Granulomatosis with Polyangiitis Presenting as Pancreatic Pseudotumor and Peripancreatic Lymphadenitis: Diagnostic Challenges and Review of 55 Cases

Introduction

ANCA-associated vasculitis (AAV) is a group of diagnoses of systemic vasculitis of small to medium-sized vessels. The group includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Typically, GPA is associated with PR3/cANCA, and is characterized by granulomatous lesions of the lungs, kidneys, and ENT sphere, frequently also affecting the peripheral nervous system, skin, and joints [1]. By contrast, MPA is typically associated with MPO/pANCA and causes necrotizing glomerulonephritis in most patients. Involvement of the lungs (pulmonary capillaritis), skin lesions (purpura), and systemic symptoms are also common [2]. Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma, eosinophilia, and nasal polyps. Gastrointestinal involvement of AAV is relatively rare, with an estimated incidence of 5–11% for GPA, but more common for MPA (30–56%); mostly involving the small intestine and colon [3,4]. Pancreatic AAV is exceedingly rare, but potentially underreported due to low awareness among clinicians, lack of routine ANCA testing in pancreatic disease, histological confirmation challenges, and the tendency to publish only unusual or confirmed cases. The clinical picture is protean and can resemble that of pancreatitis, but also that of pancreatic cancer [5–54]. Distinguishing pancreatic AAV from pancreatic cancer is critical because the 2 conditions have vastly different treatments and prognoses. While pancreatic cancer often requires surgery and chemotherapy, pancreatic AAV typically responds well to immunosuppressive therapy. Misdiagnosis can result in unnecessary invasive procedures with significant morbidity. Moreover, because imaging findings can be similar in both conditions, accurate diagnosis relies on careful histopathologic and serologic evaluation to avoid delays in initiating appropriate treatment. Autoimmune pancreatitis (AIP) is another important differential diagnosis of pancreatic AAV because the 2 conditions can present with overlapping clinical, radiological, and even histological features [55]. Here, we report an additional case of pancreatic GPA in a patient who underwent partial pancreatectomy for suspected pancreatic adenocarcinoma. This case is notable for combining several hallmark features of pancreatic GPA and is distinguished by the presence of significant peripancreatic lymphadenitis, which expanded the differential diagnosis to include tuberculosis, lymphoma, IgG4-related disease, and sarcoidosis, a feature that was rarely emphasized in prior reports. We also review the current literature comprising 54 cases and discuss this histologically distinct subtype of autoimmune pancreatitis.

Case Report

LITERATURE REVIEW:

The characteristics of all 55 cases of ANCA-associated vasculitis involving the pancreas, 42 GPA (76%), 12 MPA (22%), and 1 EGPA (2%), are presented in Table 1, and a summary comparing the results for GPA and MPA characteristics is shown in Table 2. The sex ratio was balanced (22F/17M in GPA; 6F/6M in MPA), the average age of GPA patients was younger (53 years, 20–85) compared to those with MPA (67 years, 32–84). Most MPA cases were reported from Far East Asian medical centers (9/12, 75%), GPA cases occurred more often in Europe (22/42) and North America (13/42), and only 5/42 (12%) were in Asia. However, since ethnicity was not reported in most case reports, no firm conclusions can be drawn. Many, but not all patients (42, 76%) exhibited 1 or more digestive symptoms, including epigastric (18) or abdominal pain (17), nausea and vomiting (17), and jaundice (11). Notably, 13 (24%) were not associated with any digestive signs or symptoms, in particular MPA cases (6/12, 50%) compared to GPA (7/42, 17%).

Radiological studies revealed a pancreatic mass (30) and/or a pseudocystic lesion (8) in 35 patients (67%), in particular GPA cases with no predilection for location within the pancreas. Bile and/or pancreatic duct dilatation was found in 8 patients, 6 of whom presented with jaundice. Pancreatitis was observed in 25 (45%), 13 (27%) of whom showed signs of a mass or pseudocyst in addition. Masses/pseudocysts were more common in GPA (30/42, 71%) than in MPA (5/12, 42%); whereas pancreatitis was more common in MPA (7/12, 62%) than in GPA (18/42, 43%). Pseudocysts were not reported in MPA patients. Surprisingly, normal radiological features were reported in 1/42 GPA and 3/12 MPA patients.

