Abstract
Malignant fibrous histiocytoma (MFH) and inflammatory myofibroblastic tumor (IMT) are uncommon primary non-epithelial cell tumors of the pancreas. In addition, there are inflammatory pseudotumors (IPT) that may arise in the course of autoimmune pancreatitis (AIP). In the English language literature, only 24 cases of IMT and nine cases of MFH in the pancreas have been reported to date. We investigated three individual spindle cell tumors of the pancreas that were identified as MFH, IMT, and IPT, respectively, using immunohistochemical and molecular analysis. Both the MFH and the IMT, but not the IPT, showed nuclear p53 expression and mutations of the p53 gene. The MFH and the IMT also had higher mitotic and Ki-67 (MIB-1) indexes than the IPT. The IPT was found to be a tumor-like case of AIP. Many IgG4-positive plasma cells, which are considered to be a feature of AIP, were found in all three tumors. It is concluded that in this series of spindle cell tumors of the pancreas, apart from immunohistochemical features, the demonstration of p53 mutations may be helpful in distinguishing true neoplastic tumors from pseudotumors such as IPTs arising in the context of AIP.
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Introduction
Malignant tumors of the pancreas are mostly of epithelial origin, predominantly ductal adenocarcinomas. Non-epithelial malignant tumors of mesenchymal origin are extremely rare and account for only 0.6% of the cases [4, 25]. The most common among the latter are leiomyosarcomas, liposarcomas, neurogenic sarcomas (schwannomas or peripheral neuroectodermal tumors), and malignant lymphomas [25, 43]. These tumors may cause difficulties in the differential diagnosis, even after extensive immunohistochemical analysis [25, 43]. In particular, in tumors with a spindle cell pattern, it may be difficult to distinguish malignant fibrous histocytomas (MFH) (now often called myxofibrosarcomas [11]) from inflammatory myofibroblastic tumors (IMT) or inflammatory pseudotumors (IPT), but this distinction is crucial for predicting the prognosis and selecting the proper treatment [7, 11, 43].
In the pancreas, so far, only nine cases of MFH [1, 3, 12, 14, 23, 26, 27, 33, 46] and 24 cases of IMT [2, 8, 10, 17, 20, 24, 28, 31, 32, 34–36, 39, 41, 42, 44, 47, 48, 50, 52] have been reported in the English language literature. Furthermore, IPT and IMT have often been used synonymously [10, 48, 50], though they can differ in their pathogenesis [29, 30]. We recently encountered representative cases of primary MFH, IMT, and IPT. On these cases, we conducted immunohistochemical and gene mutational analyses which, we believe, provide valuable clues for the characterization of these tumors and important information for the differential diagnosis. We will also discuss the relation of IPT to autoimmune pancreatitis (AIP).
Patients’ histories
Case 1
A 44-year-old woman was admitted to the hospital in May 2003 with a mass in the left upper abdomen and epigastralgia. She had a history of uterine cervical cancer (early stage) that had been successfully operated on 4 years earlier. Blood tests revealed mild anemia and slightly elevated levels of the tumor marker immune-suppressor acid protein (IAP) (521 μg/ml, normal <500 μg/ml). C-reactive protein (1.1, <0.3 mg/dl) was elevated, but immunoglobulins were not examined. Liver function tests and pancreatic enzymes were normal and there was no elevation in markers of cholestasis (alkaline phosphatase, bilirubin, etc). Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) revealed a tumor mass in the dorsal area of the stomach and enlarged peripancreatic and para-aortic lymph nodes. The latter lymph nodes appeared to obstruct the left ureter, causing hydronephrosis. Angiography results revealed that the tumor originated from the pancreas. A creatinine clearance test for 24 h showed dysfunction of the kidney. Administration of Ga-diethylenetriamine pentaacetic acid (DTPA) did not result in enhancement of the mass. A malignant pancreatic tumor with lymph node metastasis was diagnosed and the tumor and a lymph node were resected. However, as the tumor adhered firmly, radical resection was not achieved. After the operation, the patient received extensive chemotherapy. During a follow-up period of 20 months, there was no recurrence.
