Indiana Association 
of Pathologists, Inc.
Histology Laboratory, Indiana Medical History Museum 

Final Diagnosis: Fibroblastic reticular cell tumor (Cytokeratin-positive interstitial reticulum cell tumor)

Discussion: Fibroblastic reticular cells are responsible for producing the reticulin network in lymph nodes and play a role in lymphocyte homeostasis by secreting IL-7 and CCL19, the ligand for CCR71. These cells are derived from the myeloid lineage.2 The development of tumors from fibroblastic reticular cells are rare and when found are primarily located in lymph nodes, most commonly around the mediastinum.3,4 However, there have been reports of extra-nodal primary sites such as the spleen and most recently the breast.4,5

Histologically these tumors show varying areas of cellularity with a dense collagen background with the presence of mixed chronic inflammation. There is marked pleomorphism with large epithelioid cells with abundant cytoplasm along with long cytoplasmic processes. The nuclei are large, clefted, and folded. On first glance these tumors may look somewhat similar to a Hodgkin's lymphoma or AITL given the mixed inflammation, which is likely due to chemotactic factors like IL-7, CCL19, and possibly IL-5 due to presence of numerus eosinophils in some tumors. Additionally the cells may contain intranuclear cytoplasmic inclusions. Mitotic activity was low. The differential diagnosis consists primarily of follicular dendritic cell tumor, interdigitating dendritic cell tumor, fibroblastic reticular cell tumor, and inflammatory myofibroblastic tumor.4

In our patient the following stains were positive: CK AE1-AE3, EMA, CK5/6, CD99, and Calretinin. The tumor cells were negative for CD21, CD35, CD1a, SMA, steroidogenic factor-1 and S-100 protein synaptophysin, CD68, chromogranin A, Melan A, OCT3/4, and Glypican-3.

Due to the similar morphology, differentiation must be made by immunohistochemical staining characteristics. Typically follicular dendritic cells express CD21 and CD35, therefore lack of these along with the absence of EBV weigh against a FDC tumor. Similarly S100 is typically expressed in interdigitating dendritic cells and absent expression of S100, CD35, CD21 suggest that the cells are more likely to be fibroblastic reticular cells. Inflammatory myofibroblastic tumors express anaplastic lymphoma kinase (ALK) which is helpful in most cases. Although there have been some reports of negative ALK staining of IMT in organs such as the spleen, this diagnosis should be rendered based on careful morphologic and immunohistochemical analysis.4

In reviewing the literature, it appears that CD21, CD23, CD34, CD35, CD45, S100, EBV are typically negative in fibroblastic reticular cell tumors, while vimentin, smooth muscle actin, CK8/18, desmin, CD31, and CD68 are typically positive with variable cytokeratin positivity.3,4 More recently, Izquerdo et al. have cautioned that these tumors can have a much wider range of staining and recommend at least 4 subtypes of FBRCTs based on variable combinations of antigenic expression. Notably they suggest a wider range of cytokeratin positivity along with EMA.6 One way to provide support for the diagnosis is to perform electron microscopy looking for "microvillus- like interdigitating processes". A small case series suggests a relatively poor prognosis (9 months) for these patients, but this is still debatable given the small sample size.7


1. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 2007;8:1255–1265. doi: 10.1038/ni1513

2. Balogh P, Fisi V, Szakal AK. Fibroblastic reticular cells of the peripheral lymphoid organs, Unique features of a ubiquitous cell type. Mol Immunol. 2008;46:1–7. doi: 10.1016/j.molimm.2008.07.014.

3. Andriko, JW. Kaldjian, EP. Tsokos, M. et al: Reticulum cell neoplasms of lymph nodes: A clinicopathologic study of 11 cases with recognition of a new subtype derive rom fibroblastic reticular cells. Am J Surg Pathol 22:1048-1058, 1998

4. Martel, M. Sarli, D. Colecchia, M. et al. Fibroblastic reticular cell tumor of the spleen: report of a case and review of the entity. Human Pathology. 2003;34(9):954–957. doi: 10.1016/s0046-8177(03)00399-x.

5. Li, H. Shen, P. Liang, Y. Zhang, F. Fibroblastic reticular cell tumor of the breast: A case report and review of the literature. Experimental and Therapeutic Medicine. 2016;11(2):561-564. doi:10.3892/etm.2015.2922.

6. Suárez-Vilela, D. Izquierdo, FM. Méndez-Alvarez, JR. Escobar-Stein, J.Neoplasms of dendritic cells: related cell origins and diagnostic markers. Fibroblastic reticulum cells and fibroblastic reticulum cell tumors show several immunophenotypic profiles. Human Pathology; 2012: 1530-1531. doi: 10.1016/j.humpath.2012.04.015

7. Chan, AC. Serrano-Olmo, J. Erlandson, RA. Rosai, J. Cytokeratin-positive malignant tumors with reticulum cell morphology: a subtype of fibroblastic reticulum cell neoplasm? Am J Surg Pathol. 2000;24:107–116. doi: 10.1097/00000478-200001000-00013.

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