An unusual case of a tuberculous granuloma of the liver presenting thirteen years after intravesical BCG – therapy for bladder cancer

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DOI: 10.5604/01.3001.0014.3017 POL PRZEGL CHIR, 2020: 92: 1-4 AHEAD OF PRINT

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ABBREVIATIONS

BSG – Bacillus Calmette-Guérin CT – computed tomography FNH – focal nodular hyperplasia NMR – nuclear magnetic resonance PCR – polymerase chain reaction

SIRS – Systemic inflammatory response syndrome USG – ultrasound

INTRODUCTION

Since the 1970s, the treatment of superficial malignant neopla- sms of bladder has involved the use of enemas with Bacillus Cal- mette-Guérin (BCG) suspension. The efficacy of such therapy is estimated at as much as 70–90% for in situ papillary carcinoma.

That said, treatment is burdened with considerably high risk of adverse events, both local (bladder, testes, epididymis, penis or prostate gland) and generalized, which include: fever, pneumonia, miliary tuberculosis, osteomyelitis, arthritis and (extremely rarely) systemic inflammatory response syndrome (SIRS). The incidence of more severe and long-term complications is estimated at 5% [1–3]. Hepatobiliary complications are observed in 0.7–3% of patients [4, 5]. The authors present a case report of tuberculous granuloma of the liver diagnosed extremely late, thirteen years after the end of BCG treatment.

CASE REPORT

In January of 2014, a 49-year-old female patient with an uncle- ar segment VII tumor of the liver, detected in July 2013 during

abdominal ultrasound due to pain in the right upper abdomen, was admitted to the Department of Liver and General Surgery, CM UMK in Bydgoszcz. CT and NMR (Fig. 1.) revealed a focal lesion in segment VII of the liver, with radiographic features of focal nodular hyperplasia, or FNH.

During history taking in 2000, the patient had abdominal ultrasound due to non-specific symptoms of dyspepsia and general malaise. The examination revealed a bladder tumor further identified as an early malignant lesion (Carcinoma urotheliale papillare non invasivum; G2). Electroresection of tumor was performed and supplemented with ten BCG intravesical infu- sions. There were no early treatment complications. The patient remained under urological observation for the following six years.

In 2006, she underwent elective surgery to remove a right breast lump (fibroadenoma).

On January 16, 2014, the patient had anatomic hepatic resection of segment seven. She was discharged on day 6 after surgery with the wound healed by primary intention. After consulting at the pulmonary center, no treatment was undertaken in this regard.

During further follow-up until April 30, 2019, the patient’s he- alth had remained unchanged.

RESULTS

The sample sent for histopathological examination after hepatic resection (segment VII with tumor) contained a lesion me- asuring 2 x 2.6 x 2 cm. Macroscopically visible solid, grayish mass. Microscopic examination revealed numerous granulomas with small foci of caseation necrosis, surrounded by fibrous tissue, containing: Langhans giant cells, epithelial histiocytes and

An unusual case of a tuberculous granuloma of the liver

presenting thirteen years after intravesical BCG

– therapy for bladder cancer

Wojciech Szczęsny

^1AE

, Łukasz Szylberg

^2,3B

, Maciej Słupski

^1D

, Andrzej Marszałek

^3D

,

Jakub Szmytkowski

^1E

1Chair and Clinic of General Surgery, Liver Surgery and Transplant Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland; Head: Maciej Słupski MD PhD

2Chair and Department of Clinical Pathomorphology, Collegium Medium in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland; Head: Dariusz Grzanka MD PhD

3Department of Cancer Pathology, Greater Poland Cancer Center, Poznan, Poland; Head: prof. Andrzej Marszałek MD PhD

Article history: Received: 03.09.2019 Accepted: 07.07.2020 Published: 03.09.2020

ABSTRACT: The authors present the case of a female patient with a tumor of segment VII of the liver, which was postoperatively identified as a tuberculous granuloma. The patient was admitted for elective surgery for a liver tumor, which had been diagnosed a few months before. Computed tomography and nuclear magnetic resonance were performed, based on which focal nodular hyperplasia was suspected. Thirteen years prior to admission the patient had undergone a transurethral resection of superficial bladder carcinoma, followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG-therapy). Upon surgery, segment VII of the liver was resected; postoperative course was uneventful. After the identification of granuloma, the patient was referred to a phthysiatric clinic for further diagnostics and treatment. The authors have deemed this case worthy of reporting primarily due to the exceptionally long period between the completion of BCG therapy and the onset of hepatic tumor.

