Introduction
Solid pseudopapillary epithelial neoplasm (SPEN) was first reported in 1959 by Dr.
Frantz as a “papillary cystic tumor of the pancreas” and later described by multiple
names in the literature reflecting its biology and histogenesis. In 2010, the World
Health Organization (WHO) for the first time defined it as SPEN. It is a rare pancreatic
tumor accounting for only 2 to 3% of all pancreatic neoplasms and 1 to 3% of exocrine
pancreatic neoplasms.[1] SPEN is most commonly observed in young women (∼90%) with a median age of ∼30 years.[2] Despite unknown etiopathogenesis, its incidence was observed to be increasing rapidly
in the past 10 years due to technological advancement. Due to such low incidence,
its clinical and pathologic features have not been extensively studied. Even its etiology
and differential status remained challenging. In practice, diagnosis of SPEN was also
found to be very difficult due to its vague and nonspecific abdominal symptoms.[3]
In the present study, we bring our experience with SPEN in Indian patients with its
clinical, radiological, histopathological, and surgical findings to provide a reference
for the management of this rare disease.
Case History
In this retrospective study, a total of four patients have undergone surgery for SPEN
during the period from January 1, 2018 to December 31, 2020. All these patients' demographic,
clinical, imaging, surgical, pathological, survival, and follow-up data were extracted
from hospital medical records and evaluated. All the necessary ethical approvals were
procured from the institutional ethics committee prior to study commencement.
From the records, a total of four patients were identified; three were females (75%)
and 1 (25%) was male. The patients' age ranged from 13 to 25 years. Symptoms on presentation
were largely varied and nonspecific. However, the most common symptoms were found
to be pain and swelling in the abdomen with a palpable abdomen mass (in one patient).
In all the patients, serum tumor marker tests like Ca19–9, carcinoembryonic antigen
(CEA), and Ca-125 (in female patients) were done and reported as normal. Preoperative
radiological examinations such as transabdominal ultrasonography and computed tomography
(CT) were also performed. In these imaging studies, large complex solid cystic lesions
in various regions of the pancreas were revealed. Axial contrast-enhanced CT images
also revealed a large, enhancing solid heterogeneous, well-circumscribed mass originating
in the pancreatic body and tail. No perilesional fat stranding and calcification were
noted.
Later a positron emission tomography (PET) scan was done, revealing an abnormal and
high F-18 fluorodeoxyglucose (FDG) uptake in the solid, enhancing part of the pancreatic
lesions ([Fig. 1]). The tumor location in two patients (50%) was found to be the head of the pancreas,
followed by the head and body, and the tail of the pancreas, one in each patient.
The mean diameter of the tumor was ∼12 cm. Further, to determine the radiological
findings in SPEN, all the suspected patients underwent endoscopic ultrasound fine-needle
aspiration (EUS-FNA) and biopsy of the pancreas through the transduodenal approach
or transgastric route. The cytology was reported as papillary neoplasm of the pancreas,
while the biopsies were reported as SPEN. To confirm the diagnosis and to avoid any
diagnostic dilemma, immunohistochemical staining (IHC) was performed on all biopsies.
After confirmation of SPEN on IHC, three patients (75%) with tumors on the head, neck,
and body of the pancreas underwent pancreaticoduodenectomy. The remaining one patient
(25%) with a tumor on the tail of the pancreas underwent a distal pancreatectomy.
The perioperative and postoperative periods were uneventful in all the patients. The
radical specimens were reported as SPEN on final histopathology report. IHC revealed
strong positivity for pancytokeratin (Pan CK), β-catenin, CD56, and synaptophysin.
All the data related to clinical and pathological features of the patients with SPEN
of the pancreas are presented in [Table 1].
Fig. 1
A and B: FDG avid mixed solid cystic lesion in head of pancreas. C and D: FDG avid mass in pancreatic tail infiltrating into splenic hilum. E: Large FDG avid mass in body and tail of pancreas. F: FDG avid mass in body of pancreas.
Table 1
Clinical and pathological characteristics of patients with solid pseudopapillary neoplasms
of the pancreas
|
Gender
|
Age (y)
|
Symptoms
|
Tumor location on pancreas
|
Tumor size (mm)
|
Postoperative complication
|
Therapy/intervention
|
IHC findings
|
Tumor markers
|
Metastasis
|
|
Female
|
25
|
Upper abdominal pain radiating to back
|
Tail
|
12.2 × 8.5 × 6.0 cm
|
None
|
Distal pancreatectomy
|
Pan CK: positive
LCA: negative
CD99: negative
Beta catenin: positive
CD56: positive
Chromogranin: negative
AR: negative
ER: negative
TFE 3: negative
Synaptophysin: negative
|
Ca 19–9- 46.19; CEA: 1.1; AFP: 4.16
|
No
|
|
Female
|
20
|
Pain in abdomen
|
Head
|
5.4 × 5.2 × 8.3 cm
|
None
|
Whipple's surgery
|
AE1/AE3: positive
Beta catenin: positive (nuclear),
Synaptophysin: negative
Chromogranin: negative,
CD56: positive
|
Ca 19.9 <3.0
Ca125 5.31, CEA 1.67
|
No
|
|
Female
|
13
|
Pain and lump in abdomen
|
Head
|
11.1 × 7.5 cm
|
None
|
Whipple's surgery
|
Pan Ck: positive
LCA: negative
Synaptophysin: positive
Chromogranin: negative
CD56: positive
Beta catenin: positive.
