Recurrent metastatic primary inflammatory myofibroblast tumour of the gallbladder following pancreaticoduodenectomy

Abstract

Inflammatory myofibroblast tumour (IMT) is an uncommon soft tissue tumour with an unpredictable clinical course: mostly benign, occasionally locally aggressive and rarely capable of metastasis. Diagnosed mainly in the mesentery, omentum, retroperitoneum, pelvis and lungs, IMT is extremely rare as a primary gallbladder tumour. Despite improved radiographical capabilities, differentiating the tumour from other more common causes of gallbladder neoplasms necessitates histopathological and immunohistochemistry tests. Once diagnosed, malignant potential should be taken into consideration, striving for an en bloc R0 resection and postoperative long-term follow-up with routine ancillary imaging. The authors present the case of a recurrent primary IMT of the gallbladder, after two surgical treatments, including a pancreaticoduodenectomy. Now 3 years after initial diagnoses the patient is asymptomatic, but has developed local and distant metastases and is being treated with systemic corticosteroid.

Background

Inflammatory myofibroblast tumour (IMT) is a rare mesenchymal tumour, with a predilection for children and young adults. This tumour is most commonly found in the abdomen and pelvis but has been described as originating from almost every anatomical location. Although the majority of the cases are benign, extrapulmonary IMT has the potential to recur (25%) and metastasise (<2%).¹ Only eight cases of primary gallbladder IMT have been reported, all but one without recurrence and none exhibiting distant metastasis.^2–9 We present a case of primary gallbladder IMT with local and metastatic recurrence after two resections: an incomplete initial resection and a second pancreaticoduodenectomy (Whipple surgery). This case illustrates the malignant potential of gallbladder IMT and engenders the importance of high suspicion for non-concordant findings when faced with a benign biopsy and the need for a complete surgical resection as a principal treatment.

Case presentation

An 82-year-old woman with known essential hypertension, dyslipidaemia, mitral valve prolapse and recently diagnosed anaemia presented with postprandial epigastric pain that started 5 days prior. The pain was intermittent, burning in nature, non-radiating and severe (10/10). She also complained of acholic stool, dark urine and a moderate weight loss. She did not have nausea, vomiting, fever or change in bowel movements. Surgical history included a hysterectomy and breast cyst removal decades earlier. The patient lived independently and continued to work almost full time. Family history was unremarkable.

Investigations

On physical examination, the patient had scleral icterus and a non-tender, soft abdomen. Laboratory studies were notable for a leucocytosis of 20 000 cells/mm³, elevated direct and total bilirubin, and elevated liver function tests. Other laboratory values and tumour markers (carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9 CA 125) were within normal ranges.

Abdominal ultrasound revealed a lesion involving the gallbladder, and CT demonstrated a gallbladder mass extending into the adjacent liver, as well as extensive localised adenopathy (figure 1). Magnetic resonance cholangiopancreatography showed an extensive large infiltrative lobulated mass involving the gallbladder and segments 4, 5 and 6 of the liver. It also demonstrated smaller adjacent masses within the mesentery, following the hepatoduodenal ligament, compressing the common bile duct (CBD) and duodenum. The patient underwent endoscopic retrograde cholangiopancreatography, which showed a lobulated mass compressing the CBD, compatible with a gallbladder mass. During the procedure, a metal stent was placed in the CBD. At her initial admission, she was treated for cholangitis, with nothing by mouth, intravenous fluids and antibiotics. She improved clinically and was discharged with normal bilirubin and hepatic enzymes levels.

Figure 1.

Abdominal CT images on presentation showing multiple solid enhancing mass filling the gallbladder fossa region and involving the adjacent liver. These appear somewhat confluent. One mass appears to partially fill the lumen of a structure which is likely the gallbladder. This mass measures 2.3 cm in diameter. It is multilobulated and appears to traverse the wall of the apparent gallbladder.

