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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 23-March-2007, Vol 120 No 1251

Primary diffuse large B-cell lymphoma of the gallbladder with cholelithiasis masquerading as acute cholecystitis: case report and literature review
Wan-Ting Huang, Shih-Sung Chuang, Chao-Cheng Huang, Chin-Li Lu,
Hock-Liew Eng
Primary non-Hodgkin lymphoma (NHL) of the gallbladder (GB-NHL) is exceedingly rare. We present our experience on a 78-year-old male with chief complaints of fever, chills, and epigastric dull pain. Abdominal computed tomography (CT) scan showed a few stones and focally thickened gallbladder wall. He received cholecystectomy under the preoperative diagnosis of acute cholecystitis with septic shock, while pathologic examination revealed cholelithiasis and diffuse large B-cell lymphoma without acute inflammation. Staging procedures revealed a stage IE tumour and the patient received adjuvant radiotherapy. Relapse as a large retroperitoneal mass was noted 32 months later and he passed away three years after initial diagnosis.
A literature review revealed 20 cases of GB-NHL. We find that, including our current case, the median age is 63 years and 8 of 19 (42%) tumours are associated with gallstones. The mean and median survival of 15 patients with complete follow-up information is 75 and 36 months, respectively. Mucosa-associated lymphoid tissue (MALT) lymphoma seems to carry a longer survival than non-MALT lymphomas.

Primary extranodal presentation of non-Hodgkin lymphoma (NHL) occurs in up to 50% of cases with gastrointestinal tract being most commonly involved.1,2 Secondary involvement of gallbladder by NHL is not uncommon, however, primary NHL of the gallbladder (GB-NHL) is exceedingly rare.
To date, only 20 cases of GB-NHL were reported in the English literature.3–20 Some of the cases might not be genuine primary GB-NHL as the staging procedures were incomplete. We report our experience on a patient with cholelithiasis and primary GB-NHL, who presented with acute abdomen masquerading as acute cholecystitis. We reviewed all the reported primary GB-NHL cases and discussed the clinicopathological features and their association with cholelithiasis.

Case report

Clinical history—A 78-year-old male presented with fever, chills, and epigastric dull pain for several days. Physical examination revealed clear consciousness with low blood pressure (86/42 mmHg) without definite abdominal mass or peripheral lymphadenopathy. Complete blood count showed leucocytosis with white blood cell count at 38.3 × 109/L with 92.5% polymorphonuclear leucocytes.
Biochemical studies revealed elevated alanine aminotransferase (93 U/L; reference: 0–40 U/L) and alkaline phosphatase (455 U/L; reference: 28–94 U/L). Both hepatitis B surface antigen (HBsAg) and anti-HCV antibody were negative.
Abdominal ultrasonography and computed tomography (CT) scan showed several stones in the gallbladder and common bile duct with focal thickening and oedematous change of the gallbladder wall (Figure 1A). The patient received cholecystectomy under the preoperative diagnosis of acute cholecystitis with septic shock.
Postoperative lymphoma staging procedures including bone marrow aspiration/biopsy and abdominal and pelvic CT scans revealed a stage IE tumour. He received radiotherapy and was free of disease until a follow-up CT scan revealed a 10-cm retroperitoneal mass with encasement of aorta at 32 months.
He did not receive any further radiotherapy or chemotherapy, and died of relapsed disease 3 years after initial presentation.
Figure 1(A). CT scan shows a large stone (vertical arrow) and focal wall thickening (horizontal arrow) corresponding to the incidental finding of lymphoma. (B) Photomicrograph at scanning power shows an impacted stone in the gallbladder lumen with ulcerated mucosa and diffuse and transmural lymphocytic infiltration except in the right lower corner where the muscular wall is not infiltrated. (C) High-power photomicrograph shows diffuse sheets of large atypical lymphocytes expressing B-cell marker CD20 (Inset). (D) Polyacrylamide gel electrophoresis of the polymerase chain reaction product using FR3 probes for the immunoglobulin heavy chain gene shows a distinct single band, indicating monoclonality (Lanes 1 and 2, sample in duplicates; NC, negative control; PC, positive control)
Histopathology and immunohistochemistry—The gallbladder measured 10.5 × 5.0 × 2.5 cm and contained more than 10 yellow-brown stones measuring up to 2.2 cm. The mucosa appeared greenish with focal ulceration. A solid and fleshy tumour, 1.5 cm in diameter, was identified beneath the focally ulcerated mucosa with total effacement of the gallbladder wall, which measured up to 1.0 cm in thickness.
Under low-power microscopic examination, there was an impacted stone with focal erosion and ulceration of the mucosa (Figure 1B). Under higher power, the mucosa was expanded by diffuse lymphoid infiltrate, which extended transmurally to involve the full thickness of the gallbladder wall. The lymphoid cells were large atypical lymphocytes with vesicular nuclei, prominent nucleoli, and moderate amount of cytoplasm (Figure 1C).
Immunohistochemically, these large atypical lymphocytes expressed CD10, CD20 (Fig. 1C Inset), bcl-2, bcl-6, and MUM1—but not CD3, CD5, or p53 protein, thus indicating a diffuse large B-cell lymphoma (DLBL) of germinal centre B-cell origin. There were no acute suppurative cholecystitis, lymphoepithelial lesions, or plasmacytic differentiation of the lymphoma cells.
Immunohistochemical stain against cytokeratin with anti-AE1/AE3 antibody was negative for lymphoepithelial lesions, excluding mucosa-associated lymphoid tissue (MALT) lymphoma.
Molecular study—Clonality study for FR3 region of the immunoglobulin heavy chain gene rearrangement was done with polymerase chain reaction method using paraffin-embedded tissue section as previously described.21 The experiments were run in duplicates with appropriate positive and negative controls. Polyacrylamide gel electrophoresis revealed a single distinct band indicating monoclonality (Figure 1D).

