Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the liver with hepatic lymphoma history: a case report and literature review

DOI: https://doi.org/10.21203/rs.3.rs-84946/v1

Abstract

Background

Inflammatory pseudotumor (IPT)-like follicular dendritic cell (FDC) sarcoma of the liver is very rare and mostly occurs in females. Up to now, 19 cases were reported in the English literature. Surgical resection remains the preferred method for the management of this kind of tumor.

Case presentation

We reported a case of a 47-year-old male patient who had hepatitis B virus infection history and presented with up-abdominal discomfort. He underwent liver resection of segment VII for hepatic non-hodgkin lymphoma (B-cell lymphoma) 19 years ago. Serum alpha fetoprotein was normal. Imaging studies revealed a well-circumscribed, solid mass in the right hepatic lobe and was diagnosed as HCC or hepatic lymphoma. Right hemihepatectomy was performed and the patient was disease free after a follow-up of 20 months. Histological feature showed a mixture of chronic inflammatory cells and variable amounts of spindle cells. Immunohistochemical studies demonstrated that all the tumor cells showed strong nuclear in situ labeling for EBV-encoded small RNAs (EBER) and strongly positive staining with CD21 and CD35. A diagnosis of hepatic IPT-like FDC sarcoma was rendered. The coexistence of IPT-like sarcoma and non-Hodgkin’s lymphoma in same patient is extremely rare. He remains disease-free more than 40 months after surgical resection.

Conclusion

To our knowledge, this is the first report to demonstrate hepatic IPT-like FDC sarcoma in a patient with primary hepatic non-hodgkin lymphoma history. Complete surgical resection should be pursued. 

Introduction

Primary hepatic sarcomas are extremely uncommon, accounting for less than 0.1% of all primary malignancies of the liver [1]. Follicular dendritic cell (FDC) sarcoma is a very rare tumor, which have been receiving increasing attention since the first described in 1986 [2]. Its clinicopathological characteristics have not been fully investigated and it has a wide range of age distribution and organ involvement [3]. More than half of the cases occur in the lymph nodes, mostly in the neck area, which is generally considered to be an aggressive neoplasm. Extranodal follicular dendritic cell tumors have been reported in the liver or spleen [3, 4]. Histologically, there are two types of FDC tumor: conventional and inflammatory pseudotumor (IPT)-like [5]. IPT-like FDC contains a few spindle cells with prominent lymphocytes and plasma cell infiltration with some neoplastic cells resembling Hodgkin cells [6]. Due to these morphologic features, IPT-like FDC tumors are commonly misdiagnosed as inflammatory lesions and occur almost exclusively in the liver or spleen with a slight female predominance. Recent study indicated that these tumors had a risk of recurrence and metastases [3]. The pathogenesis and causes are still unknown. EBV infection is considered as one of the most important etiologies of this tumor. Almost 100% of the IPT-like FDC tumors have always been shown to be associated with the Epstein–Barr virus (EBV) infection [7]. Surgical resection of the tumor remains the standard treatment.

The distinction of IPT-like FDC sarcoma from other tumors is very challenging. The tumor appears as a well defined, heterogeneous arterial enhanced mass without significant portal and venous washout. Central tumor necrosis or hemorrhage may be present. The definite diagnosis of IPT-like sarcoma should rely on histopathology. The tumor is a mixture of lymphocytes, plasma cells, and spindle cells. In IPT-like FDC sarcoma, at least one of the markers for FDCs should be positive, including CD21, CD23, CD35, Fascin, Clusterin, CXCL13 and epidermal growth factor receptor (EGFR) [8].

In this report, we present a case of IPT-like FDC of the liver with hepatic non-hodgkin lymphoma (NHL) history and review the related literature.