CT-guided liver needle biopsy and endoscopic gallbladder biopsy were performed. The liver biopsy showed chronic inflammation, fibrosis and granulation tissue suggestive of inflammatory or infectious process (figure 2). Numerous plasma cells were identified, with a negligent IgG4 stain reactivity. The liver needle biopsy did not have morphological results consistent with IMT, as defined by the WHO classification and described in previous publications. The decision to operate was made due to the obstructing nature of the undiagnosed lesion. Preoperative differential diagnosis included the following: primary or secondary gallbladder, biliary tract or liver mass. It was thought to be benign (adenoma, fibroma, lipoma) or malignant (adenocarcinoma, sarcoma, gastrointestinal stromal tumour, lymphoma, melanoma, carcinoid and others).¹⁰

Figure 2.

Liver biopsy. Normal liver parenchyma on the left and loose storiform to fascicular spindle cell proliferation on the right (A; H&E stain, ×20 magnification) showing elongated myofibroblastic cells in whorled fibrotic stroma admixed with a lymphoplasmacytic infiltrate in the background of blood vessels (B, C; H&E stain, ×40 magnification). Spindle cells are smooth muscle actin-positive (D).

Outcome and follow-up

Six weeks after the patient’s initial admission, she underwent diagnostic laparoscopy, cholecystectomy, and segment 4 and 5 liver resection. The main mass was found to be in the gallbladder, with local spread to the adjacent liver (gallbladder fossa and segments 4/5). There was additional gross tumour on the surface of the duodenal wall and surface of the pancreas. A frozen section analysis from the gallbladder lesion was found to be negative for malignancy, with only inflammatory changes. Due to the ‘negative’ frozen biopsy (for malignancy), the surgeons decided to avoid an R0 procedure that would necessitate a pancreaticoduodenectomy. Gross tumour was left behind on the duodenum and pancreas. Final pathology was positive for IMT with positive margins. The patient’s postoperative course was unremarkable, and a decision was made to clinically and radiographically follow the patient, every 3 months with CT imaging, without further treatment. The option of steroid therapy was discussed with the patient, yet she opted for follow-up without medical or surgical interventions, due to the side effects of steroid use, low overall risk of IMT progression and recurrence, and her advanced age.

The patient did not show up for follow-up, until 14 months after her surgery, when imaging revealed local progression of the tumour. At this point, she refused surgical treatment and continued surveillance imaging. However, she suffered from multiple bouts of ascending cholangitis, necessitated multiple stent placements and eventually a percutaneous transhepatic cholangiography with biliary drainage. The patient developed septic shock secondary to ascending cholangitis and was admitted to the intensive care unit. Her hospitalisation was further complicated by upper gastrointestinal bleeding secondary to duodenal invasion. After she clinically stabilised, the patient opted for surgical intervention given the high risk of further complications from the tumour’s progression. At this point, CT demonstrated a large confluent mass extending from the gallbladder fossa into the liver hilum and invading the pancreatic head and duodenum. The portal vein, CBD and hepatic artery were widely displaced by the mass (figure 3).

Figure 3.

Abdominal CT images at 19 months after initial presentation, status post gallbladder excision, 4/5 liver segmentectomy and common bile duct stent placement. Imaging demonstrates masses involving the gallbladder fossa and the adjacent liver, pancreas and duodenum.

Four months after discharge the patient underwent exploratory laparotomy, pancreaticoduodenectomy, hepatic segmentectomy (segment 6), excision of a large abdominal and diaphragmatic tumour, diaphragmatic repair, and suture repair of the inferior vena cava (IVC) and portal vein. The mass was adherent to retroperitoneal structures, including the anterior wall of the IVC. Her intraoperative and postoperative course were largely uneventful. She was discharged to rehabilitation at postoperation day (POD) 7 and returned home on POD 18.

