Solid pseudopapillary neoplasm of pancreas with distant metastasis during pregnancy: a diagnostic and treatment challenge

Abstract

Solid pseudopapillary neoplasms (SPNs) are rare pancreatic cystic neoplasms occurring predominantly in young women and diagnosis is often a challenge. This report describes the case of a 23-year-old primigravida who presented with abnormally elevated liver blood tests at 24 weeks of gestation. Imaging studies were suggestive of SPN with metastatic liver disease. A multidisciplinary team approach decided on a preterm caesarean delivery of a healthy female child at 36 weeks of gestation. Subsequently, a CT-guided biopsy was performed, with confirmation of SPN in the anatomopathological study. Subpartial pancreatectomy, partial gastrectomy, cholecystectomy, total splenectomy and partial hepatectomy were successfully performed. A 3-month control CT scan and positron emission tomography-CT studies revealed disease recurrence with pulmonary and liver metastatic disease. The patient was started on a palliative chemotherapy protocol with good tolerance. To our knowledge this is the first case of a SPN described in pregnancy with distant metastasis and disseminated recurrence after surgical treatment.

Background

Pancreatic cystic neoplasms (PCNs) are a heterogeneous group of pancreatic cysts that includes intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), serous cystic neoplasms (SCNs) and other rare cystic lesions, such as solid pseudopapillary neoplasms (SPNs) and cystic neuroendocrine tumours (cNET), all of which have diverse clinical, radiological and pathological features.¹ SPNs account for 3% of PCNs and the cellular origin of these neoplasms remains unclear.² They occur predominantly in young women (>90%), in the second and third decades of life.³ They are frequently asymptomatic or minimally symptomatic.⁴ These neoplasms can be detected in many imaging modalities, such as ultrasonography (US), CT and MRI, which can be used to differentiate them from other pancreatic lesions.⁴ The majority of these neoplasms (>90%) run a benign course, however, distant organ and lymph node metastases can be seen in 5%–10% and 2% of cases, respectively.³ Surgical resection is the treatment of choice.² SPNs are particularly rare during pregnancy, with only a few reports addressing diagnosis and treatment of these neoplasms during pregnancy.⁵ Therefore, the best management of SPNs remains a clinical challenge in pregnancy. Herein, we report a case of a SPN diagnosed in the third trimester of pregnancy in a 23-year-old woman.

Case presentation

A 23-year-old primigravida presented to the follow-up obstetrics consultation at 24 weeks of gestation (June 2019) with an isolated elevation of liver blood tests in the routine second trimester laboratory panel. Her only report was of mild nausea and to which she had been previously medicated for. The patient was otherwise asymptomatic.

Her personal medical history was positive for acute appendicitis in 2013, complicated by a pelvic abscess in the immediate postoperative period, requiring surgical reintervention. She was also a smoker of approximately 10 cigarettes per day until the end of the first trimester. She had no known allergies and her only medications were a multivitamin and an antiemetic drug (Nausefe). The patient denied any recreational drug use and alcohol consumption. Her family history was positive for ovarian cancer (paternal great-grandmother) and lung carcinoma (paternal grandfather).

Her pregnancy had been followed since the 4th week of gestation without any previous issues. There were no relevant findings in the routine fetal sonographic studies performed so far.

Physical examination showed a pregnant woman in good general condition and no evidence of jaundice. There was no cervical, supraclavicular or axillary lymphadenopathy. There were no palpable abdominal masses. No other changes were found.

Blood work revealed elevated aspartate transaminase (AST) (58 U/L, reference: <35 U/L), alanine transaminase (ALT) (119 U/L, reference: <35 U/L) and gamma-glutamyltransferase (GGT) (142 U/L, reference: <33 U/L), with no other changes in the remaining liver chemistry.

No therapeutic measures were implemented and new appointment and laboratory blood tests were scheduled for re-evaluation.

In July 2019, the patient presented with increasing nausea and new-onset feeling of fullness in her upper abdomen. Physical examination showed mild icteric sclera without any other changes. The follow-up liver blood tests revealed a deterioration, with increasing levels of AST (74 U/L), ALT (200 U/L), total bilirubin (TB) (2.61 mg/dL, reference: 0.30–1.20 mg/dL) and direct bilirubin (DB) (2.34 mg/dL, reference: <0.20 mg/dL).

