Castleman’s disease masquerading as pancreatic neuroendocrine tumour

Abstract

Castleman’s disease (CD) is a rare lymphoproliferative disorder. This case report, to the best of our knowledge, is the first report of CD simulating a pancreatic neuroendocrine tumour. The patient was a 58-year-old woman who initially presented with bilateral iritis and underwent investigation for possible systemic rheumatological disease. CT of the chest demonstrated an incidental finding of a well-demarcated retropancreatic mass. As the mass was found to enhance on DOTATATE (tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate) positron emission tomography, a diagnosis of pancreatic neuroendocrine tumour was made. The patient underwent an open distal pancreatectomy and splenectomy. Histopathological examination revealed the unexpected diagnosis of hyaline vascular CD of a lymph node posterior to the pancreas. After 2 years of follow-up, there is no evidence of disease recurrence.

Background

This is the first reported case in the literature of Castleman’s disease (CD) mimicking a pancreatic neuroendocrine tumour. Additionally, this case study is important as it highlights a significant dilemma in the field of pancreatic surgery; the difficulty in confirming a diagnosis histologically prior to undertaking major surgery. Thus, clinicians must balance the risk of failing to resect a pancreatic malignancy with the risk of performing a major operation that may not be required. In general, surgery is indicated when either malignancy is suspected or for benign disease, such as unicentric CD (UCD), that is associated with symptoms.

Case presentation

The patient was a 58-year-old woman who was initially referred to an ophthalmologist with bilateral ocular pain and erythema. The iritis was initially managed with a course of prednisolone and acetate/phenylephrine eye drops and responded well. The patient had another flare of symptoms leading to investigation for underlying systemic disease, specifically, sarcoidosis. CT chest showed an incidental finding of a pancreatic lesion and the patient was referred to an hepatopancreaticobiliary (HPB) specialist.

The patient’s additional medical history included hypothyroidism and dyslipidaemia for which she was treated with levothyroxine and atorvastatin, respectively. She was a non-smoker and had minimal alcohol intake. There was no family history of any malignancy, CD or diabetes mellitus.

Investigations

Laboratory results, including serum markers were unremarkable; CA125 6 U/mL (0–35), CA199 19 U/mL (<37), carcinoembryonic antigen 4.8 μg/L (<5), alpha-fetoprotein 7.0 kunits/L (<10), chromogranin A 39 μg/L (<102), gastrin 7 pmol/L (6–55), metanephrines 71 pmol/L (<500) and normetanephrines 457 pmol/L (<900).

The initial high-resolution CT scan of the chest, performed for investigation of possible sarcoidosis, showed a 28×25 mm retropancreatic mass. A subsequent dedicated CT scan of the pancreas demonstrated a non-calcified mass arising from the posterior midbody of the pancreas with uniform enhancement on the arterial phase (figure 1). There was no change in size of the mass in the 3-month interval between the scans.

Figure 1.

This axial slice of an abdominal CT scan demonstrates the non-calcified retropancreatic mass.

Further characterisation with MR cholangiopancreatography (MRCP) demonstrated a well-delineated 28×30 mm ovoid mass at the posterior body of the pancreas (figures 2 and 3).

Figure 2.

This axial slice of an abdominal MR cholangiopancreatography scan demonstrates the well-circumscribed ovoid mass immediately posterior to the pancreas.

Figure 3.

This axial slice of an abdominal MR cholangiopancreatography scan demonstrates the well-circumscribed mass is inseparable from the splenic artery.

As the mass was well-demarcated and arterially enhancing, suspicion of a neuroendocrine tumour of the pancreas was raised. A DOTATATE positron emission tomography (PET) scan was arranged which demonstrated a DOTATATE positive retropancreatic mass (figure 4). Thus, a diagnosis of neuroendocrine tumour of the pancreas was made. There was no evidence of regional or distant metastases on any of the scans.

Figure 4.