KEYWORDS: BCG therapy, bladder carcinoma, liver, tuberculous granuloma

Authors’ Contribution:

A – Study Design B – Data Collection C – Statistical Analysis D – Manuscript Preparation E – Literature Search F – Funds Collection

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life-threatening vascular fistulas [2, 7]. According to published literature, all those complications are observed quite early, within a few hours to a maximum of several months after admini- stration of BCG infusion. Gonzales et al. published a literature review on adverse events associated with BCG therapy and pre- sented data from their own clinical material. On this basis, they distinguished between early complications (occurring up to three months) and late complications (at least one year after starting BCG treatment) [8]. The authors of this report conducted their own search of the available literature and found no description of an equally long latency period before the onset of a complication after BCG treatment. Due to the exceptionally rigorous observation of the patient (annual abdominal ultrasound and chest X-ray every two years) for the first six years after the end of urological treatment and two years of close follow-up after an excision of a breast lump, it can be established with a high pro- bability that at this time, the patient did not develop any patho- logical changes until July 2013.

The diagnosis of hepatic tuberculosis may be difficult, especially in cases where no specific changes are observed outside the liver [9].

Hepatic tuberculomas resemble tumors and may be confused with primary or secondary malignant liver tumors. In a paper published by Xing et al. 682 tissue specimens obtained during lymphocytes (Fig. 2A.). Most granulomas were located within

the hepatic triads. In the surrounding liver parenchyma, there was lymphatic infiltration.

Ziehl-Neelsen staining was performed to identify the etiologi- cal factor of the granulomas; Mycobacterium tuberculosis was not identified. In order to analyze the morphology of granulomas and the surrounding parenchyma, additional histochemi- cal and immunohistochemical stains were performed: Gomori, CD68, CD3, CD4, CD8, CD20, IL-1 and TNF-α (Fig. 1B.–1H.).

Gomori trichrome stain showed significant fibrosis obliterating the granulomas and a moderate degree of fibrosis around the liver parenchyma. Immunohistochemical staining for CD68, IL-1 and TNF-α was positive in epithelial histiocytes and Langhans giant cells. Moreover, all lymphocytes expressed TNF-α and IL-1. T (CD4+) and B (CD20+) cells were widely dispersed within the granulomas. The presence of CD3+ and CD8+ T cells was found in the cells surrounding the granulomas. Macro- and microscopic imaging in conjunction with clinical data gave gro- unds to establish a final diagnosis of granuloma with most likely tuberculous etiology.

DISCUSSION

The authors present a case report of tuberculous granuloma of the liver, a distant complication of treatment with BCG enemas of superficial bladder cancer, done thirteen years earlier. Since the completion of treatment, the patient has remained under close urological monitoring, including regular abdominal ultrasound.

BCG adjuvant therapy in superficial bladder cancer was intro- duced in 1976 by Morales et al. [6]. The mechanism of therapeutic effect has not been fully clarified; we consider the induction of phagocytosis with the subsequent activation of the cytokine cascade (IL12, interferon, TNF), leading to the activation of T lymphocytes, including the so-called natural killer cells [6]. As already mentioned, the complication rate for this therapeutic method is estimated at 3–5%. Severe, generalized complications such as miliary, pneumonia or granulomatous hepatitis are less common (0.7–3%). There are also reports of eye changes and Fig. 1. NMR image of the abdomen. Arrow points at the lesion in segment VII of the liver.

Fig. 2. (A) Granuloma consisting of epithelioid cells with multinuclear Langhans cells. HE x 200; (B) Gomori staining; (C) IHC staining for CD3; (D) IHC staining for CD4; (E) IHC staining for CD8; (F) IHC staining for CD20; (G) IHC staining for CD68; (H) IHC staining for TNF-α.

A B

C D

E F

G H

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the liver triads [11]. Differential diagnosis of granulomas should include: sarcoidosis, Hodgkin’s lymphoma, primary biliary cirr- hosis, drug-induced lesions (allopurinol, sulfonamides), fungal and bacterial infections (actinomycetes, brucellosis, cat scratch disease, syphilis), parasitic (schistosomiasis) and viral (hepatitis C, cytomegalovirus) [12]. The authors of the latest reports are concerned with the usefulness of the polymerase chain reaction (PCR) as an auxiliary diagnostic tool for the differentiation of extrapulmonary tuberculosis and non-tuberculous granulomas, especially in cases of focal lesions with a negative Ziehl-Neelsen staining result. Appropriate diagnostic sensitivity is ensured by a combination of the clinical picture, histopathological examination and PCR [13].