Gross findings showed tumour deposits involving the CBD, head of the pancreas, duodenum, liver and diaphragm. The largest tumour was 11.5 cm in largest dimension. All resection margins were negative. There was no lymphovascular invasion or lymph node involvement (0/5). Microscopically the tumour showed a fascicular arrangement of spindled to stellate myofibroblastic cells with marked atypia in a more fibrous stroma admixed with a variable inflammatory infiltrate composed of plasma cells, lymphocytes, neutrophils, macrophages and mast cells. Occasional necrotic and myxoid areas were noted, and rare mitotic figures were identified. The morphology of this tumour did not appear to be dedifferentiated liposarcoma. Immunohistochemistry examination of the specimens revealed the tumour positive for vimentin, actin, desmin (focally) and IgG4 (focally) (figure 4). The following stains were negative: anaplastic lymphoma kinase (ALK), cytokeratin 5 and 7, thyroid transcription factor-1, p40, Melan-A antibody, and special stains for fungus and mycobacteria. Next-generation sequencing platforms (Sema4 and FoundationOne) were used to determine the genomic profile of the solid tumour. Genetic assays were negative for fusion genes, such as ROS1 and NTRK3. Murine double minute 2 (MDM2) immunohistochemistry staining was negative.

Figure 4.

Histopathology of duodenal mass excised during the pancreaticoduodenal procedure showing loose storiform to fascicular spindle cell proliferation (A) and elongated fibroblastic cells with abundant eosinophilic cytoplasm and mild cytological atypia admixed with a lymphoplasmacytic infiltrate (B; H&E stain, ×20 magnification). Spindle cells are desmin-positive (C) and smooth muscle actin-positive (D; H&E stain, ×40 magnification).

During follow-up the patient maintained weight and returned to work. Unfortunately, 10 months after the Whipple procedure, imaging revealed recurrences in the anterior surface of the left lobe of the liver and the right abdominal wall musculature and peritoneum, near the inferior surface of the liver. She also had multiple pulmonary nodules measuring up to 1.2 cm in the right upper lobe. Lung biopsy from one of the lesions was consistent with IMT (figure 5). It has been 3 years since the patient’s initial presentation. She is currently being treated with dexamethasone and is without disease-related symptoms.

Figure 5.

Lung biopsy taken 10 months after pancreaticoduodenectomy showing an infiltrating dense spindle cell proliferation (A; H&E stain, ×20 magnification) composed of fibroblastic cells with abundant eosinophilic cytoplasm and nuclear pleomorphism with a mixed inflammatory background (B; H&E stain, ×40 magnification).

Discussion

Since it was first described in 1939,¹¹ the range of IMT presentations and properties has been gradually broadened through case reports and small case series. This heterogeneous group of myofibroblastic proliferations has a common component of inflammatory cell infiltrate, with variability in cell type and amount. Historically considered a benign entity, reports starting from the late 1990s showed that some cases can demonstrate aggressive behaviour, and as such complete en bloc surgical resection became the mainstay of treatment.¹² IMT can occur at any age and present throughout the body, yet has a predilection for the first and second decade and most frequently involves the abdomen and pelvis. The most common intra-abdominal involvement is in the mesentery, omentum and liver.^{1 13}

IMT has an unknown aetiology and pathology, with recent studies suggesting a neoplastic nature. It is debated whether IMT causes the inflammatory infiltrate, or an inflammatory reaction induces its development.¹³ In up to 60% of cases, IMTs are immunoreactive for the ALK protein, a finding that supports their classification as a neoplasm.¹⁴ ALK protein is a tyrosine kinase receptor and a member of the insulin growth factor receptor family. Clonal abnormalities of ALK result in fusion proteins with constitutive activation of ALK tyrosine kinase domain, causing abnormal neoplastic proliferation.¹⁵

The definitive diagnosis of IMT is made with histopathological and immunohistochemistry of the tissue, from a biopsy or a resected specimen. Imaging is non-diagnostic, as IMTs are often not readily distinguishable from other neoplastic or benign lesions. Nevertheless, imaging frequently reveals a lobulated heterogeneous solid mass with or without calcifications. Grossly, IMTs appear as a circumscribed or multinodular firm, white or tan mass, with a whorled fleshy or myxoid cut surface. Histologically IMTs are divided into three main patterns, showing either a cellular proliferation of myofibroblasts in a loose myxoid background, compact spindle cells with storiform to fascicular growth pattern, or a hypocellular tumour with sclerotic stroma. A variable mixed inflammatory infiltrate is common, with lymphocytes and plasma cells typically predominating. The presence of highly atypically myofibroblasts is rare and associated with poor outcome. Immunophenotype characteristics include reactivity for vimentin, actin and desmin. Differential diagnosis includes calcifying fibrous pseudotumour, follicular dendritic cell tumour and gastrointestinal autonomic nerve tumours.