This axial slice from the DOTATATE positron emission tomography scan indicates avidity of the retropancreatic mass, incongruent with the surrounding pancreatic tissue. ROI, region of interest; SUV, standardised uptake value.

Differential diagnosis

The patient was discussed at our institution’s HPB multidisciplinary team (MDT) meeting. The consensus opinion was that the lesion represented a non-functional NET of the pancreas and that given the lesion was greater than 2 cm, the appropriate management would be resection via distal pancreatectomy and splenectomy. Differential diagnoses of arterialised pancreatic lesions, including renal cell carcinoma metastases, melanoma and breast tumours, were considered unlikely.^1–3

Treatment

The patient underwent a bilateral subcostal incision for distal pancreatectomy and splenectomy. Intraoperatively, the tumour was identified at the posterior aspect of the body of the pancreas and in close proximity to the origin of the splenic artery and confluence of the portal vein. Intraoperative ultrasound confirmed the location of the tumour and the pancreas was subsequently transected at the neck, on the left side of the portal vein. Intraoperative frozen sectioning of the neck margin of the pancreas was negative for malignancy as was the splenic artery stump.

Outcome and follow-up

The patient had a satisfactory postoperative course, with the drain removed without any signs of postoperative pancreatic leak. She did not have any acute issues and was ultimately discharged home 12 days after surgery.

Routine histopathological examination of the 26×16×20 mm mass demonstrated a well-circumscribed lesion which abutted the outer surface of the pancreas without invading it. The mass was an atypical enlarged lymph node consistent with CD.

The lymph node showed abundant follicular structures comprising a mix of centroblasts and centrocytes, with intermingled small lymphocytes. Some of the follicular structures were hyalinised (figure 5). Immunohistochemistry was performed on the specimen, showing a predominance of CD20-positive B cells within the follicles and negative for BCL-2, which is consistent with a reactive population. The interfollicular zone included a mixed population of CD20-positive B cells, CD3-positive T cells and scattered small T cells within the follicles. CD21 and CD23 highlighted the follicular dendritic cell meshworks, with variable size of the follicles (figure 6), while no atypical vascular proliferation was demonstrated by immunohistochemistry for CD31 and Erythroblast transformation-specific (ERG). The specimen was negative for human herpesvirus-8 (HHV-8). These features favoured a diagnosis of hyaline vascular type CD rather than plasma cell variant (figure 7).

Figure 5.

H&E 12.5×. Normal pancreas top right, fat top left. Pale areas are lymphoid tissue.

Figure 6.

H&E 100×. Close-up showing a hyalinised blood vessel, characteristic of hyaline vascular Castleman’s disease.

Figure 7.

CD21 stain 12.5×. CD21 highlights the follicular dendritic cell meshwork confirming the follicular architecture.

After further discussion at our MDT meeting, the patient was referred for haematological review. A fluorodeoxyglucose PET scan was performed 7 months postoperatively to assess for the presence of multicentric CD (MCD). This showed avidity at the operative site only, in keeping with expected postoperative changes, indicating successful treatment of UCD. She was subsequently discharged from the haematology clinic after a period of 2 years of follow-up.

The patient developed type 3c diabetes mellitus 6 months after the operation and has been managed by an endocrinologist. She was also registered in the national registry for patients without a functioning spleen (Spleen Australia) and is currently on lifelong prophylactic antibiotics.

Discussion

CD is a rare lymphoproliferative disorder, that was first described in 1956 by Benjamin Castleman, who identified a cohort of cases with benign hyperplastic lymph nodes.^{4 5} The disease has an incidence of approximately 21–25/1 000 000 people.⁶

The aetiology of CD is poorly understood. Possible causal factors include neoplasia, autoimmune and viral processes.⁷ CD can be classified into subtypes based on histopathological features, including hyaline vascular and plasma cell variants.⁸ The condition can also be classified based on the extent of the disease; unicentric and multicentric. UCD involves a single lymph node or a region of lymph nodes. In contrast, MCD is defined by multifocal lymphadenopathy. A subset of MCD is attributable to the human HHV-8, while the remaining cases of MCD are idiopathic. MCD is a life-threatening condition, commonly associated with systemic inflammation and elevated levels of several inflammatory mediators, including interleukin-6.⁷ The treatment of MCD is complex and is not discussed here.