Investigations

To establish a probable diagnosis, blood tests, endoscopic and imaging studies were conducted in the beginning of August 2019.

Laboratory tests showed a stable pattern of abnormally elevated liver tests: AST 74 U/L, ALT 118 U/L, GGT 52 U/L, TB 2.66 mg/dL, DB 1.29 mg/dL, alkaline phosphatase 282 U/L (reference: 30–120 U/L). Pancreatic amylase was within the normal range. Haematological investigations were within the normal range. Urine had a macroscopic brownish colour and dipstick analysis showed presence of bilirubin (++) and urobilinogen (++++). Serologies and autoimmune disease markers (antineutrophil cytoplasmic antibodies, antinuclear antibody, anti-liver–kidney microsomal antibody) were irrelevant. Serum tumour markers revealed increased alpha-fetoprotein (134 ng/mL, reference: <9 ng/mL), but consistent with pregnancy status, and an elevation of carbohydrate antigen (CA) 15.3 (31.6 U/mL, reference: ≤31.4 U/mL), CA 19.9 (43 U/mL, reference: 0–37 U/mL), CA 72.4 (8.53 U/mL, reference: ≤6.90 U/mL), Cyfra 21-1 (5.35 ng/mL, reference: <3.30 ng/mL) and neuron-specific enolase (NSE) (44.10 ng/mL, reference: <17 ng/mL). CA 125 and carcinoembryonic antigen were within the normal range.

Abdominal ultrasound revealed hepatomegaly and a nodule (18×12 cm) extending to the left hypochondrium. Non-gadolinium-enhanced abdominal MRI (figure 1) emphasised an exuberant hepatomegaly of 28.5 cm, and revealed an expansive lesion of 12×12 cm (background of intermediate T2 signal with globular peripheral areas of bright T2 signal) that caused vascular and biliary compression and another identical lesion of 1.2 cm in the VIII hepatic segment. An expansive solid lesion with central cystic areas, with peripheral diffusion restriction, of 14×12 cm occupied the pancreatic tail, with no separation from the greater gastric curvature and determining compression and deflecting the homolateral kidney. A homogeneous splenomegaly was also identified. As the mass did not show a cleavage plane from the greater gastric curvature, an upper gastrointestinal endoscopy was performed. No lesions were identified but sites of extrinsic compression were documented in gastric body, fundus and duodenum (segment D2).

Figure 1.

Non-gadolinium-enhanced abdominal MRI emphasised a hepatomegaly of 28.5 cm, and revealed an expansive lesion of 12×12 cm (background of intermediate T2 signal with globular peripheral areas of bright T2 signal) that caused vascular and biliary compression and another identical lesion of 1,2 cm in the VIII hepatic segment. An expansive solid lesion with central cystic areas, with peripheral diffusion restriction, of 14×12 cm occupied the pancreatic tail, with no separation from the greater gastric curvature and determining compression and deflecting the homolateral kidney. A homogeneous splenomegaly was also identified.

After a multidisciplinary discussion the decision was to deliver the baby at 36 weeks of gestation and then perform a CT-guided biopsy. At 35 weeks and 4 days of gestation, fetal lung maturation was initiated (dexamethasone 6 mg, 12/12 hours, 4 doses). A caesarean-section was performed mid-August 2019, at 36 weeks of gestation. A healthy female infant was delivered, with a weight of 2405 g. Her Apgar scores were 9 and 10, at 1 and 5 min, respectively. The anatomopathological study of the placenta excluded neoplastic disease.

Several days after the delivery, the CT-guided biopsy was performed and the anatomopathological study was suggestive of SPN of the pancreas, with positive staining for vimentin, CD10, CD56, β-catenin and CK AE1/AE3; chromogranin A, synaptophysin and progesterone receptors (PRs) were absent.