|
Ca 19.9 <3.0
CEA 1.67
|
No
|
|
Male
|
24
|
Pain and swelling in the abdomen
|
Head and body
|
14 × 15 × 17 cm
|
None
|
Whipple's surgery
|
CK7: negative
CK20: negative
PAX-8: negative
Beta-catenin: positive
ER: negative
PR: negative
|
Ca 19.9–1.25
|
No
|
Abbreviations: AR, androgen receptor; CD, cluster of differentiation; CEA, carcinoembryonic
antigen; CK, cytokeratin; ER, estrogen receptor; LCA, leukocyte common antigen; Pan
CK, Pancytokeratin; PR, progesterone receptor; TFE3, transcription factor E3.
Papanicolaou's staining (Pap stain) of cellular smears showed tumor cells with minimal
cytological atypia forming rosettes ([Fig. 2A] and [2B]). Cells were also showing eccentric nuclei with prominent granular cytoplasm. Histology
of the tissues (hematoxylin and eosin [H&E] staining) with 10X magnification revealed
pseudopapillary architecture ([Fig. 2C]). Whereas on 40X magnification, tumor cells were observed to be arranged around
thin fibrovascular cores forming pseudorosettes ([Fig. 2D]). Tumor cells also showed perinuclear vacuoles, large intracytoplasmic hyaline globules,
and eosinophilic cytoplasm in moderate amount.
Fig. 2
A and B (PAP Stain): Cellular smear showing tumor cells with minimal cytological atypia forming
rosettes. Cells are also showing eccentric nuclei with prominent granular cytoplasm.
C (10x H and E): Solid nests of poorly cohesive tumor cells forming a cuff surrounding
blood vessels, resulting in a pseudopapillary architecture. D (40x H and E): Tumor cells arranged around thin fibrovascular cores forming pseudo-rosettes.
Tumor cells showing a moderate amount of eosinophilic cytoplasm with large intracytoplasmic
hyaline globules and perinuclear vacuoles.
Discussion
With the advancement of technology and imaging modalities, early identification and
accurate diagnosis of pancreatic tumors is helping patients to live longer compared
with patients from the previous decade. Non-neoplastic and neoplastic pancreatic tumors
present as encapsulated masses with a variable amount of hemorrhagic, cystic, and
solid components. Pancreatic cystic lesions are further divided into four groups:
intraductal pancreatic mucinous lesions, SPENs, mucinous cystic lesions, and serous
cystic lesions.[4] Among all the pancreatic cystic lesions, SPEN is extremely rare.
Among these pancreatic tumors, non-neoplastic lesions include the intrapancreatic
accessory spleen, congenital anomalies (annular pancreas, heterotopic pancreas, pancreatic
lobulation, nesidioblastosis, and rare miscellaneous conditions), cysts, pseudocysts,
granulomatous inflammation, and pancreatitis, whereas neoplastic lesions include metastatic
tumors, mesenchymal tumors, lymphoid tumors, pancreatoblastoma, solid pseudopapillary
tumor, acinar cell tumors, pancreatic intraepithelial neoplasia, intraductal papillary
mucinous neoplasms, cystic pancreatic lesions, anaplastic carcinoma, ductal adenocarcinoma,
pancreatic neuroendocrine tumor, pancreatic lymphoma, other epithelial exocrine tumors,
and rare miscellaneous neoplasms.
Among all those cystic neoplasms, SPEN is an uncommon, indolent, low-grade malignant
tumor of unknown etiology. SPEN was frequently reported in young females and the female-to-male
ratio was generally observed to be 10:1.[5] In a systematic review conducted by Law et al,[6] the mean age of the patients was found to be 28.5 years (SD ± 13.7 years). Results
from our study are in agreement with the previous studies, where 75% of our patient
cohort were females. The average age was also observed to be 20.5 years. On clinical
presentation, nonspecific symptoms were reported such as early satiety, vomiting,
nausea, bloating, weight loss, palpable abdominal mass/discomfort, and abdominal pain.
In many patients, SPENs are often identified incidentally. It was also reported that
there is no correlation between tumor size and symptoms leading to patients presenting
themselves to clinics in later stages of the disease. With respect to tumor localization,
they were often found in the tail, followed by the head and body. However, in our
patient series, the head followed by the tail and body of the pancreas was reported
to be the most common tumor location. In some exceptional cases, multicentric tumors
and extrapancreatic sites such as the duodenum, liver, omentum, retroperitoneum, and
mesocolon were also found to show these tumors representing synchronous tumor spread.