Case Presentation

We evaluated a 47-year-old man with onset right upper quadrant abdominal pain with no other associated symptoms. He had hepatitis B virus infection history and no hepatitis C infection. Magnetic resonance imaging (MRI) from the First Hospital of Yi Chang revealed a 19x15x 13cm tumor in the right lobe of the liver. The right portal vein and right hepatic vein were not visualized, postcava was compressed (Fig 1a, 1b). This patient received hepatic segmentectomy in our hospital because of NHL (B-cell lymphoma) of the liver in 1999. He had no fever, anemia, weight loss or constitutional symptoms. Abdonimal ultrasound disclosed a 17.5x14.2x13.6 cm mass in the right lobe of the liver (not shown). There was no virus infection history, alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA) were within normal ranges, and other laboratory tests were unremarkable. Hepatocellular carcinoma or sarcoma was suspected. There was no abnormality in any other area of the abdomen. The chest radiograph showed normal, with a normally sized heart. The ICG-R15 was 4.2%. The patient agreed to a right lobotomy of the liver. The abdomen was carefully inspected during operation, and no other lesions were noted within the mesentery, small bowel or spleen. Frozen sections of lymph-nodes were all negative for tumor. The right lobe of the liver was notably atrophied, likely secondary to thrombosis of the right portal vein, which was showed on MRI imaging. The patient tolerated the surgery well, the patients recovered smoothly, and he was discharged on postoperative day 7.

Surgical specimen was collected for histological examination and were processed with standard paraffin technique and stained with routine hematoxylin-eosin procedures. Immunohistochemical (IHC) and in situ hybridization analyses were performed on a 4-um thick section. The patient did not receive any adjuvant therapy, and is currently well and alive. He is asymptomatic with no evidence of recurrence more than 40 months after operation.

Histological Findings

Excision of the mass measured a 20x18x15cm. It was well delimited from the surrounding parenchyma, the surgical margins were free of tumor, and had areas of necrosis and hemorrhage in the centre of the tumor (Fig.2A). Microscopically, the hepatic tumor comprised spindle-like cells forming a vaguely storiform pattern, with a vague cellular border and eosinophilic cytoplasm (Fig.2B, hematoxylin-eosin stain, ×200) and diffuse sheets with the infiltration of small lymphocytes and plasma. The nuclei were oval to elongated, with small or inconspicuous nucleoli. The cell boundary was indistinct. Mitoses of the tumor cells were negligible.

Immunohistochemical studies

The submitted tissue was fixed in formalin, embedded in paraffin, and cut into 4-um slice for further analysis. For immunohistochemical studies, antigen retrieval by microwaving in sodium citrate buffer was performed. Spindle-like cells were found to express CD21 (Fig. 2C) and CD35 (Fig. 2D) but not CD23, SMA, desmin, ALK1, S-100. No chromosomal abnormality was observed. EBV-encoded nuclear RNA in situ hybridization was performed. EBV-encoded nuclear RNA signals were positive on the spindle cells (Fig. 2E), but not on the surrounding lymphocytes. The positive stain rate of Ki67 in spindle cells was about 25% (Fig.2F). Based on these findings, a follicular dendritic cell tumor of the liver was diagnosed. The post-operation period was unremarkable and the patient received regular follow-up after discharge. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Discussion

FDC tumors are very rare neoplasms that may mainly arise in lymph nodes and extranodal sites, which have a heterogeneous histology with spindle tumor cells and variable degrees of pleomorphism and arrange in fascicular or storiform patterns. The FDC tumors received increasing attention since the first case of a tumor with follicular dendritic cell differentiation was reported by Monda et al. in 1986 [2]. By now, there are less than 100 cases of follicular dendritic cell tumors have been reported in the English literature [2, 9]. The differential diagnosis includes Hodgkin's disease, sarcoma, leiomyosarcoma, gastrointestinal stromal tumor and inflammatory pseudotumor [1012]. According to immunohistochemical analyses, the most commonly used FDC tumor markers include CD21 (C3d receptor, positive in 93% of cases) and CD35 (C3b receptor, positive in 89% of cases). Other quite specific markers used are: R4/23 (63%), Ki-67 (5%-50%), EMA (41%), vimentin (61%), HLA-DR (57%), CD45 (21%) and S-100 protein (31%). The tumor cells typically lack expression of CD1a, CD 68, and desmin [9, 13].

