Multifocal EBV-Associated and CMV-Correlated Post-Transplant Smooth Muscle Tumor: A Case After Liver Transplantation

doi:10.21203/rs.3.rs-864614/v1

Download PDF

Case Report

Multifocal EBV-Associated and CMV-Correlated Post-Transplant Smooth Muscle Tumor: A Case After Liver Transplantation

https://doi.org/10.21203/rs.3.rs-864614/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Introduction

Immunodeficient patients, including the recipients of solid organs, exhibit an increase in the incidence of neoplasms. Post-transplant smooth muscle tumor (PTSMT) is a distinct and infrequent entity of these groups of neoplasms. Epstein–Barr virus (EBV) is considered to be involved in the etiology of this neoplasm.

Case report

A 28-year-old man who underwent liver transplantation presented with abdominal pain and diarrhea for several months. He had a history of resistant systemic cytomegalovirus (CMV) infection after transplantation. On physical examination, he had mild abdominal tenderness. Spiral chest and abdominopelvic CT scan with contrast showed a liver lesion with ring enhancement; furthermore, it showed a solid lesion in the spleen and multiple small lesions in lower lobes of both lungs. Colonoscopy revealed multiple small raised polypoid lesions throughout the rectum and colon. Microscopic evaluation of colon mucosa biopsy using IHC study was in favor of spindle cell neoplasm with high proliferative index. He underwent a right hemicolectomy. A microscopic study showed spindle cell proliferation with mild atypia and a mild increase in mitotic rate without any necrosis, with features of smooth muscle tumor. Trucut biopsy of liver mass was also in favor of smooth muscle tumor. According to transplantation history and considering the possibility of EBV-associated smooth muscle tumor, EBV encoded RNA (EBER) chromogenic in-situ hybridization (CISH) study on paraffin block of colon lesions was requested, which demonstrated EBV RNA in tumor cell nuclei and immunoblasts of the adjacent lymph node, suggesting EBV-associated smooth muscle tumor. In addition, PCR for CMV was requested on paraffin block of the colon lesions, which also showed a positive result. PCR for EBV and CMV viremia were negative. The dosage of immunosuppressive agents was reduced, and currently, he is being followed, with slow expansion in the size of the lesions.

Conclusion

Although the incidence of post-transplant smooth muscle tumors (PTSMTs) is low, it should be remained in the differential diagnosis in post-transplantation patients, especially dealing with multifocal tumors. As strong stimulant for smooth muscle tumors, close follow-up and screening for EBV and CMV infection and early treatment at the time of diagnosis are recommended to avoid these virus-induced tumors.

Pathology

EBV

CMV

smooth muscle tumor

post-transplant smooth muscle tumor

EBER

Immunodeficient patients exhibit the increased incidence of neoplasms, whether the immunodeficiency is in the context of genetic disorders, acquired immunodeficiency syndrome (AIDS), or rigorous immunosuppressive therapy for organ transplantation (1, 2). The development of neoplasms is a well-known complication after solid-organ transplantation. Among these neoplasms, post-transplant smooth muscle tumor (PTSMT) is a distinct and infrequent entity, which may appear in the peripheral soft tissue, intracranial space, and visceral sites. Tumor multiplicity is also common. Epstein–Barr virus (EBV) is hypothesized to play a role in the etiology of this neoplasm(2, 3, 4, 5). Herein, we present a new case of multifocal EBV-associated, cytomegalovirus (CMV) correlated PTSMT occurring in the gastrointestinal tract, liver, and lungs after liver transplantation.

A 28-year-old man, presented with abdominal pain and diarrhea for several months. Two years ago, he underwent liver transplantation from a deceased donor due to acute liver failure. During routine post-transplantation follow-up visits, he developed subclinical hypothyroidism and one episode of acute cell-mediated rejection, which were controlled by the administration of levothyroxine (100µg/day) and immunosuppressive pulse therapy, respectively. He also had resistant systemic CMV infection. He had about 10 kg weight loss during the last 6 months. There was no history of fever or lymphadenopathy. Other past medical histories before transplantation and family history were not significant. He was taking prednisolone, Prograf, and CellCept. On physical examination, the vital signs were stable (blood pressure: 110/70 mmHg, the pulse rate: 68/min, temperature: 36.9°C), but he had mild abdominal tenderness. The main laboratory data are shown in Table 1.