Literature review

The pertinent clinical features of the previously reported 20 patients and the current case are summarised in Table 1. There are 8 males and 13 females and the median age is 63 years (mean, 57; range, 4–82). If we exclude the two cases with lymphoblastic lymphoma (LBL; aged 4 and 26, respectively), the median age is 65 years (mean, 62; range, 29–82).
The most common presenting symptoms and signs include epigastric pain with or without tenderness, nausea, and vomiting. In one patient, the disease was an incidental finding during right hemicolectomy for Dukes’ C colonic adenocarcinoma.7 Image studies by ultrasound and/or CT scan showed cholelithiasis in 8 (42%) of the 19 cases. No correct diagnosis was established before surgery in any case.
Operative or autopsy findings documented enlargement of regional or para-aortic lymph nodes in seven cases.4,5,8,14,19,20 as well as involvement of liver or spleen in two cases.4,9 These later two cases (Cases 2 and 9 in Table 1) should probably be excluded from primary GB-NHL since there was extensive lymphoma involvement in multiple organs and might present secondary tumours.
Histologic and immunophenotypic studies revealed that the majority of primary GB-NHL was mature B-lineage lymphomas except one case each of precursor B-LBL and precursor T-LBL.12,15 For the remaining cases, exact histologic subtype according to the new World Health Organization (WHO) classification of lymphoid neoplasms could not be ascertained as some of the cases were reported decades ago with old diagnostic terms such as lymphosarcoma and reticulum cell sarcoma.
However, it seems that around half of the 21 cases are high-grade lymphomas including our current case as DLBL. There were 8 cases (38%) of MALT lymphoma including one tumour with concurrent marrow involvement14and the other with subsequent gastric mucosa-associated lymphoid tissue (MALT) lymphoma 5 years later.17
Of the 21 cases, treatment modality was available in only 9 patients, including 2 with radiation, 5 with chemotherapy, and 2 with combined radiation and chemotherapy. One patient with MALT lymphoma didn’t receive chemotherapy until after a relapse in the gastric mucosa 5 years later. 17 One patient died from complications of colon cancer (Case 7).
Complete follow-up data were available in 15 patients, including 4 with MALT lymphoma and 11 with non-MALT lymphoma. The mean and median survival of these 15 patients was 75 and 36 months, respectively. The case number of MALT lymphoma patients was too small for statistic analysis. However this lymphoma type seemed to carry a longer survival than that of non-MALT lymphomas (Figure 2).
Figure 2. Cumulative survival cures of 15 primary gallbladder lymphomas with complete follow-up data, including 4 with mucosa-associated lymphoid tissue (MALT) lymphoma and 11 with non-MALT lymphoma
Note: The total case number of MALT lymphoma patients is small. However, this lymphoma type shows a longer survival than that of non-MALT lymphomas, although the difference is not statistically significant.


