IPT-like FDC sarcoma generally occur in abdominal organs (such as liver and spleen). The ratio of male to female is 1∶2. 2, with an average age of 54.5 years[6]. Patients are asymptomatic or present with abdominal distension or pain, sometimes accompanied by systemic symptoms, such as significant weight loss, fever, weakness, etc., and often associated with EBV infection[7].
Histologically, the neoplastic spindled cells are dispersed within a prominent lymphoplasmacytic infiltrate. The nuclei usually show a vesicular chromatin pattern and small but distinct nucleoli. Nuclear atypia is highly variable; usually most cells are bland-looking, but some cells with enlarged, irregularly folded or hyperchromatic nuclei are almost always found. Some tumour cells may even resemble Reed-Sternberg cells [8]. Necrosis and haemorrhage are often present.In occasional cases, the tumour may be masked by massive infiltrates of eosinophils or numerous epithelioid granulomas[9].The neoplastic cells are often positive for follicular dendritic cell markers, such as CD21, CD35,CD23 and D2-40 ,with the staining ranging from extensive to very focal.The neoplastic cells are consistently associated with EBV[10].EBV provokes inflammation and neoplastic transformation, and most EBV-associated lesions share some histologic features observed in EBV + carcinoma with lymphoid stroma.Both of our cases had ulceration and a dense inflammatory background,but no monoclonal hyperplasia observed in immunohistochemistry or gene rearrangement .Meanwhile a large number of IgG positive plasma cells were observed, but the number of IgG4 positive cells was very little.
So far, a total of 5 cases of IPT-like FDCS were reported plus our two cases. Table 1 lists the clinical datas of these cases .Comparing to the first report[3],our patients had no obvious clinical symptoms.From the colonoscopy results and pathological features, our two cases and the first reported cases were highly similar.The difference is that FDC marker was only D2-40 positive in our first case.Most FDC sarcoma cases are positive for one or more FDC-associated antigens, such as CD21, CD23, or CD35. However, many cases showed only focal and/or weak staining for these markers [2, 11]. Xie et al[12]conclude that podoplanin (D2-40) is a sensitive and specific FDC marker, which is superior or equal to CD21 in evaluating both reactive and neoplastic FDCs.K-C et al[4] found spindle tumor cell growth pattern resembled GIST or meningioma in focal areas,with mitoses frequent for more than 10 per 10 high-power fields(HPF). and in-situ hybridizationstudy was negative for Epstein Barr virus RNA.Although the site and the gross morphology of this case is very similar to our two cases. We still saw that the histological morphology is more inclined to conventional FDCS.In our cases,the oval or fusiform tumor cells were covered by lymphocytes and plasma cells, with low mitotic activity. Kazemimood et al[5] found large, pleomorphic stromal cells with marked atypia, irregular to multilobed large nuclei, and hyperchromatic smudged chromatin pattern.Atypical mitoses were identified, and there were cells with Reed-Sternberg–like morphology. D2-40 was the only FDC marker expressed in IHC studies and Epstein-Barr virus-encoded mRNA (EBER) was negative. From clinicopathological features of the five cases ,we can see that the morphology of EBV positive IPT-like FDCS mimicking a colonic polyp is relatively mild with rare mitosis.To our knowledge, the cases we presented here were the second and third cases of EBV-positive IPT-like FDC sarcoma mimicking a colonicl polyp reported so far in the literatures.
Table I. Clinical datas of five cases of IPT-like FDCS mimicking a colonic polyp
Case No. | Age (year)/sex | Presentation | Site of involvement | Tumor size (cm) | EBV | Treatment | Outcome and follow-up (months) |
1[3] | 78/female | Abdominal discomfort and bloody stool | Transverse colon, 50 cm from the anal verge | 3.9 | + | polypectomy | no tumour 5 months after the operation |
2[4] | 35/female | Bloody stools for one year | 60 cm above the anal verge | 5 | - | lymph node enlargement and right hemicolectomy | No tumor 7 months after the operation |
3[5] | 53/female | Abdominal discomfort | Right colon | 3 | - | right colectomy | No follow-up was recorded |
4 | 50/female | bloody stool | 50 cm from the transverse colon to the anus | 1.5 | + | radical resection | no tumour 32 months after the operation |
5 | 56/female | bloody stool | 70 cm from the transverse colon to the anus | 3.2 | + | radical resection | no tumour 4 months after the operation |
Accordingly, this will require consideration of a wide differential diagnosis. (1)Inflammatory myofibroblast tumor(IMT):The tumor cells are fusiform fibroblasts and myofibroblasts with loose myxoid or edema in the stroma. The infiltrating inflammatory cells are mostly mature plasma cells, lymphocytes and eosinophil.but IPT-like FDC sarcoma is lack of myxoid stroma.The expression of immunoreactivity for ALK in IMT is high, and the positive rate can reach 89%, suggesting that ALK can be used as an indicator for the diagnosis of IMT.The ALK here ware all negative, so IMT could be excluded by combination of morphology and immunohistochemistry. (2) Hodgkin lymphoma (HL): It is common in middle-aged men and histologically typical in variable numbers of Hodgkin/
Reed-Sternberg (HRS) cells admixed with a rich inflammatory background.Classic diagnostic Reed- Sternberg cells are large, have abundant slightly basophilic cytoplasm, and have at least two nuclear lobes or nuclei.The HRS cells are positive for CD30 in nearly all cases and for CD15 in the majority.Follicular dendritic cell markers (e.g. CD35, CD21) are negative and could be excluded by immunohistochemistry and genetic testing.(3)IgG4-related disease:It is associated with autoimmune diseases, and is characterized by systemic damage and elevated serum IgG4 level.Histopathological features include diffuse lymphoplasma cell infiltration, fibrosis, and obstructive phlebitis, as well as large amounts of IgG4-positive plasma cell infiltration.
