chief cells and dense, strong staining in sustentacular cells (Figure 3). Synaptophysin, chromogranin, neuron-specific enolase, and CD99 were positive in chief cells. CD117 was patchy positive. The lesion was negative for CK7, AE1/3, CD10, CK19, and PAX8. A final diagnosis of low-risk paraganglioma was made. The postoperative course was uneventful and the patient’s blood pressure returned to normal.

3. Discussion

Paragangliomas are often symptomatic, and may cause sympathetic symptoms such as dry mouth, flushing of the face, racing heart, dilated pupils, constipation, fatigue, profuse sweating, headache, tremors, panic-like symptoms, and generalized weakness due to exhaustion [4]. However, the most classical presentation has the triad of headache, palpitations, and profuse sweating.

Paragangliomas are non-epithelial tumors arising from the neural crest, which is the chief cell of the sympathetic and parasympathetic chains. The majority of paraganglioma secreting hormones are known as functional paraganglioma; those that do not secrete are known as non-functional [3,4]. All paragangliomas have metastatic potential, so they are referred to as metastatic and non-metastatic instead of benign and malignant [3,4].

Paragangliomas often present a diagnostic challenge due to their variety of locations and symptomatology. Diagnosing paragangliomas located in proximity to gastric and pancreatic regions presents a challenging task, as there are many differential diagnoses, which pose diagnostic complexity [4]. FNAC is the most common preoperative diagnostic procedure in these locations. The morphologic overlap between paragangliomas and NETs is significant: the distinction can be confidently made only with immuno-peroxidase stains in cell block preparation. A definite diagnosis can be achieved through a combination of immunohistochemistry (IHC) stain using markers such as synaptophysin, chromogranin, S100, CD117, pan-CK, and GATA3 performed in cell block preparation. Paragangliomas are immunoreactive to S100 (on sustentacular cells), synaptophysin, chromogranin, and GATA3.5 [5].

Kapila et al. [6] stated that “the initial morphologic diagnosis of five of the seven paragangliomas are considered malignant (four undifferentiated and one adenocarcinoma)”. These authors concluded that the major diagnostic dilemma was to differentiate paraganglioma from neuroendocrine carcinoma [6].

The study by Lanke et al. [7] mentioned that “among 15 patients diagnosed with pancreatic paragangliomas, who underwent EUS-FNA; six were correctly diagnosed as paragangliomas; six were misdiagnosed as NET; one had no diagnosis; one was diagnosed as spindle cell neoplasm; and one was diagnosed as pseudocyst”. These authors concluded that paragangliomas should be included in the differential diagnosis of peripancreatic/pancreatic masses and highlighted the difficulties in establishing an accurate preoperative diagnosis even after a second-round evaluation [7].

The study by Nikas et al. [8] showed that the preoperative diagnosis of abdominal extra-adrenal paragangliomas with FNA or fine-needle biopsy is feasible. Diagnostic pitfalls exist, but can be significantly avoided within a multidisciplinary setting and with the application of IHC on the cytologic or histologic material [8].

A significant proportion of paragangliomas have a genetic predisposition. Approximately 75% of paragangliomas are sporadic; the remaining 25% are hereditary [2]. Mutations of the genes SDHA, SDHD, SDHB, RET, NF1, VHL, MAX, TMEM127, MEN 2A, and MEN 2B, have been associated with paragangliomas [2,9,10]. Genetic testing and counselling play a pivotal role in identifying at-risk individuals who require management. Patients are offered genetic testing [9,10].

Management of paragangliomas requires a multidisciplinary team approach. Treatment options include surgical resections and pharmacological control of catecholamines excess. In their experience, Omaima et al. [11] suggest that “treatment of paraganglioma and pheochromocytoma with octreotide might be of value in patients with paragangliomas and pheochromocytomas, having a quick and sustained treatment effect with minimal reported side effects” [11]. Loco-regional management for paragangliomas includes observation, surgical resection, and radiation, whereas the management of NETs takes a multidisciplinary approach, with surgical resection as the gold standard, followed by neoadjuvant therapy based on resectability and stage. NETs require active patient surveillance.

In their study, Asa et al. [9] summarized that “clinical, biochemical, radiologic, and morphological features of paragangliomas are all important features that are required to properly structure a management plan for patients with such tumors. Clarity is assisted by using a comprehensive pathology reporting module that ensures collection and collation of the various components required for proper diagnosis”.

Palade et al. [12] mentioned in their study that there is still much to debate regarding paragangliomas. They concluded that “the fact that they have a high rate of genetic inheritance has been proven, but clear correlations between gene mutation and the behavior of paragangliomas remain to be established. The lack of consensus among the practitioners regarding the necessity of surgery and the surgical approach is a result of the rarity of these tumors and the lack of experience in treating them. With the development of efficient conservative therapies, such as radiotherapy, proton therapy, and chemotherapy, studies should be carried on harmonizing all treatment methods and issue standardized guidelines”.

4. Conclusions

Paragangliomas can have many differential diagnoses. It is difficult to make a diagnosis based on FNAC alone. A cell block from FNA with adequate IHC can help differentiate paragangliomas from NETs. The presence of S100 positivity in sustentacular cells and GATA3 reactivity aid in confirming paragangliomas, as these markers are typically negative in NETs. However, the possibility of paragangliomas versus NETs should always be given with FNAC results, noting that “A definite diagnosis cannot be concluded”.