The pathogenesis of primary GB-NHL is unknown. Carcinoma is the most common cancer of gallbladder with complex aetiology, but there is a strong association with gallstones.22 There are compelling evidences to suggest a causal link: presence of gallstones in 65–90% of patients with gallbladder carcinoma; the frequencies of gallstones and gallbladder carcinoma run in parallel in a defined population; and the risk of developing gallbladder carcinoma increases in direct proportion to gallstone size. We speculate that the same causal link exists in gallstones and GB-NHL. In this review, 42% of patients with GB-NHL were known to have gallstones with the histology type spanning from MALT lymphoma to DLBL.
In our patient who had 10 more stones up to 2.2 cm, we have shown that the lymphoma is identified beneath the ulcerated mucosa of an impacted stone, which gives an evidence of possible gallstone-related lymphomagenesis. Due to the rarity of GB-NHL, it is difficult to collect a large cohort of cases in a single study to explore the relationship between gallstones and lymphoma. Detailed case reports such as ours are important to form the database for future systemic reviews.
MALT lymphoma is a low-grade B-cell lymphoma recapitulating the lymphoid architecture of Peyer’s patches in terminal ileum. It is most common in the stomach and arises from MALT acquired as a consequence of H. pylori infection. MALT lymphoma exemplifies the close association between chronic infection and lymphomagenesis.
A similar mechanism of MALT lymphomagenesis in stomach may apply in gallbladder. As in stomach, there is sparse lymphoid tissue or only a few intraepithelial lymphocytes between the surface epithelial cells in normal gallbladder mucosa. Lymphoid hyperplasia or reactive lymphoid follicles can be found in the gallbladder with chronic inflammation suggesting that MALT lymphoma may arise from chronic inflammatory lesions as in the stomach with H. pylori infection.
One alternative hypothesis of tumour cell origin is that clonal lymphoid cells deriving from lymphoid tissue outside the gallbladder may home to this organ by adhesion molecules.23 This is supported by the report of Stephen et al, who observed a sequential development of MALT lymphoma affecting stomach, small intestine, and gallbladder by the same single clone of lymphoma cells as demonstrated by molecular methods.24
In general, patients with MALT lymphoma have a better prognosis with or without adjuvant chemotherapy than those with non-MALT lymphomas (Figure 2). In the earlier reports of primary GB-NHL, many patients died shortly after operation either due to operative complications, sepsis, or disease progression. The majority of these cases were probably high-grade lymphomas, most likely DLBL as our current case.
As a victim of stage IE tumour, our patient received postoperative radiotherapy without chemotherapy and was free of disease for 32 months until a retroperitoneal relapse occurred. Precursor LBL of gallbladder is extremely rare and the only two cases reported in the literature were free of disease after chemotherapy.12,15
The experience from these cases indicates that stage IE GB-NHL is a systemic disease and chemotherapy is justified in cases other than MALT lymphoma, with or without concurrent radiotherapy.
In conclusion, primary GB-NHL is exceedingly rare and had never been diagnosed preoperatively. Thorough pathological examination of the cholecystectomy specimen is important, especially for those with gallstones, as there is a strong association between gallstones and carcinoma/lymphoma of the gallbladder.
Most GB-NHLs are non-MALT lymphomas with aggressive behavior and adjuvant chemotherapy is highly recommended; even the disease is limited in the GB at initial staging.
Author information: Wan-Ting Huang , MD, Chao-Cheng Huang, MD, Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung83305, Taiwan; Shih-Sung Chuang, MD, Department of Pathology; Chin-Li Lu, Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
Correspondence: Hock-Liew Eng MD, Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niaosung Hsiang, Kaohsiung Hsien, Taiwan, ROC.
Fax: +886 7 7333198; email:
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