However, such multicentric, extrapancreatic tumors were not reported in our patients.
Often, SPEN is misdiagnosed and usually there is no evidence of an endocrine syndrome,
elevated pancreatic enzymes, cholestasis, abnormal liver function tests, serum tumor
markers, and pancreatic insufficiency to determine it. Therefore, clinicians should
always consider a differential diagnosis of SPEN, especially when the patient is young.[3]
Regular laboratory parameters, tumor markers, and clinical and radiological findings
are proven to be of no help/unremarkable. In such scenarios, to reach a definite preoperative
diagnosis, preoperative percutaneous biopsies, tissue sampling with EUS-FNA, and cytology
should always be considered. Except for the tumor cell dissemination, EUS-FNA was
proven to be a reliable tool for accurate diagnosis of SPEN by characterizing the
cytomorphological features.[7] The characteristic features of SPEN can be diagnosed readily based on characteristic
cytological and histological features.[3]
On cytology, cellular smears showed tumor cells with minimal cytological atypia forming
rosettes. Cells had eccentric nucleus with prominent granular cytoplasm. On histology,
SPENs can demonstrate various microscopic patterns such as solid, cystic, and pseudopapillary
arrangements. In many patients, cells demonstrate solid nests of uniform, polygonal
cells with abundant cytoplasm (clear to granular). In our patient cohort, tumor cells
have showed perinuclear vacuoles and large intracytoplasmic hyaline globules with
moderate amount of eosinophilic cytoplasm. The characteristic pseudopapillary architecture
or pseudorosettes were clearly visible in all our patients in accordance with the
previous studies.[3]
[8] Such rosette formations generally contain degenerated cells, tumor cells, and viable
cells arranged around the thin fibrovascular cores giving that typical pseudopapillary
architecture. To confirm the diagnosis further, IHC tests were performed, where IHC
analysis of the specimens was reported to have shown strong positivity for Pan CK,
β-catenin, and CD56. Whereas synaptophysin was positive in a single case, progesterone
receptor (PR) and estrogen receptor (ER) were negative in all cases. β-catenin localization
was also reported to be strongly positive in these patients due to SPEN somatic point
mutations in exon 3 of CTNNB1.[9] Runjan and Stefano[10] have also emphasized the importance of the β-catenin pathway to diagnose and differentiate
SPEN from look-alike pancreatic endocrine tumors and have also confirmed its presence
in 90% of cases.[8]
[10] On the other hand, with PR, all the patients in our study were reported negative
contrary to multiple studies.[1]
[11]
[12] Although there is a female preponderance for SPEN, ER positivity is very uncommon
and it was negative in all our patients.
After confirmation of SPEN, as a standard of care in the management protocol, all
our patients have undergone a complete R0 resection (distal pancreatectomy or pancreaticoduodenectomy:
Whipple's surgery). Generally, in unresectable cases, patients were recommended to
undergo radiotherapy, chemotherapy, transarterial chemoembolization, alcohol injection,
and/or liver transplantation. Postoperative samples have shown no metastasis or invasion
to regional lymph nodes and our reports are consistent with previous studies.[13] Multiple studies have reported the prognosis, and the 5-year survival rate is excellent
in ∼97% of the patients even with metastasis, if treated from time to time. The strong
prognostic factors for patients' prolonged survival include the level of surrounding
tissue invasion, lymph node involvement, and vascular and perineural invasion, unbalanced
translocation between chromosomes 13 and 17, trisomy of chromosome 3, double loss
of X chromosomes, DNA aneuploidy, dedifferentiation, nuclear pleomorphism, high mitotic
count, significant nuclear atypia, extensive tumor necrosis, and diffuse infiltrative
growth pattern.[14] Regular follow-up is also a key for early detection of disease and prolonged survival.
All the patients in our study were on regular follow-up and have shown no signs of
recurrence or metastasis.
Conclusion
To summarize, SPEN is an uncommon, asymptomatic, low-grade malignant tumor that was
typically seen in young women. Due to its diagnostic dilemma, preoperative percutaneous
biopsies, tissue sampling EUS-FNA, cytology, and IHC should be strictly considered
for a definite diagnosis. A multidisciplinary team approach will always improve treatment
accuracy and will help in timely management. Complete R0 resection is the only effective
option in all stages of the disease and the prognosis is also proven to be good. All
the time, the pathologist should be familiar with the SPEN's salient clinical, microscopic,
cytopathological, histopathological, and immunohistochemical features to differentiate
them from other circumscribed pancreatic neoplasms such as neuroendocrine lesions.
Finally, a minimum of 5-year follow-up after the surgical resection is highly recommended
to identify the possible signs of recurrence of the SPEN.