The pathological differential diagnosis also includes IgG4-related sclerosing disease (IgG4SD), due to similar histological appearance.¹⁶ In the present case, the immune-histochemical stains for IgG and IgG4 did not meet the cut-off supportive for diagnosis of IgG4-related disease: IgG4/IgG plasma cell ratio >40%; IgG4+plasma cells/high-power field >30 in surgical specimen or >10 in biopsy specimen.¹⁷ IMT and IgG4SD can be distinguishable by their clinical, radiological and pathological features, yet a subset of tumours are indistinguishable due to overlapping features. Differentiating between the two is significant as IgG4SD can be treated effectively with steroid therapy alone. Reported cases of spontaneous regression of tumours initially thought to be IMTs have led to question the criteria for diagnosis.¹⁸ In a study by Saab et al,¹⁶ IMT was found to be more common in younger patients, it was usually a circumscribed mass rather than an infiltrative one, and it had less abundant lymphoid aggregates as compared with IgG4SD, although their findings were based on 36 cases. Further accumulation of cases is needed to accurately clarify between IMT and IgG4SD.

IMT has the potential to transform into an aggressive disease, with recurrence and relapses occurring years from diagnosis. According to the most recent WHO classification from 2013, the tendency for local recurrence is 25% for abdominopelvic lesions, and metastasis rate is less than 2%.¹ To date, there is no accurate prediction criteria for the behaviour of IMT. The tendency of recurrence has been higher in cases without complete surgical resection. In addition, intra-abdominal and retroperitoneal IMTs have a higher tendency for multiple recurrences, invasion into adjacent structures and metastases.^19–21 In one of the largest published series of IMT cases, Coffin et al ¹⁵ selected 59 patients specifically to analyse atypical or worrisome features. Thirty-three patients had local recurrences. Abdominal and pelvic IMTs had a recurrence rate of 85%. Recurrent and metastatic IMTs were larger, with mean diameters of 8.7 and 11 cm, respectively. Cytoplasmic ALK reactivity was associated with local recurrence, but absent ALK expression was associated with death from disease or distant metastasis. The authors concluded that other proliferative, apoptotic and prognostic markers do not correlate well with morphology or outcome.¹⁵

Primary IMT of the gallbladder is extremely rare. A total of eight cases have been reported so far, the first in 1990 by Ikeda et al.³ Table 1 summarises the demographic, clinical, morphological and prognostic factors of these reports. Of the eight cases, only one exhibited recurrence. Maruyama et al ⁶ reported a case of a 63-year-old woman with a primary IMT of the gallbladder who underwent cholecystectomy. She had a recurrence in the pancreas head and tail 13 months after her operation. The patient responded to vinorelbine (VNB) and methotrexate (MTX) combination chemotherapy.⁶ There is only one case report of primary gallbladder IMT with concurrent lesions outside the abdomen, with a 43-year-old man who presented with extensive disease in the gallbladder, bile ducts, lung and lymph nodes. He was successfully treated with high-dose prednisolone, without reported recurrent disease.³

Table 1.