Case 2
A 64-year-old male was admitted to the hospital in October 1995 for left lower thoracic pain at inspiration and an abdominal mass in the left upper abdomen. His past history was not informative. A blood test revealed mild anemia and elevated serum amylase (269, 50∼228 IU/l), elastase (470, 100–400 ng/dl), and IAP (739, <500 mg/ml). Liver function tests were normal, and there was no sign of bile duct stenosis. Immunoglobulin was not examined. US, CT, and MRI results revealed a well-circumscribed homogeneous mass originating in the pancreas body. After administration of Ga-DTPA, the area surrounding the mass was enhanced. Endoscopic retrograde pancreatography showed an irregular stricture of the pancreatic duct in the body. A pancreatic carcinoma was suspected and a resection of the tail and body of the pancreas was performed. No metastasis was found during operation. Five years after the operation, the patient is disease-free.
Case 3
A 40-year-old male was admitted to the hospital with epigastric pain and fever. He had been free of disease until this event. He had noticed thirst, polydipsia, and weight loss for the last 6 months and was found to have diabetes and acute hepatitis. Two months later, he developed jaundice, general fatigue, epigastric pain, and restlessness. He was referred to our hospital and diagnosed as having a pancreatic mass and acute obstructive cholangitis. Laboratory data revealed marked anemia, leukocytosis, elevated levels of bilirubin, bile tract markers, CA19-9 (41.3, <37 IU/ml), and serum ferritin (941, 25–280 ng/ml). Immunoglobulin was not examined. Abdominal ultrasound and CT results disclosed a large low-density mass in the head of the pancreas with diffuse swelling of the body. A diagnosis of pancreatic carcinoma was made clinically and a Whipple procedure was performed.
After the operation, the patient suffered from diabetes, which was controlled by insulin injection. However, 8 months after the operation, his general condition worsened and he died. An autopsy was not performed.
Materials and methods
Tissues
Specimens from the pancreatic tumors were fixed in 10% formalin and processed to obtain 4-μm paraffin sections that were stained with hematoxylin and eosin, Azan, silver, elastica van Gieson, periodic acid–Schiff , and alcian blue.
Immunohistochemistry
For immunohistochemistry, the standard streptavidin–biotin technique was applied. The list of antibodies used and their sources as well as staining conditions are summarized in Table 1. Negative control stains were performed by omitting the primary antibodies or substituting nonimmune rabbit or swine sera. The number of cells showing nuclear staining for p53 and Ki-67 (MIB-1) was determined in areas with high cellularity and recorded as the number of positive cells per 100 tumor cells.
Genetic analysis
For the detection of p53 and K-ras mutations, genomic DNA was extracted from sections cut from paraffin-embedded tissue blocks. Briefly, the sections were deparaffinized with xylene, washed with 100% ethanol, and subsequently dried. Tumor tissue was scratched off the slides with a fine needle. DNA was extracted and purified with DNAeasy extraction kits (QIAGEN, Valencia, CA, USA). Polymerase chain reaction (PCR) was performed as previously described [37]. PCR Amplicon was ligated to the vector with a TOPO cloning kit (Invitrogen, Carlsbad, CA, USA). After blue–white selection, purified vector was digested with EcoRI. An about 100-bp insert clone was loaded onto a 3% agarose gel. The positive clone was amplified using a VIC dye sequence kit (Applied Biosystems, Foster City, CA, USA) and a purified Qiagen kit. Direct sequencing was carried out with a Perkin Elmer ABI Prism 310 sequence analyzer (Applied Biosystems).
Results
Pathological findings
Case 1
The left-sided pancreatectomy specimen contained a well-encapsulated, light yellowish firm mass measuring 8.3×5.6×6.0 cm (Fig. 1a). Microscopic spindle- to oval-shaped tumor cells mixed with variable numbers of polymorphic or multinucleated giant cells were arranged in a storiform pattern (Fig. 2a). There were some areas with high cellularity, and atypical mitoses were also seen. Lymphocytes, plasma cells, and eosinophils infiltrated within the tumor area (Fig. 2b). There were areas of stromal myxoid changes, but no necrosis or hemorrhage was found. The resected lymph node revealed a metastasis of the pancreatic tumor.