Initial laboratory testing demonstrated mild to moderate elevated levels of pancreatic biomarkers (amylase, lipase, or trypsin) in 29 (53%) patients, 10 (18%) patients had normal levels, and no results were reported in the remaining 16 (29%). Higher levels were correlated with pain and a diagnosis of pancreatitis but were not specific. ANCA testing found 6 patients (10.9%) had positive ANCA levels before presenting with pancreatic AAV. A total of 28 patients (51%) were tested for ANCA at the initial evaluation for pancreatic disease, 6 (11%) after pancreatic surgery and histological evaluation, and 7 (13%) were tested several months later when extra-pancreatic manifestations appeared. Overall, 46 of all 55 cases (84%) were positive for ANCA, 33/42 (79%) GPA cases were ANCA-positive, 28 presented with anti-PR3 and/or cANCA, 4 with anti-MPO and/or pANCA, and 1 was ANCA-positive with no further details, 6 (14.3%) were ANCA-negative, and 4 (7.3%) had no results reported. In contrast, all 12 MPA cases were ANCA-positive, 11 (89%) had anti-MPO and one (11%) cANCA. Finally, the only EGPA case was positive for anti-MPO.

A diagnosis of AAV had already been made in 10 (18%) cases before pancreatic disease occurred. The time to diagnosis ranged from 0 to 6 months, with 1 case diagnosed 2 years after symptom onset. Ten patients (18%) underwent pancreatectomy (5 Whipple procedures, 4 partial/distal, and 1 total pancreatectomy) for presumed pancreatic adenocarcinoma leading to a diagnosis of GPA (9) and MPA/PAN (1). Pancreatic disease was the first (12) or one of the first (30) AAV manifestations in 42/55 (78%) patients. Of note, only 4 cases had isolated pancreatic disease (7%), but the available follow-up data was very limited. All the other patients presented with extra-pancreatic manifestations (50, 92%), 30 (55%) of which occurred concomitantly with pancreatic disease, and 8 (15%) appeared 1 month to 2 years later. Renal involvement was observed in all 12 cases of MPA, whereas pulmonary manifestations were detected in 8 cases; as expected, none had ENT involvement. In contrast, extra-pancreatic manifestations of GPA frequently involved the ENT sphere (25, 60%), remarkably including 4 cases of typical strawberry gingivitis. The following organs were also currently involved in patients with GPA: the lungs (26), kidneys (22), and skin (13). Arthralgia/arthritis (7), other gastrointestinal/pelvic manifestations (9), neuropathy (4), ophthalmologic lesions (3), and heart disease (2) were reported less frequently.

Overall, diagnosis of GPA and MPA was confirmed by histological examination of pancreas tissue in a total of 21 cases (38%) – 16 GPA and 5 MPA. Tissue was obtained either following pancreatectomies (10), or with conclusive biopsies (3 by EUS-FNA, 3 by laparotomy), and 5 at autopsy. Eight patients had inconclusive EUS/ERCP-FNA biopsies, and several preoperative biopsies were also inconclusive if they were attempted. Granulomatous inflammation (12) and/or (necrotizing) vasculitis (12) was found in 14 GPA cases. All 5 histological pancreatic exams of MPA showed necrotizing vasculitis in the absence of granulomatosis. A total of 37 (67%) patients exhibited histological evidence of ANCA-associated vasculitis in other organs, stemming from kidney biopsies (11 for GPA, 7 for MPA), followed by 9 ENT and 6 lung biopsies, all in GPA patients, and the 5 autopsies.

Corticosteroids were the primary treatment (89%), with cyclophosphamide (60%) and rituximab (18%) used in combination, indicating a preference for traditional immunosuppressive therapy. Other immunosuppressive regimens were used more rarely (9 times azathioprine, once mycophenolate, twice methotrexate, and twice intravenous immunoglobulins). Several patients underwent plasmapheresis (PEX) (6), required dialysis (10, more frequently for MPA [4/12] than for GPA [6/42]), or received bile/pancreatic duct stenting (5) or drainage of pseudocysts (4). Eight patients did not receive any immunosuppressive treatment for pancreatic AAV, 2 had unknown outcomes after surgery, several experienced spontaneous resolution, and 1 had a fatal outcome. Short-term outcome (2–18 months) was favorable in most cases with available follow-up data (35/49, 71%). Outcome was not reported for 6 patients. Information about long-term outcome (>2 years) was not available except for 2 patients, 1 of whom had a relapse. Nevertheless, 2 patients remained on dialysis, 1 received a renal transplant, and 11 (22%) died from disease-associated complications such as necrotizing pancreatitis with DIC, alveolar hemorrhage, renal failure, cerebral bleeding, or from sepsis after receiving immunosuppression (2). Mortality was higher for MPA (5/11, 45%) than for GPA (6/38, 16%).