Clinical, morphological and prognostic characteristics of published cases of primary inflammatory myofibroblastic tumour of the gallbladder

Authors	Year	Age, sex, presenting symptom	Comorbidity	Gross morphology	ALK status	Initial treatment	Follow-up	Recurrence (time after diagnosis)
Current case	2020	82 F, jaundice and epigastric pain	Anaemia, HTN, DL, MVP	Polypoid	Negative	Cholecystectomy, hepatic segmentectomy (4b, 5)	3 years	Local and distant (32 months)
Yamada9	2018	50 M, asymptomatic	Diffuse large B cell lymphoma	Polypoid	Diffusely positive	Gallbladder bed resection	6 years	None
Maruyama6	2017	63 F, abdominal fullness and pain	None	NA	Negative	Cholecystectomy	NA	Pancreatic recurrence (13 months)
Sinha2	2017	36 F, chronic bloating and dyspepsia	None	Unclassified	Not performed	Extended cholecystectomy, partial pyloric and duodenal resection, lymphadenectomy, Billroth II anastomosis	NA	NA
Badea4	2014	65 F, abdominal pain, asthenia, weight loss	IHD, AS, obesity, DM-II	Non-polypoid	Not performed	Hepatic segmentectomy (4b, 5), lymphadenectomy	3 months	None
Ozsan8	2013	66 M, abdominal pain, nausea and vomiting	None	Unclassified	Not performed	Hepatic segmentectomy (4b, 5)	NA	NA
Muduly7	2012	35 F, chronic RUQ abdominal pain and fever	None	Non-polypoid	Not performed	Radical cholecystectomy, hepatic segmentectomy (4b, 5), lymphadenectomy	2 years	None
Beheranwala5	2005	51 F, acute RUQ abdominal pain	None	Non-polypoid	Equivocal	Cholecystectomy, colectomy	3 months	None
Ikeda3	1990	43 M, jaundice, fever, weight loss	None	NA	NA	High-dose prednisolone	NA	NA

ALK, anaplastic lymphoma kinase; AS, aortic stenosis; DL, dyslipidaemia; DM-II, diabetes mellitus type 2; F, female; HTN, hypertension; IHD, ischaemic heart disease; M, male; MVP, mitral valve prolapse; NA, not available; RUQ, right upper quadrant.

First-line treatment for IMT consists of total surgical excision. There is little evidence regarding optimal therapy for inoperable, relapsed and/or metastatic IMTs. The following options were used, with varied efficacy, in previously published IMT case reports: steroids, non-steroidal anti-inflammatory drugs and cytotoxic chemotherapeutic agents (including VNB, MTX, vincristine, doxorubicin, cyclophosphamide, etoposide, paclitaxel, ifosfamide, cisplatin, carboplatin and 5-fluorouracil). Due to the rarity of non-benign IMT, a treatment of choice after surgical resection has not yet been determined.⁶

Our case is the first in the literature describing distant site metastases after primary gallbladder IMT removal. It serves to demonstrate the importance of complete resection, as suggested by the extensive local progression of the tumour. To our knowledge, our case is the only primary gallbladder IMT where initial surgical intervention did not include complete removal of tumour burden. Due to its obscure oncological behaviour, we cannot determine to what extent the lack of R0 resection in the first operation influenced the later development of metastases.

We would advocate to limit reliance on core needle biopsies or intraoperative frozen section analysis, as they are less accurate and can mislead the surgical approach. Although both showed apparently non-malignant histology in our case, the clinical and radiographical course were alarming. This discordance highlights the importance of including IMT in the differential diagnosis of unknown lesions that demonstrate inflammatory changes.

This case also emphasises that a complete extensive resection of IMT, as was achieved in the second operation, does not eliminate the chance of local and distant recurrence, raising questions regarding the possibility of micrometastasis or other pathological features that could explain the spread of this poorly understood mesenchymal tumour. Additionally, this case raises the question of whether adjuvant systemic therapy is warranted after surgical resection of IMTs that exhibit aggressive behaviour, such as infiltrative advancement or recurrence.

Learning points.

• Inflammatory myofibroblast tumour (IMT) is a rare but potentially malignant cause of gallbladder neoplasm, associated with a pathological morphology of infiltrative inflammatory cells that can be misperceived as non-cancerous.

• Resection of symptomatic aggressive IMT in the elderly should be considered, as it can offer a disease-free interval with improved quality of life in the right surgical candidate.

• Complete resection of IMT is important to reduce the chance of local progression and distant metastatic lesions.

• Long-term follow-up is mandatory in all cases diagnosed as IMTs.