Case 2
The left-sided pancreatectomy specimen contained a light yellowish firm mass in the pancreatic body measuring 10.0×9.0×8.5 cm (Fig. 1b). The tumor consisted of mainly microscopic spindle- to oval-shaped cells arranged in a storiform pattern. There were scattered polymorphic or multinucleated cells (Fig. 2c,d), but nuclear polymorphism was less than in case 1. Mitoses were not found. The stroma was rich in collagen, and there was extensive lymphoplasmacytic infiltration.
Case 3
The Whipple resection specimen contained a mass 7.5×3.6×2.0 cm in size in the head of the pancreas. The tumor had a hard consistency and its cut surface was solid, lobulated, and relatively well circumscribed. The normal pancreatic tissue was replaced by a meshwork of microscopic spindle-shaped fibroblastic cells arranged in a storiform pattern and some foamy histiocytes (Fig. 2e). The spindle cells showed nuclear enlargement and hyperchromatism (Fig. 2f). Mitoses were not found. Detailed examinations of the tumor and its surrounding pancreatic tissue revealed features of autoimmune pancreatitis, such as periductal lymphoplasmacytic infiltration or venulitis. The lymphoplasmacytic infiltration extended into the pancreatic parenchyma, replacing most of the acinar cells and encasing medium-sized ducts. Mild inflammatory changes were also seen in the bile duct wall, the gallbladder, and the ampulla of Vater.
All clinicopathological features are summarized in Table 2.
Immunohistochemistry
Table 1 summarizes the immunohistochemical results. In case 1, spindle cells and pleomorphic cells showing a storiform pattern were positive for vimentin but negative for epithelial, muscle, neural, adipocytic, or lymphoma markers as well as anaplastic lymphoma kinase (ALK) and CD34. Between the tumor cells, there were CD68 positive macrophages. The tumor cells showed frequently positive for p53 to an extent of 25% level (Fig. 3a). The MIB-1 index of the tumor cells was 19% of the cells (Fig. 3b). In case 2, the spindle cells were also positive for vimentin and negative for epithelial, neural, and lymphoma markers, including ALK and follicular dendritic cell markers. Single spindle cells were positive for smooth muscle actin (SMA) and HHF35 but negative for CD34. They were positive for p53 at a level of 9% and the MIB-1 index was 7% of the cells (Fig. 3c,d). CD68 positive macrophages were present. In case 3, the spindle cells were positive for vimentin but negative for CD34, cytokeratin, EMA, S-100, myoglobin, or desmin. P53 was negative (Fig. 3e). The MIB-1 index was less than 1% (Fig. 3f).
Scattered IgG4-positive plasma cells were consistently detected in all three cases but most conspicuous in case 3.
Genetic analysis
Because nuclear p53 expression was found in cases 1 and 2, direct DNA sequencing for p53 exon 5–8 was carried out (Fig. 4). In case 1, two point mutations were detected: G-to-A transversion at codon 238, resulting in an amino acid change from cysteine to tyrosine, and T-to-C transversion at codon 272, resulting in an amino acid change from valine to alanine. In case 2, one point mutation was found, G-to-T transversion at codon 294, resulting in an amino acid change from glutamate to asparatate. On the other hand, the tumors in both cases 1 and 2 carried a wild-type K-ras oncogene.
Discussion
In this study, we analyzed the immunohistochemical and molecular features of three pancreatic tumors that shared a microscopic spindle-cell pattern with abundant collagen production admixed with inflammatory cells. This analysis revealed that individual features of the three tumors allowed them to be typed as MFH, IMT, and AIP-associated IPT.
The first step in the investigation of these tumors was to distinguish them from undifferentiated carcinomas, which may show a sarcomatoid pattern [16, 43]. As our tumors were negative for cytokeratin, this possibility could be easily excluded. The next tumor to be ruled out was a sarcomatous nodule in association with a mucinous cystic neoplasm [49, 53]. We, therefore, examined multiple sections but failed to find any evidence of a cystic lesion. The diagnoses we finally considered were MFH, IMT, and IPT.