Immunohistochemistry, clinical manifestations and laboratory examination of two cases were inconsistent with the disease, and the diagnosis could be excluded. (4) Interdigitating dendritic cell (IDC) sarcoma: It is difficult to distinguish from histological morphology, it requires more immunophenotypic analysis. The IDC sarcoma shows positive for S100 and Vim,but negative for FDC markers (such as CD2l, CD23, cD35, etc.) .(5)Inflammatory fibroid polyp (IFP): It consist of edematous spindle-shaped stromal cells and an inflammatory infiltrate rich in eosinophils,and stromal cells are diffusely positive for CD34 and fascin.They are negative for CD21, CD23, and EBER.
Epstein–Barr Virus (EBV), also known as human herpesvirus 4 (HHV-4), is a member of the
subfamily of Gammaherpesvirinae.EBV infects more than 95% of adults worldwide. EBV is transmitted through saliva and primarily infects B cells and epithelial cells, but macrophages and dendritic cells also play important roles in EBV infection[13].Previous studies revealed that EBV was clonally expanded in the tumor cells[14]。FDC tumors can be recognized by their expression of CD21, to which EBV can bind[15].Moreover, the major oncogene of EBV, LMP1, was demonstrated in most cases of IPT-like FDC sarcoma[16] These findings support the idea that EBV is related to the pathogenesis of IPT-like FDC sarcoma. Lewis et al [17] suggested FDCs were of mesenchymal cell origin which was capable of differentiating along different pathways. Under stimulation of the Epstein-Barr virus(EBV),some of them would develop a myofibroblastic phenotype and be positive for SMA and vimentin. whereas others would acquire FDC characteristics and express CD21 and CD35.Similarly, Shia et al[18]proposed that under certain oncogenic stimuli,such as EBV infection, the mesenchymal cells in IPT-like conditions undergo transformation into FDCs, and as has been observed in Castleman’s disease, such cells then undergo “dysplasia” and eventually become neoplastic.
Go et al[19] showed BRAF mutations were present in 18.5% of FDCS and 40% of inflammatory pseudotumor-like variants of FDCS cases. However, no cases with BRAF V600E were identified here. Han et al[20] found del-LMP1 might be involved in the tumorigenesis of inflammatory pseudotumour-like FDC tumour.Griffin et al[21] found mutations of the nuclear factor kappa B pathway and cell cycle regulatory genes in an approach of targeted re-equencing of FDC sarcomas.A study by Perry et al[22] demonstrated cytogenetic abnormalities of a near diploid clone with loss of chromosomes 3 and 14 in one FDCS case and a hypodiploid clone with loss of chromosomes 5, 6, 9, 14, 16, and 22 in another FDCS case.
0utcome data are limited,most cases are treated by surgical resection, with or without adjuvant chemotherapy and/or radiation.Ge et al[6]follow up thirty-four patients with IPT-like FDCS,one patient (2.9%) died of disease, 4 (11.8%) were alive with disease, 29 patients (85.3%) were alive with no evidence of disease.
In conclusion, IPT-like FDCS mimicking a colonic polyp is a low-grade malignant tumor having not been fully recognizedby pathologists and clinical physicians. Detection of EBV and FDC-related immune markers plays an important role in differential diagnosis. Radical resection is the best and preferred treatment option.The long-term follow-up needs to be carefully monitored.Strengthening the understanding of the disease might help to reduce misdiagnosis and missed diagnosis.