Table 1

The main laboratory data of the patient
Parameter(unit)	Result	Reference range
WBC(x 10³ /µL)	4.9 (with 20% atypical lymphocytes)	4.5–11
HB(g/dL)	12	14–18
MCV(fl)	72.15	80–96
PLT(x 10³ /µL)	185	150–450
ALT(IU/L)	23	3–40
AST(IU/L)	20	3–40
ALP(IU/L)	112	80–306
Total Bilirubin(mg/dL)	0.95	0.2-1
Direct Bilirubin(mg/dL)	0.3	0.1–0.3
BUN(mg/dl)	14	6–20
Creatinine(mg/dl)	1.2	0.5–1.3
Fasting blood sugar(mg/dl)	114	70–99
HBS Ag	Non- reactive	Non- reactive
HCV Ab	Non- reactive	Non- reactive
HIV Ab	Non- reactive	Non- reactive
CMVviremia PCR	Positive	-
AFP(ng/ml)	4.23	0.89–8.78
CA19-9	14.82	< 37

Abdominopelvic ultrasonography revealed a solid liver mass. Spiral chest and abdominopelvic CT scan with contrast were done showing the mentioned lesion with ring enhancement M: 22x16 mm in the lateral aspect of segment VIII, in addition to a solid lesion in spleen and multiple small lesions in lower lobes of both lungs measuring 5 to 20 mm (Fig. 1). Colonoscopy was done, which revealed multiple small raised polypoid lesions throughout the rectum and colon (Fig. 2). Microscopic evaluation of the colon mucosa biopsy using IHC study was in favor of spindle cell neoplasm with high proliferative index. He underwent a right hemicolectomy. The gross morphologic evaluation showed multiple small submucosal polypoid lesions. A microscopic study showed spindle cell proliferation with mild atypia and a mild increase in mitotic rate ( Ki-67: 15%) without any necrosis with features of smooth muscle tumor (Fig. 3A,B). Trucut biopsy of the liver mass was also in favor of smooth muscle tumor (Fig. 3C). IHC study with smooth muscle actin (SMA) confirmed the diagnosis (Fig. 3D). According to transplantation history and immune deficiency status of the patient and considering the possibility of EBV-associated smooth muscle tumor, an EBER CISH study on paraffin block of colon lesions was requested, which demonstrated EBV RNA in tumor cell nuclei and immunoblasts of the adjacent lymph node, suggesting EBV-associated smooth muscle tumor (Fig. 4). Although there was no serologic or molecular test for EBV in the patient’s documents, he had a history of prolonged and resistant CMV infection. Thus, polymerase chain reaction (PCR) for CMV was requested on paraffin block of the colon lesions, which also showed positive results (40,000 copies/ml). PCR for EBV and CMV viremia were negative. The dosage of immunosuppressive agents was reduced, and currently, he is being followed, with slow expansion in the size of the lesions.

The written informed consent was requested and obtained by the patient for publishing the case report and the publication of the accompanying images. Also, our institutional approval was not required to publish the case details.

Immunosuppressed patients are susceptible to a variety of neoplasms, whether the immunodeficiency is due to genetic disorders, AIDS, or immunosuppressive therapy for organ transplantation. Lymphoma and cutaneous malignancies are the most commonly reported neoplasms. PTSMT is also a rare entity in this field. This was first expressed by Pritzker et al. in 1970, and in 1995 Lee et al. noticed the role of the EBV in tumorigenesis (1, 2, 3). Conventionally, the condition has been more frequent in AIDS patients, and a small number of cases have been solid organ transplant recipients (3). The vast majority of PTSMTs appear after kidney transplantation (60%), and the liver is the most common location in both the pediatric and the adult patients. Lungs, lymph nodes, adrenal gland, spleen, heart, kidney, and less often, the central nervous system may also be involved (5, 6). The precise incidence is not known, but they are reported to arise in less than 1% of the immunodeficient population. The average time it takes for this tumor to appear following an organ transplantation is 4 years (6, 7, 8).

The pathogenesis of EBV-SMT is not well recognized. EBV is a DNA herpes virus with a potential to immortalize infected cells. It has traditionally been related to the pathogenesis of Burkitt lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and other B-cell lymphomas in immunodeficient patients (6, 9, 10). Since EBV-PTSMT can be developed in various organs, some authors hypothesized that SMT may originate from smooth muscle cells of the blood vessel wall. Immunosuppression may permit an abnormal pass of EBV into smooth muscle cells, which could direct to a latent infection and consequent neoplasm formation altered by cytogenetic incidences (11, 12).