The diagnosis of MFH, which was made in the first patient, was based on the tumor’s microscopic features (i.e., anaplastic spindle cells arranged in a storiform pattern), its sole positivity for vimentin, and the immunohistochemical exclusion of any other tumor, such as malignant peripheral nerve sheath tumor, by the negativity for the respective tumor markers. So far, only nine cases of MFH of pancreatic origin have been reported [1, 3, 12, 14, 23, 26, 27, 33, 46] (Table 3). A review of these cases revealed that their features compare well with those of our case. In addition, we detected nuclear p53 expression and a p53 mutation. This finding is in accordance with the 35% positivity rate for nuclear p53 expression recently reported in MFHs of various origins [9]. In our case, the demonstration of a p53 mutation clearly established the neoplastic nature of the tumor and distinguished it from any non-neoplastic pseudotumor.
In the second patient, we diagnosed an IMT. This is a low-grade tumor composed of fibroblasts and myofibroblasts in association with inflammatory cells, whose molecular pathogenesis was partially elucidated recently. In approximately 50% of IMTs, various gene aberrations including the anaplastic lymphoma kinase gene at chromosome 2p23 have been identified [13, 15, 32, 38, 45]. In our case, no ALK gene abnormality was found. However, an ALK gene abnormality is more often seen in children or young adults than in elderly people. This may explain why we did not detect an ALK gene abnormality in our case [6, 22]. The diagnosis of an IMT was, therefore, based on the microscopic diagnostic criteria such as fasciitis-like, fascicular, and sclerosing areas with a prominent chronic inflammatory infiltrate. In addition, we found nuclear p53 expression and a p53 mutation, findings that have also been reported in IMTs [51].
In the third patient, the tumor expressed neither SMA, S100 and CD34 nor nuclear p53. Together with its histological features, we concluded that the tumor represented an IPT. IPTs that arise in the course of AIP must be clearly distinguished from MFHs or IMTs, considering their different pathogenesis and therapy (i.e., its treatment with steroids). However, many previous reports of IMTs in the pancreas did not give any consideration to IPTs arising in the course of AIP (Table 4). Judging from the published illustrations and the descriptions, we believe that many previous cases of IMTs and IPTs arose in the setting of AIP [2, 8, 10, 17, 19, 20, 24, 28, 31, 32, 34–36, 39, 41, 42, 44, 47, 48, 50, 52] (see Table 4).
IMTs and IPTs associated with AIP have many clinicopathological features in common. First, both are mass-forming lesions which commonly focus on the pancreas head and cause obstructive jaundice. Therefore, such patients are often suspected to suffer from pancreatic ductal adenocarcinoma [18, 19]. Second, involvement of the distal bile duct, as reported in many IMTs, is a common finding in patients with AIP [18, 19]. Third, a lymphoplasmacytic infiltrate and myofibroblasts arranged in a storiform pattern are seen in both lesions [10, 26, 48, 50].
It has been reported that IgG4-positive plasma cells are abundant in AIP which help to establish its diagnosis [18, 54]. In this study, the demonstration of IgG4-positive plasma cells was not useful for the differential diagnosis as these cells were also found in both the MFH and the IMT. Nevertheless, constant presence of IgG4 cells in these tumors might indicate non-incidental occurrence of mesenchymal tumors with background of AIP.
In summary, we report three cases of tumorous spindle cell lesions of the pancreas, two of which were found to be neoplasms and the other an inflammatory process. p53 expression and gene mutation provided an important clue for distinguishing the two true neoplasms from the pseudotumor.
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Mizukami, H., Yajima, N., Wada, R. et al. Pancreatic malignant fibrous histiocytoma, inflammatory myofibroblastic tumor, and inflammatory pseudotumor related to autoimmune pancreatitis: characterization and differential diagnosis. Virchows Arch 448, 552–560 (2006). https://doi.org/10.1007/s00428-006-0157-x
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DOI: https://doi.org/10.1007/s00428-006-0157-x