Due to the rarity of the diagnosis, after a multidisciplinary discussion, it was decided to transfer the case to a reference hospital for pancreatic tumours. There, the patient underwent an endoscopic ultrasound (EUS) and a fine needle aspiration (FNA) biopsy, to confirm the definitive diagnosis. A hypoechoic, heterogeneous, expansive solid mass occupying the pancreatic tail was identified. The EUS-FNA biopsy confirmed the diagnosis of SPN (the immune profile of the anatomopathological study was similar to the previous study).

Differential diagnosis

The differential diagnosis included IPMN, MCN, SCN, acinar cell cystadenocarcinoma, SPN, cystic islet cell tumours, pancreatic pseudocysts, cNET, gastrointestinal stromal tumour, nuclear protein in testis carcinoma, primitive neuro-ectodermal tumour, sarcoma and pancreatoblastoma.

Treatment

A multidisciplinary discussion was held to delineate the optimal management plan and the decision was then discussed with the patient, who agreed with the proposed treatment.

Subpartial pancreatectomy, partial gastrectomy, cholecystectomy, total splenectomy and partial hepatectomy were performed in October 2019. Anatomopathological study confirmed a SPN with metastatic liver disease, tumor–node–metastasis classification: pT3N0M1 (Union for International Cancer Control, 8th edition). Microscopic positive margins were identified in the left lobe and in the segment VI of the liver.

Outcome and follow-up

A control CT scan was performed in January 2020 (figure 2) which revealed an enlargement of the right hepatic remnant with heterogeneous density. Multiple scattered nodules were identified, with an average diameter of 3 cm, and the largest measuring 4.3 cm in segment VI.

Figure 2.

Abdominal and pelvic CT scan with contrast (coronal image), revealing a dimensional enlargement of the right hepatic remnant with heterogeneous density. Multiple scattered nodules were identified, with an average diameter of 3 cm, and the largest measuring 4.3 cm in segment VI.

Because of the possibility of metastatic involvement, a positron emission tomography-CT (FDG-F18) was scheduled which suggested diffuse liver metastasis and bilateral pulmonary metastasis in activity. A cranioencephalic CT scan was performed for evaluation of cerebral metastasis, without further evidence of disease.

A multidisciplinary discussion took place to decide on further treatment possibilities and the proposed treatment was to start the patient on a palliative chemotherapy protocol with FOLFIRINOX. The patient agreed with the proposed treatment and, at the time, she is still undergoing chemotherapy cycles with good tolerance.

Discussion

SPN of the pancreas is a rare exocrine pancreatic tumour which was first described by Frantz in 1959.⁴ Despite extensive investigations, the histogenesis has remained obscure and still hypothetical.⁶ The majority (85%–90%) of SPN have beta-catenin gene exon-3 mutations and, in 10%–15%, mutations are present in other exons. The aberrant protein expression in SPN is strongly correlated with mutations in beta-catenin gene. Mutations in beta-catenin gene exon-3 leads to Wnt signalling activation, which plays an important role in the development of SPN.² SPNs are considered to be hormone-sensitive neoplasms because they commonly express PRs.² As reported in literature, the higher prevalence of these neoplasms among young women and the increased rate of tumorous growth when serum progesterone levels are elevated (such as in pregnancy), could suggest that PRs are responsible for the regulation of tumorous cell replication, but this direct link has not yet been established.^{5 7}

The presentation of SPN is non-specific. The most common symptoms are abdominal pain, nausea, vomiting and weight loss.³ They can also present as a palpable abdominal mass, dyspepsia, asthenia, pruritus, weight loss, back pain, jaundice and pancreatitis.² A considerable percentage of the patient population is asymptomatic and the neoplasm is incidentally detected.⁵

SPN can be detected by US, CT or MRI. Imaging studies during pregnancy should take into account the risk to the fetus. Modalities without emission of ionising radiation are preferred and should be considered. US and MRI are not associated with any known adverse fetal effects.⁵ These neoplasms present in cross-sectional imaging modalities as mixed solid and cystic pancreatic lesions and well-demarcated, echo-poor, solid or solid-cystic lesions in ultrasound examinations.³ The majority of SPNs are located in the body and tail of the pancreas.⁴ EUS-FNA can help in definitive diagnosis of SPN: it is safe, reliable and provides cytological specimens preoperatively which can guide a targeted surgical approach.²