Greater than 50% of patients with EBV-SMT present with multiple tumors, and this multifocal involvement appears to be the result of multiple infectious events rather than metastases from a single neoplastic site. EBV-SMTs are often slow-growing and invading only locally. Despite the common multifocal presentation of EBV-SMTs, they are not often fatal (9, 13, 14).

Smooth muscle tumors have a wide range of clinical behavior and pathologic features. The lesions can be broadly classified into those with obvious malignant signs of leiomyosarcoma, and ‘borderline’ cases with little pleomorphism, cellular crowding, and mitotic activity with ‘uncertain biological potential’. Intratumoral T lymphocytes may also be identified. (1, 3, 5). The most reliable methods for detection of EBV within cancer cells are demonstration of EBV RNA by in situ hybridization (ISH) and PCR (2, 3).

Although serology confirms previous EBV infection, it has little bearing on diagnosis, recurrence monitoring, or disease burden (9).

Surgical excision with negative margins, especially in unifocal lesions, is frequently curative(5, 9, 15). Reducing immunosuppressive medication may allow EBV-specific cytotoxic T-cell responses to proliferate, but the risk of graft rejection must also be considered. Incorporating antiviral medicine that reduce EBV viral load and cyclosporine by sirolimus (as an oncogenesis inhibitor) improve disease control and may lead to better outcomes. Antiviral therapy, chemotherapy, and radiotherapy have not been demonstrated to be effective in all cases, but they may be useful in patients with unresectable neoplasms (5, 9).

Krenzlin et al. recently discovered that mouse CMV can be reactivated in perivascular, intratumoral pericytes of glioblastoma, as well as its involvement in tumor promotion (16). Human CMV has also been identified as a cancer-causing virus by demonstrating its presence in > 90% of common tumor types such as breast cancer, while being absent in surrounding normal tissue. Having invaded many cell types in tumor tissues, CMV can cause all the ten proposed hallmarks of cancer. This virus exhibits cellular tumor-promoting and immune-evasive methods, hijacks proangiogenic and anti-apoptotic systems and promotes immunosuppressive effects in the tumor micro-environment(17–19).

Using recent detection methods (ISH, PCR, electron microscopy, DNA and RNA sequencing, immunostaining of tissue specimens, and flow cytometry) some research groups have discovered a high prevalence of CMV in breast, colon, and prostate cancer, rhabdomyosarcoma, hepatocellular cancer, salivary gland tumors, neuroblastoma and brain tumors (medulloblastoma and glioblastoma (GBM)(20–26).

Our case was a post-liver transplant patient with consequent colon polyposis, liver and lung lesions, which histologically were compatible with EBV-associated smooth muscle tumor. Despite the fact that he was not checked for EBV infection during post-transplantation follow-up, he had recurrent and resistant systemic CMV infection. Generally, according to previous investigations, CMV infection should also be considered as a stimulator for smooth muscle proliferation besides EBV infection.

The incidence of PTSMTs is low. However, it should be remained in the differential diagnosis in post-transplantation patients, especially dealing with multifocal tumors. As strong stimulators for smooth muscle tumors, close follow-up and screening for EBV and CMV infection and on time treatment at the time of diagnosis are suggested to prevent these virus-induced tumors.

Ethics approval and consent to participate: Our institutional approval was not required to publish the case details.

Consent for publication: The authors give their consent for publication
Availability of data and materials: All the data are available.
Competing interests: The author declare no competing interest.
Funding: None