IPT-like FDC tumor of the liver is an extremely rare tumor and only 20 cases have been reported in the English literature, including ours [1, 6, 9, 10, 1322]. (Table 1). In 1996, Shek and colleagues reported the first case of hepatic FDC sarcoma.[14] The most common main complaint of the patient was epigastric pain and weight loss. Malaise, anemia and fever were also part of the initial presentation in some patients. In five cases, patients were completely asymptomatic and the mass was found incidentally by using CT scan and abdominal ultrasound. The age of all the patients at initial presentation ranged from 19 to 82 years (mean 49.4 years), the mean tumor diameter was 11.9 cm (3-20cm), and the mean reported survival was more than 30 months (follow-up ranging from 6 to 108 months). The histology is similar to that of the conventional hepatic FDC tumor and it is generally considered to be a distinctive variant. This variant is characteristically restricted to the abdomen and seems to be a separate clinicopathologic entity. Comparing with conventional FDC sarcoma, it has a marked female predominance (female to male ratio, 4:1), whereas conventional FDC sarcomas are not more prevalent in only one sex [23]. IPT-like FDC sarcomas have prominent inflammatory component, which makes it difficult to distinguish them from inflammatory pseudotumors. IPT-like FDC sarcomas are strongly associated with the presence of EBV (80%), which is rare for conventional FDC sarcomas. Both IPT-like FDC sarcomas and conventional FDC sarcomas show generally a indolent clinical behavior, nevertheless, conventional FDC sarcomas of the liver can be more aggressive than IPT-like FDC ones, and may recur or metastasize and even lead to death.

Table 1

Characteristics of patients with hepatic FDC sarcoma of the liver.

Case

Sex

Age

(year)

Main complaint

Diameter

(cm)

EBV

Treatment

Recurrence/Survival

Published year

1

F

68

Malaise, weight loss, anemia

11

+

SR

No/>30 m

1996[15]

2

F

35

Epigastric discomfort, fever,weight loss

20

+

SR

Yes/>30 m

1996[14]

3

M

37

Malaise, weight loss, anemia

15

+

SR

No/>24 m

1998[16]

4

F

19

Right upper quadrant pain, weight loss, palpable mass

12

+

SR

No/40 m

2001[6]

5

F

56

Gastrointestinal discomfort

15

+

SR

Yes/NA

2001[6]

6

F

40

Epigastric pain, weight loss

12.5

+

SR

No/108 m

2001[6]

7

F

49

Incidental at ultrasound

4.2

+

SR

No/9 m

2001[6]

8

F

31

Abdominal distention, weight loss

15

+

SR

No/60 m

2001[6]

9

F

57

Epigastric pain, weight loss

9.5

+

SR

No/36 m

2001[10]

10

F

51

Epigastric pain, weight loss

12

+

SR

No/12 m

2001[10]

11

M

82

Incidental on a CT abdomen

15

-

SR

No/18 m

2005[1]

12

F

30

Incidental at ultrasound

5.5

+

SR

No/12 m

2006[17]

13

F

57

Abdominal pain, vomiting, dizziness, liver dysfunction

13

+

SR

No/24 m

2008[13]

14

F

78

Incidental at ultrasound

3

+

TACE

27 m

2010[18]

15

F

59

Asymptomatic

6

+

SR

NA

2010[19]

16

F

53

Right upper quadrant pain, fever, anemia, jaundice

11.5

-

SR

No/6 m

2011[9]

17

M

56

Right upper quadrant abdominal pain

11

NA

SR

No/12 m

2011[20]

18

F

31

Palpable abdominal mass

20

+

SR

NA

2016[21]

19

M

19

Painless swellings around several joints

6

-

SR

NA

2016[22]

SR, surgical resection; TACE, Transcatheter Arterial Chemoembolization

The initial diagnosis of FDCS is based on clinical examination, imaging and pathologic assessment. The role of imaging is mainly in describing the extent of the mass and staging. When suspected a mass in the liver, the diagnosis of IPT-like FDC sarcoma is very difficult without pathological findings. It is noteworthy that the diagnosis of IPT-like FDC sarcoma should be based on the recognition of FDCs from microscopic appearance. Actually, the distinction of hepatic IPT-like FDC sarcoma from other liver tumors is usually impossible without immunohistochemistry. However, sometimes IPT-like FDC sarcoma can be difficult to consider the disease because the tumor shows bland spindle cells without nuclear atypia and the overshadowing chronic inflammatory infiltrate. Shek et al. [14] reported a case of primary IPT-FDC tumor of the liver that was initially misdiagnosed as an inflammatory pseudotumor. The tumor recurred 30 months after complete resection of the "inflammatory pseudotumor "[14]. CD21 and CD35 have been widely used as the preferred FDC markers, which were expressed in almost IPT-like FDCs. EBV infection is identified as a key role in the genesis of IPT-like FDC sarcoma. Almost all IPT-like FDC sarcomas exhibited positive EBER by in situ hybridization. LMP-1 gene, the major oncogene of EBV, was identified in several cases of IPT-like FDC sarcomas [15, 23]. However, the pathogenic mechanism of EBV in IPTFDC sarcoma remains unclear and further investigation is required.