Immunohistochemically, practically all of these tumours express vimentin, β-catenin, alpha-1 antitrypsin, alpha-1 antichymotrypsin and cyclin D1. PRs are regularly detected, androgen receptors are expressed in about 80% of cases, but oestrogen receptors are usually negative. CD10, CD56, CD1, FLI-1 and epithelial markers, such as CK AE1/AE3, and CAM 5.2 can also be focally positive. NSE may be either negative or positive.^{2 5 6} In contrast with other reported cases, our case has the particularity of having absent PRs, suggesting that the tumorous growth rate might have depended on another unknown mechanism. Histological variants of SPN include clear cell, pleomorphic and oncocytic subtypes.²

Surgical resection is the treatment of choice for SPNs and organ preservation is advocated when technically feasible. Distal pancreatectomy with spleen preservation is typically recommended for SPNs located in the body and tail of the pancreas. Central pancreatectomy with distal pancreatojejunostomy or pancreaticogastrostomy is preferred for SPNs located in the neck of the pancreas. Pylorus-preserving pancreaticoduodenectomy is recommended for SPNs located in the head of pancreas. Enucleation can be performed for small SPNs which are distant from the pancreatic duct.² The mean tumour size is about 6–8 cm, and its diameter may reach up to 15–22 cm. Macroscopically, a sharp demarcation from the pancreatic tissue is typical, making the surgical removal easy. Sometimes they can be surrounded by a delicate or thick capsule. When the tumour is voluminous, extensive necrotic and haemorrhagic areas may be seen.⁶

It is generally accepted that the majority of these neoplasms run a benign course, however distant organ and lymph node metastases can be seen.^{3 6} SPNs outside the pancreas can occur in the retroperitoneum, liver, stomach, mesentery, duodenum, omentum, ovary and lung. The most common manifestation of malignant behaviour in SPNs is peripheral parenchymal infiltration but locoregional disease can also be found in regional lymph nodes, portal vein, colon, spleen and blood vessels.² Resection of liver metastasis is advocated at the time of the resection of the primary neoplasm and even in recurrences, when surgically feasible. The role of chemotherapy and radiation therapy in SPNs is not clear. Surgical treatment of solitary metastasis in SPNs is not the standard of care but debulking can be performed.² The 5-year survival is excellent, reaching 93.6%%–98.8% even in the presence of metastases, and the 10-year disease-specific survival rate can reach 96%. The local recurrence rate is low (less than 10% after 5 years of resection), however, when the tumours are located in the head of the pancreas, the disease-free and the overall survival rates drop considerably when comparing with other locations. When metastases develop, they usually occur late on the disease course: 8–15.8 years after complete resection of the primary.^{2 6}

In our case, this neoplasm could have had a misleading presentation with symptoms which are quite common during pregnancy, namely nausea and upper abdominal fullness; had it not been for the concern given to the borderline elevation of the routine blood panel tests, the close clinical monitoring and the further investigation performed. In the absence of a focused examination and a strong clinical suspicion, the diagnosis of these tumours may prove difficult and be delayed for quite some time.

There are no current management and treatment guidelines for pregnant women with this type of neoplasms, hence, decisions on the optimal treatment timing can be challenging.

To our best knowledge, there are only 13 case reports described in literature (table 1), but this is the first case which presented with distant metastasis at diagnosis and recurrence after surgical treatment. Considering that the majority of SPNs run a benign course, surgical treatment can be withheld until the end of the pregnancy with excellent outcomes, as described by Yee et al⁷ and Tanacan et al³. Nevertheless, there are several cases of SPNs which complicated gestation due to associated maternal instability, either on account of tumour rupture, rapid tumour growth or even malignant transformation. In these situations emergent surgical intervention is performed, regardless of the gestational age,⁵ and in the majority of reported cases, despite being carried out during pregnancy, the surgical treatment brought no impact to fetal development. It is therefore crucial to weigh the benefits and the risks of a potential surgical procedure during pregnancy. Careful preoperative planning and preparation by an experienced surgery, neonatal, anaesthesia, and maternal–fetal medicine team will often accomplish a successful surgical intervention without fetal compromise or unnecessary delivery.⁸ Despite the burden of disease in the case presented, the decision to maintain the pregnancy was based on the proximity to the term of the gestation, and then a late preterm baby was delivered so that more aggressive treatment options could be sought. Although it was expected a local recurrence of the disease because of microscopic positive margins as described above, on a short-term follow-up consultation there was a sudden disseminated disease recurrence with metastatic disease in liver and lungs. The patient was started on a pancreatic cancer-based chemotherapy protocol, which discloses how little we know and the lack of evidence on the best management approach to these tumours. In the future, an effective neoadjuvant chemotherapy protocol may prove useful to improve the outcome of surgical treatment in cases of disseminated metastatic disease.