Discussion

This case, presenting with a pancreatic mass, highlights the challenges in accurately diagnosing pancreatic AAV. To avoid unnecessary surgery, a targeted evaluation – including ANCA testing, imaging, biopsies, and a systematic assessment for ENT, pulmonary, renal, and cutaneous involvement – is essential to identify key clinical, serological, and radiological clues of pancreatic AAV. AAV presents with a wide spectrum of clinical manifestations; pancreatic involvement is extremely rare, with only 55 cases reported in the medical literature. It is a significant clinical challenge in several aspects. First, it causes a variety of nonspecific symptoms, mainly abdominal pain, nausea, and jaundice, opening a large differential diagnosis; second, specific laboratory and radiology features might be missing; and third, it can present as acute pancreatitis, as pancreatic pseudocyst, or pancreatic mass, thereby mimicking pancreatic adenocarcinoma. The consequences for the patient are multiple, with major morbidity and mortality due to misdiagnosis and delays in diagnosis and treatment. This is illustrated by the relatively high overall mortality rate (20.0%) reported in the present case series, in particular for patients with MPA (45%) compared to GPO (16%). Furthermore, 10 cases (18%) underwent surgery, either partial or total pancreatectomy, together with splenectomy in some cases. These procedures are associated with endocrine and exocrine pancreas insufficiency, thrombocytosis, post-splenectomy infections, and increased risk of certain cancers, particularly lymphomas and leukemias.

Pancreatic disease was the first or one of the first AAV manifestations in many patients (78%). However, the diagnosis of AAV was already known in 11, and 30 other cases had concomitant other AAV disease manifestations. Therefore, depending on the type of vasculitis, ENT, pulmonary, or renal involvement are almost always present, and should be investigated actively. As in our case, signs indicative for diabetes mellitus, including hyperglycemia and elevated HbA1c levels, were previously reported in 11/23 (48%) cases with AAV-related pancreatic disease [51]. Indeed, diabetes is more common in AAV patients (29% in MPA, 20% in GPA) than in the general adult US population (14.7%) [55]. However, we can only speculate whether diabetes is a risk factor for or a complication of pancreatic AAV.

ANCA are sensitive markers for AAV, with anti-PR3 or anti-MPO antibodies present in 70–90% and 95% of the GPA and MPA cases, respectively [1,2]. This was confirmed by our study, with an overall 84% of patients having ANCA positivity. However, ANCA were not always tested during the initial evaluation of a pancreatic mass or pancreatitis. Moreover, the absence of elevated ANCA levels did not preclude the diagnosis of pancreatic GPA: whereas all MPA cases were ANCA-positive, 6 GPA cases were ANCA-negative. Levels of pancreatic markers, such as lipase, amylase, and trypsin, were often normal or moderately elevated despite clinical and radiological findings supportive of pancreatitis. Jaundice was correlated with bile duct obstruction by a pancreatic mass in the head.

Imaging studies are often nonspecific, revealing pancreatic masses, pseudocysts, or signs of acute pancreatitis that can be confused with other hepatopancreatic pathologies. Differentiating pancreatic AAV from pancreatic cancer or AIP remains extremely challenging, as imaging features can significantly overlap. While certain findings – such as ductal dilation in cancer or diffuse enlargement with a capsule-like rim in AIP – may guide diagnostic suspicion, mass-like lesions in GPA often lack distinctive characteristics.

The diagnostic value of biopsies is limited, as they yield inconclusive results in a significant number of cases. Given that only 3 conclusive EUS-FNA and 8 inconclusive EUS/ERCP-FNA biopsies have been reported, the sample size is far too limited to derive reliable sensitivity and specificity values, so robust accuracy metrics cannot be established. In our case, 3 fine-needle aspirations failed to provide a definitive diagnosis. Additional pancreatic biopsy techniques are now available that may improve the diagnostic yield. Overall time to diagnosis was rather short, probably due to the acute onset of symptoms and the urgency of potential serious consequences of a pancreatic mass/pseudocyst.