-Lee ES, Locker J, Nalesnik M, Reyes J, Jaffe R, Alashari M, Nour B, Tzakis A, Dickman PS. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med. 1995;332(1):19–25.
-Salamanca J, Massa DS. EBV-associated hepatic smooth muscle tumor after lung transplantation: report of a case and review of the literature. J Heart Lung Transplant. 2009;28(11):1217–20.
-Miettinen M. Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis. Mod Pathol. 2014;27:17–29.
-Purgina B, Rao UN, Miettinen M, et al. AIDS- related EBV-associated smooth muscle tumors: A review of 64 published cases. Patholog Res Int 2011; 2011:561548.
-Cerilli LA. Multiple hepatic masses in a 38-year-old male 10 years after renal transplantation. Nephrol Dial Transplant. 2005;20(8):1756–8.
-Raheja A, Sowder A, Palmer C, Rodriguez FJ, Couldwell WT. Epstein-Barr virus-associated smooth muscle tumor of the cavernous sinus: a delayed complication of allogenic peripheral blood stem cell transplantation: case report. J Neurosurg. 2017;126(5):1479–83.
-Hussein K, Rath B, Ludewig B, Kreipe H, Jonigk D. Clinicopathological characteristics of different types of immunodeficiency-associated smooth muscle tumours. Eur J Cancer. 2014;50:2417–24.
-Jonigk D, Laenger F, Maegel L, Izykowski N, Rische J, Tiede C, et al. Molecular and clinicopathological analysis of Epstein-Barr virus-associated posttransplant smooth muscle tumors. Am J Transplant. 2012;12:1908–17.
-Cela I, Shah NB, Bradly D, Loew J, Leslie W. An Epstein-Barr virus-associated smooth muscle tumor successfully treated with surgical resection: a case report and literature review. Clin Adv Hematol Oncol. 2010;8(6):423–6.
-McClain KL, Leach CT, Jenson HB, Joshi VV, Pollock BH, Parmley RT, et al. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med. 1995;332:12–8.
-Conrad A, Brunet AS, Hervieu V, Chauvet C, Buron F, Collardeau-Frachon S, Rivet C, Cassier P, Testelin S, Lachaux A, Morelon E, Thaunat O. Epstein-Barr virus-associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient. Transpl Infect Dis. 2013;15(5):E182-6.
-Deyrup AT, Lee VK, Hill CE, et al. Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol. 2006;30(1):75–82.
-Gallien S, Zuber B, Polivka M, et al. Multifocal Epstein-Barr virus-associated smooth muscle tumor in adults with AIDS: case report and review of the literature. Oncology. 2008;74:167–76.
-Deyrup AT, Lee VK, Hill CE, et al. Epstein-Barr virus–associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol. 2006;30:75–82.
-Liu Y, Chintalapati S, Dietz R, Raza AS, Wang J, Raza AS. EBV-associated hepatic smooth muscle tumor of uncertain biologic behavior after heart transplantation in a pediatric patient: case report. J Gastrointest Oncol. 2017;8(1):E21–5.
-Krenzlin H, Behera P, Lorenz V, Passaro C, Zdioruk M, Nowicki MO, et al. Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis. J Clin Invest. 2019;130:1671–83.
-Geisler J, Touma J, Rahbar A, Söderberg-Nauclér C, Vetvik K. A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity. Cancers (Basel). 2019;11(12):1842.
-Geder L, Sanford EJ, Rohner TJ, Rapp F. Cytomegalovirus and cancer of the prostate: in vitro transformation of human cells. Cancer Treat Rep. 1977;61(2):139–46.
-Nauclér CS, Geisler J, Vetvik K. The emerging role of human cytomegalovirus infection in human carcinogenesis: a review of current evidence and potential therapeutic implications. Oncotarget. 2019. 2;10(42):4333-47.
-Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121:4043–55.
-Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002;62:3347–50.
-Harkins LE, Matlaf LA, Soroceanu L, Klemm K, Britt WJ, Wang W,et al. Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae. 2010;1:8.
-Samanta M, Harkins L, Klemm K, Britt WJ, Cobbs CS. High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J Urol. 2003;170:998–1002.
-Price RL, Bingmer K, Harkins L, Iwenofu OH, Kwon CH, Cook C,et al. Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/- mice. Cancer Res. 2012;72:5669–74.
-Lepiller Q, Tripathy MK, Di Martino V, Kantelip B, Herbein G. Increased HCMV seroprevalence in patients with hepatocellular carcinoma. Virol J. 2011;8:485.
-Taher C, de Boniface J, Mohammad AA, Religa P, Hartman J, Yaiw KC, et al. High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. PLoS One. 2013;8:e56795.

Download PDF

Editorial decision: Major Revision
19 Sep, 2021
Review #2 received at journal
18 Sep, 2021
Reviewer #2 agreed at journal
11 Sep, 2021
Review #1 received at journal
03 Sep, 2021
Reviewer #1 agreed at journal
02 Sep, 2021
Reviewers invited by journal
01 Sep, 2021
First submitted to journal
30 Aug, 2021
Editor assigned by journal
30 Aug, 2021
Submission checks completed at journal
30 Aug, 2021
Editor invited by journal
30 Aug, 2021

You are reading this latest preprint version

Multifocal EBV-Associated and CMV-Correlated Post-Transplant Smooth Muscle Tumor: A Case After Liver Transplantation

Status:

Version 1

Abstract

Figures

Introduction

Case Report

Discussion

Conclusion

Declarations

References

Status:

Version 1