To conclude, the authors wish to emphasize that granulomatous changes in the liver may occur even many years after completion of BCG therapy.

liver resections due to suspected hepatocellular carcinoma were analyzed; the authors found eight cases of non-neoplastic tuberculous tumors, in their conclusions highlighting the diagnostic challenges of such cases [10]. Percutaneous biopsy of the tumor may be helpful in establishing the diagnosis. In the case presen- ted, biopsy was not performed due to: history of malignant neo- plasm, ambiguous description of the imaging examination and extensive experience of the center in hepatic and biliary surgery.

Macroscopic imaging revealed hepatic tuberculosis characterized by a broad range of morphological changes, including serous and non-keratinizing epithelial granulomas as well as caseation necrosis without component of granulomatous inflammation Other possible histopathological findings include macrophage hyperplasia, the presence of lymphocytic infiltrates in hepatic triads, and necrotic hepatocytes. Some authors note that in the course of miliary tuberculosis, tuberculous granulomas are located inside the lobes, while in tuberculosis in organs, they are present within

REFERENCES

1. Aslan G., Sevinc C., Tuna B., Ozkal S., Yorukoglu K.: Penile lesion with in- guinal adenopathy after intravesical Bacillus Calmette-Guerin instillation therapy. Indian J Urol, 2013; 29(1): 70–72.

2. Koga H., Kuroda M., Kudo S. et al.: Adverse drug reactions of intravesical bacillus Calmette-Guerin instillation and risk factors of the development of adverse drug reactions in superficial cancer and carcinoma in situ of the bladder. Int J Urol, 2005; 12(2): 145–151.

3. Miyazaki J., Hinotsu S., Ishizuka N. et al.: Adverse reactions related to treatment compliance during BCG maintenance therapy for non-muscle-invasive bladder cancer. Jpn J Clin Oncol, 2013; 43(8): 827–834.

4. Delimpoura V., Samitas K., Vamvakaris I., Zervas E., Gaga M.: Concurrent granulomatous hepatitis, pneumonitis and sepsis as a complication of intravesical BCG immunotherapy. BMJ Case Rep, 2013; 10: 2013.

5. Soylu A., Ince AT., Polat H. et al.: Peritoneal tuberculosis and granulomatous hepatitis secondary to treatment of bladder cancer with Bacillus Calmette- -Guérin. Ann Clin Microbiol Antimicrob, 2009; 8: 12.

6. Manfredi R., Dentale N., Piergentili B., Pultrone C., Brunocilla E.: Tubercu- lar disease caused by Bacillus of Calmette-Guérin as a local adjuvant treatment of relapsing bladder carcinoma. Cancer Biother Radiopharm, 2009;

24(5): 621–627.

7. Lamm D.L., van der Meijden P.M., Morales A. et al.: Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J Urol, 1992; 147(3): 596–600.

8. Gonzalez O.Y., Musher D.M., Brar I. et al.: Spectrum of bacille Calmette- -Guérin (BCG) infection after intravesical BCG immunotherapy. Clin Infect Dis, 2003; 36(2): 140–148.

9. Chien R.N., Lin P.Y., Liaw Y.F.: Hepatic tuberculosis: comparison of miliary and local form. Infection, 1995; 23(1): 5–8.

10. Xing X., Hong L., Liu W.G.: Hepatic segmentectomy for treatment of hepatic tuberculous pseudotumor. Hepatobiliary Pancreat. Dis Int, 2005; 4(4): 565–568.

11. Hersch C.: Tuberculosis of the liver. A study of 200 cases. S Afr Med J, 1964;

38: 857–863.

12. Coash M., Forouhar F., Wu C.H., Wu G.Y.: Granulomatous liver diseases: a review. J Formos Med Assoc, 2012; 111(1): 3–13.

13. Kesarwani R.C., Pandey A., Misra A., Singh A.K.: Polymerase chain reaction (PCR): Its comparison with conventional techniques for diagnosis of extra- -pulmonary tubercular diseases. Indian J Surg, 2004; 66(2): 84–88.

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The content of the journal „Polish Journal of Surgery” is circulated on the basis of the Open Access which means free and limitless access to scientific data.

This material is available under the Creative Commons – Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).

The full terms of this license are available on: https://creativecommons.org/licenses/by-nc/4.0/legalcode Wojciech Szczęsny; Chair and Clinic of General Surgery, Liver Surgery and Transplant Surgery, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland; M. Sklodowskiej-Curie street 9, 85-090 Bydgoszcz, Poland;

E-mail: wojszcz@interia.pl

Szczesny W., Szylberg L., Slupski M., Marszalek A., Szmytkowski J.: An unusual case of a tuberculous granuloma of the liver presenting thirteen years after intravesical BCG – therapy for bladder cancer; Pol Przegl Chir 2020; 92: 1–4;

DOI: 10.5604/01.3001.0014.3017 (Advanced online publication)

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