Although the histological features of pancreatic AAV, especially MPA, remain poorly described, pancreatic AAV can be regarded as a form of autoimmune pancreatitis. However, it clearly differs from the 2 previously described AIP subtypes. Table 3 summarizes the distinguishing features of pancreatic AAV compared with those of AIP subtypes. Type 1 AIP, associated with IgG4-related disease (RD), is characterized by a prominent IgG4-positive lymphoplasmacytic infiltrate, distinctive storiform fibrosis, and obliterative phlebitis [56]. In contrast, type 2 AIP, whether occurring in isolation or in association with inflammatory bowel diseases, is defined by neutrophilic infiltration and destruction of interlobular and intralobular ducts, the presence of granulocytic epithelial lesions with periductal lymphoplasmacytic infiltration, relatively limited fibrosis, and few or no IgG4+-positive cells [56]. The recently recognized type 3 AIP is a distinct, immune checkpoint inhibitor-induced, chronic inflammatory disease of the pancreas [57]. In our case of pancreatic GPA, and in most other cases with available pancreatic histology, the findings included necrotic and fibrosing granulomatous pancreatitis with multi-nucleated giant cells and necrotizing vasculitis. Our case revealed focal duct-centric inflammation and a lobular inflammatory pattern, features that can also be observed in type I AIP. Although not present in our case, IgG4-positive infiltrates were reported in some cases of pancreatic AAV without fulfilling the criteria for type I AIP. This is noteworthy, as several cases of concurrent IgG4-RD and AAV (GPA, EGPA) have fueled an active debate about the existence of a potential “overlap syndrome” [58]. Although AAV and IgG4-RD share similar clinical features, this might be a co-occurrence in the same patient instead of a histopathological link [59]. Notably, none of the 21 cases of pancreatic AAV with histology reported patterns typical of IgG4 RD. However, it remains uncertain whether comprehensive IgG4 stainings were systematically performed in those cases. Thus, pancreatic GPA, also described as pancreatic granulomatous necrotizing vasculitis (PGNV) by Tinazzi I et al [37], is a distinct form of autoimmune pancreatitis that opens an intriguing avenue for future research, with many unanswered questions. We propose to classify this as type 4 autoimmune pancreatitis. Moreover, our finding of multiple granulomatous and necrotizing GPA lymphadenitis in association with pancreatic GPA mimicking tuberculosis has not been previously described.

A thorough diagnostic workup, including active investigations for extra-pancreatic manifestations of AAV, early serological ANCA testing, and (repeated) biopsies is warranted to make an accurate diagnosis [36]. This may prevent unnecessary surgical interventions and facilitate timely initiation of appropriate immunosuppressive therapy, in general leading to favorable outcomes. Furthermore, other forms of tumefactive or mass-forming chronic pancreatitis need to be excluded by appropriate testing, in particular AIP type 1, polyarteritis nodosa, sarcoidosis, follicular pancreatitis, Castleman’s disease, syphilis, and tuberculosis.

Due to its rarity, the treatment of pancreatic involvement in AAV is not well established. Corticosteroids are the cornerstone and seem to induce rapid improvement of the symptoms and pancreatic pathology. Of note, several case reports showed improvement of pancreatitis without immunosuppressive treatment. A Japanese autopsy study on AAV has suggested that pancreatic involvement occurs in up to 10% of cases, with a range of 6.5–33% according to various studies. This is significantly higher than previously estimated and may be attributed to the often silent clinical presentation. The study by Haraguchi et al highlights the need for increased awareness and consideration of pancreatic involvement in AAV [44]. For life-threatening disease, cyclophosphamide was added in many cases. However, rituximab has emerged as an attractive alternative, offering comparable efficacy and a better long-term safety profile, including a reduced risk of cancer [60]. The choice of treatment should therefore be based on the severity of the disease, the presence of other organ involvement, comorbidities, and patient preference. In our patient, rituximab was chosen due to concerns about cyclophosphamide toxicity. Close long-term monitoring is essential due to the chronic nature of AAV and the risk of relapse or progression to other organ systems.

Although this comprehensive review includes the largest number of analyzed cases with pancreatic AAV published so far, there are several limitations of our study that make it difficult to draw firm conclusions. Many of the case reports lack important data, some were only reported in abstract form, information on follow-up was only short-term or not reported at all, and treatment and histology results were not described in sufficient detail. Finally, publication bias might have influenced the number of cases with favorable outcome in comparison those with unfavorable or fatal outcome.

In summary, we report an additional case of a patient with pancreatic GPA mimicking pancreatic adenocarcinoma who underwent pancreatectomy, and we provide a thorough analysis of all 55 published cases of AAV associated pancreatic disease (Table 1). Compared with GPA, MPA cases were rarer, the patients were older and more likely to be from Asia, had fewer digestive symptoms, more often had signs of pancreatitis, had a lower incidence of pancreatic masses, and had no pseudocysts on imaging studies. In addition, all MPA patients had renal involvement with pauci-immune crescentic glomerulonephritis, compared with 52% in GPA, while ENT involvement was found only in GPA patients. Only 1 patient with MPA underwent pancreatectomy, compared to 9 with GPA, but mortality was 2.8 times higher (Table 2). The key takeaway points are presented in Table 4.

Conclusions

In cases of unexplained pancreatitis or pancreatic masses/pseudocysts, AAV should be considered. A targeted evaluation – including ANCA testing, imaging, biopsies, and a systematic search for ENT, lung, kidney, and skin manifestations—is essential to identify key clinical, serological, and radiological clues of pancreatic AAV. A corticosteroid-based regimen, with or without additional immunosuppressants, offers effective disease control, making pancreatic surgery unnecessary. Nonetheless, pancreatic AAV, particularly MPA, remains a serious condition with high mortality, highlighting the need for further research to clarify its pathophysiology, optimize diagnostic strategies, and standardize treatment protocols for better patient outcomes.