Table 1.

Case reports of solid papillary neoplasms in pregnancy described in literature

Authors	Year	Age	Gestational age (weeks) at diagnosis	Surgical timing	Location and size (in cm)	Surgical procedure	Outcome
Duff and Greene9	1985	35	13	14 weeks of gestation	Head; N/A	Embolectomy and Whipple	SA after embolectomy
Bondeson et al10	1990	19	4	4–5 weeks of gestation	Head; 8	Whipple	Postoperative pregnancy termination
Morales et al11	1998	21	4	6 weeks of gestation	Head; 8.2	Whipple	SVD at 39 weeks
Ganepola et al12	1999	37	4	23 weeks of gestation	Tail; 12	DP, splenectomy and cholecystectomy	SVD at 41 weeks
Levy et al13	2004	27	12	16 weeks of gestation	Head; 6	Whipple	LI at 34 weeks, SVD
Hajdú et al14	2009	29	13	13 weeks of gestation	Tail; 16	DP	C-section at 38 weeks
Feng et al15	2011	26	14	14 weeks of gestation	Head; 9.5	Tumour enucleation	Labour at 38 weeks, C-section
Huang et al16	2013	29	19	19 weeks of gestation	Body and Tail; 17	Emergent exploratory reverse-T laparotomy, subtotal pancreatectomy and splenectomy	SVD at 29 weeks
MacDonald et al17	2014	23	14	18 weeks of gestation	Body and tail; 16.3	Distal pancreatectomy, splenectomy and cholecystectomy	SVD at 41 weeks
Sharanappa et al18	2015	22	16	16 weeks of gestation	Head; 12	Pylorus preserving Whipple’s pancreaticoduodenectomy	Medical termination of pregnancy
Yee et al7	2015	39	18	3 months post partum	Head; 10.6	Pylorus preserving Whipple’s pancreaticoduodenectomy	SVD at 40 weeks; uncomplicated postoperative course
Tanacan et al3	2018	26	35	4 months post partum	Head; 9	Subpartial pancreatectomy, partial gastrectomy, duodenectomy, cholecystectomy and omentectomy	C-section at 36 weeks
Huang et al5	2018	26	21	22 weeks of gestation	Tail; 13	Tumour enucleation	SVD at 39 weeks

C-section, caesarean section; DP, distal pancreatectomy; LI, labour induction; N/A, not available; SA, spontaneous abortion; SVD, spontaneous vaginal delivery.

Additional research is required to understand the pathophysiology of these neoplasms and further studies and focus are needed to develop management and treatment protocols in pregnancy and in metastatic disease.

Learning points.

• Solid pseudopapillary neoplasms (SPNs) are rare neoplasms, being more prevalent among young women between the second and third decades of life.

• In many cases, SPNs are incidental findings which become diagnostic challenges. When undetectable, they may lead to a considerable impact not only on the mother but also in the development of the fetus.

• The majority of these neoplasms run a benign course, however distant organ and lymph node metastases can be seen. In typical cases, conservative management with regular monitoring of the disease and postponement of surgical treatment is an option which appears to have a favourable outcome.

• Complete surgical resection is the treatment of choice for SPN and offers an excellent long-term prognosis.

• Metastatic SPN should be considered by pathologists when assessing liver biopsies from young female patients with a history of primary pancreatic tumour.