Patients with UCD are often asymptomatic with only mildly elevated inflammatory markers. However, symptoms can arise due to compression of the surrounding structures and systemic inflammation. UCD can be difficult to distinguish from other, more common, pathologies such as lymphoma, sarcoma and adenocarcinoma on imaging.⁹ Thus, the diagnosis of UCD is often made on postoperative histopathological assessment.¹⁰

Surgical resection remains the gold standard treatment for symptomatic UCD. Complete resection is associated with 3-year disease-free survival of over 95%.¹¹ Patients with unresectable disease may be managed with medical or radiologically-guided debulking treatments. Subsequently, if the mass becomes amenable to resection, surgical resection can be considered. Failure of debulking often leads to treatment with immunomodulators. Partially resected disease may remain stable for many years.⁹

UCD affecting the pancreas is extremely rare with only 36 previously reported cases in the literature.¹² This includes asymptomatic lesions discovered incidentally as well as symptomatic lesions due to biliary obstruction.^{13 14} In most cases, malignancy was suspected preoperatively based on radiology and CD was diagnosed postoperatively based on histopathology.¹²

While there are no reported cases of DOTATATE-positive pancreatic CD, there is a single case report of DOTATATE-positive CD in the mediastinum which was initially thought to be metastasis as the patient had a known neuroendocrine tumour of the rectum.¹⁵

In the case discussed, imaging showed an arterially enhancing 30 mm lesion that was DOTATATE-PET avid. There was some discrepancy as to whether the lesion arose from the pancreas (CT) or was separate from it, though abutting the pancreas (MRCP). Based on the information available, a diagnosis of pancreatic neuroendocrine tumour was most likely. Given the normal serum markers, including chromogranin A, this was suspected to be a non-functional pancreatic neuroendocrine tumour. A differential diagnosis other than pancreatic neuroendocrine tumour seemed very unlikely.

As is often the case in pancreatic surgery, seeking pathological confirmation of the diagnosis was challenging. Performing endoscopic ultrasound and fine needle aspiration cytology (FNAC) may have been technically possible. However, a systematic review of 404 cases of CD reported that FNAC was often non-diagnostic and histological assessment is typically required to establish the diagnosis.¹¹ In such case, a non-diagnostic test would have sustained the suspicion of malignancy and resection would have been proceeded with. Additionally, FNAC poses risks of complications, including bleeding, pancreatitis and also the risks of needle tract cancer seeding.¹⁶

When tissue diagnosis has not been established preoperatively, the risk of failing to resect a malignant tumour versus the risks of open surgery and major resection for a potentially benign condition need to be considered and the patient should be counselled about this possibility.

Learning points.

• Castleman’s disease of the pancreas can mimic a neuroendocrine tumour of the pancreas from a radiological perspective by demonstrating avidity on DOTATATE positron emission tomography and appearing as a well-circumscribed lesion that enhances on arterial phase.

• This case study underscores one of the challenges of pancreatic surgery: obtaining tissue diagnosis before committing the patient to surgery. As obtaining tissue from pancreatic lesions is technically difficult, when a lesion is considered likely to be malignant radiologically, surgery may be recommended without a tissue diagnosis.

• This case serves to remind clinicians that even lesions that appear suspicious for malignancy on imaging, may have a benign diagnosis on final histopathology. Whenever possible before major surgery, tissue diagnosis should be sought and when not possible, the patient should be counselled about the risk of the final histology being benign.

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Patient consent for publication

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