Primary NHL of the liver has rarely been reported and because there are no typical laboratory or image diagnostic findings, and pathological analysis is the standard diagnostic method[24]. The coexistence of hepatic NHL and hepatic IPT-like FDC sarcoma is extremely rare. The patient we reported in this article received hepatic segmentectomy in our hospital due to non-hodgkin lymphoma (B-cell lymphoma) of the liver in 1999 (no data available because of long time). Immunohistochemical studies demonstrated that all the tumor cells were strongly positive staining with CD20 and CD45. A diagnosis of hepatic NHL was rendered (Supplemental Figs. 1 and 2). Several studies indicated that chronic HCV infection may be associated with the pathogenesis of NHL, however, the present case has no HCV infection. The detailed mechanism of HCV-mediated lymphomagenesis remains unclear[25]. In the present case, it was misdiagnosed with HCC or non-hodgkin lymphoma at initial evaluation. Our search of the literature found no such cases. This is the first report to demonstrate hepatic IPT-like FDC sarcoma in a patient with primary hepatic NHL history.

Surgical resection is the treatment of choice for primary hepatic IPT-like FDC sarcomas and hepatic lymphoma whenever possible. The efficacy of chemotherapy and radiotherapy is unclear. Daniel et al.[26] reported that even if complete resection has been achieved for hepatic NHL, postoperative chemotherapy is mandatory. The patient did not receive chemotherapy after the first hepatectomy. Tsunemine et al. 18suggested that TACE was useful for the management of hepatic FDC sarcoma, and the patient was still alive more than 2 years after the diagnosis with hepatic tumors favorably controlled by repeated TACE. Shinagare et al.[20] reported a case which the patient was not determined to be a surgical candidate because of large tumor mass and small residual liver volume. The patient received four cycles of standard-dose CHOP and portal vein embolization in an attempt to cause hypertrophy of the residual liver. Seven months later, the patient underwent a successful resection of the mass [20]. Eighteen of the patients with hepatic IPT-FDC sarcoma have undergone partial hepatectomy.

Conclusion

In summary, we report a unique case of hepatic IPT-like FDC sarcoma with hepatic non-hodgkin lymphoma history. IPT-like FDC sarcoma is receiving increasing attention and the diagnosis may be correct with the aid of immunohistochemistry analysis, being CD 21 and CD35 the most reliable FDC markers. IPT-like FDC sarcoma should be considered in differential diagnosis when confronted with a liver tumor in a patient with primary hepatic lymphoma history. Complete resection remains the preferred method for the management of primary hepatic FDCs. In analyzing the reported cases, we brought forth differential diagnosis, and provide evidence for further exploration of the pathogenesis of the tumor. Continued accumulation of characteristics of IPT-like FDC sarcomas of the liver would help in future patient care.

Declarations

Availability of data and materials

Not applicable as all information and data is presented in manuscript.

Ethics approval and consent to participate

Ethical approval is not required as patient consent for publication was obtained.

Consent for publication

The written consent for publication of case report and accompanied images was obtained from the patient.

Competing interests

The authors declare that there are no competing interests.

Funding

This work was supported by the grants from National Natural Science Foundation of China (81902839) and National Science and Technology Major Project of China (2017ZX10203207-002)

Authors’ contributions

ELZ did the literature search and wrote the manuscript. JL and WQW helped in preparation of manuscript and edited the manuscript for scientific content. DC provide the pathological data. ZYH conceived and designed the study and revised the final manuscript. All authors read and approved the final manuscript.

Acknowledgments

The authors thank those who participated in the present study.

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