Follicular dendritic cell sarcoma
Encyclopedia
Follicular Dendritic Cell Sarcoma (FDCS) is an extremely rare neoplasm. While the existence of FDC tumors was predicted by Lennert in 1978, the tumor wasn’t fully recognized as its own cancer until 1986 after characterization by Monda et. al. It accounts for only 0.4% of soft tissue sarcomas, but has significant recurrent and metastatic potential and is considered an intermediate grade malignancy. The major hurdle in treating FDCS has been misdiagnosis. It is a newly characterized cancer, and because of its similarities in presentation and markers to lymphoma
, both Hodgkin and Non-Hodgkin subtypes, diagnosis of FDCS can be difficult. With recent advancements in cancer biology better diagnostic assays and chemotherapeutic agents have been made to more accurately diagnose and treat FDCS.
Symptoms of FDCS vary, and are largely dependent on the part of the body the tumor develops. The most common symptom is painless swelling in lymph nodes. This symptom alone, however, is nonconclusive as it is associated with many other diseases including the common cold. Other symptoms include cough, sore throat, difficulty swallowing, weight loss and tiredness. In cases that present in extranodal sites outside of the head and neck region, organ specific symptoms are observed.
, nodular lymphocyte predominate Hodgkin’s disease and angioimmunoblastic T-cell lymphoma
. Despite finally being recognized as its own disease in 1986, diagnosis of FDCS is still difficult. FDC cells are large, contain two nuclei, and form clusters with lymphocytes making them difficult to distinguish in staining. These cells are best visualized with immunostaining using the FDC markers CD21, CD35, R4/23, clusterin, and KiM4p. Marker analysis has also led to debate over the origin of the cell type; it coexpresses CD45, a leukocyte common antigen, and CD15, a monocyte common antigen. Because of the debate and difficulty of staining, pathologic diagnosis often requires morphologic, cytochemical and electron microscope analysis as well.
. MTRS contribute to microtubule
formation of many structures including the mitotic spindle during cell division. This contributes to many of the hallmarks of cancer including proliferative signaling, growth activation, and replicative immortality. Clusterin is a heterodimeric protein that aids in the clearance of cellular debris and is involved with apoptosis. Clusterin can be stained to help distinguish FDCS and is involved in the many important cancer hallmarks including resistance to cell death and evading growth suppressors.
.
The CHOP regimen consists of Cyclophosphamide
, Doxorubicin
, Oncovin, and Prednisone
(CHOP). They all exploit different pathways common in cancer cells. Cyclophosphamide slows or stops cell growth cells. It targets cells that are rapidly dividing which include cancer cells that are self-sufficient in growth signals and insensitive to antigrowth signals. More importantly, the biological actions of cyclophosphamide are dose-dependent. At high doses it is very cytotoxic; its metabolite phosphoromide adds an alkyl group to the N7 position on guanine resulting in arrested growth and cell death. The metabolite is only formed in cells with low levels of cytoplasmic aldehyde dehydrogenase (ALDH) resulting in relatively low chemotherapy toxicity in other non-cancer cells like bone marrow. It is also an immunosuppressant and decreases the inflammatory response. At low doses, while it is less cytotoxic, it shows some anti-angiogenic properties. The mechanism is not fully understood but it is thought that it interferes with the VEGF growth factors produced in and around the tumor microenvironment.
Doxorubicin interferes with cell growth and replication by intercalating in DNA. This stops topoisomerase II from relaxing the DNA strands and inhibiting transcription. Recent studies have also shown that doxorubicin may be involved in the Akt pathway. An important hallmark of cancer, Akt is part of the cell survival pathways by inhibiting apoptosis. There is also evidence that Akt is involved in angiogenesis and vascular maturation. Activation of PI3-kinase/Akt mediates VEGF production in cells. Therefore doxorubicin has a dual role in cancer treatment: it inhibits cell survival (causes apoptosis), and decreases angiogenesis.
Oncovin, more commonly known as vincristine, is a mitotic inhibitor. It binds to tubulin dimers, inhibiting the assembly of microtubule structures like the cytoskeleton and mitotic spindle. Although this drug still cannot strictly target cancer cells, cancer cells have a higher average turnover of microtubules making them more susceptible to the cytotoxicity of oncovin. Prednisone, the last drug in the CHOP combination therapy is a corticosteroid that acts as an immunosuppressant decreasing inflammation.
Although some results were seen in FDCS patients treated with CHOP, they were far from consistent. Using a chemotherapy regimen designed for another cancer is an archaic “guess-and-check” way of treating a disease. In 2008 the largest review of FDCS was published as a retrospective analysis on 98 patients and the authors recommended that surgery with no adjuvant treatment be the standard for FDCS treatment. Patients treated with surgery alone had a recurrence rate of 40% and those treated with adjuvant therapy after surgery did not have a significantly different recurrence rate. Radiation and/or chemotherapy had no significant effect in improving patients’ disease-free survival. With developments in our understanding of the hallmarks of cancer, however, novel approaches to specifically targeting and treating FDCS are being developed.
Newer cases are also starting to be treated by taxotere and gemcitabine. Taxotere is similar to Oncovin used in CHOP; it irreversibly binds beta tubulin halting formation of microtubules. Taxotere has an added benefit though; it also phosphorylates bcl-2 to halt the anti-apoptotic pathway. The dual effect of taxotere on integral cancer pathways makes it a more potent drug than Oncovin. Gemcitabene is a nucleoside analog and when incorporated into DNA during replication leads to apoptosis; the fluorine on the 2’ carbon atom stops other nucleosides from attaching. The most important part of this combination therapy, however, is the synergism between the drugs. While researchers are not entirely sure of the mechanism, there is evidence of synergistic affects of taxotere and gemcitabine when used in combination. This allows for decreased dosages of each single agent with an increased apoptotic response.
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, both Hodgkin and Non-Hodgkin subtypes, diagnosis of FDCS can be difficult. With recent advancements in cancer biology better diagnostic assays and chemotherapeutic agents have been made to more accurately diagnose and treat FDCS.
Symptoms and Presentation
Follicular Dendritic Cells are localized in germinal centers of lymphoid follicles and have an integral role in regulation of the germinal center reaction and present antigens to B cells. Most cases of FDCS develop in the lymph nodes, but about 30% develop in extranodal sites. In 1998 the largest study on the disease was a retrospective review with fifty-one patients. Of these fifty-one patients, no conclusive pattern was found in regard to age, sex, race or presentation. The median patient age was 41 (range 14-76), and while most cases presented with cervical and axillary lymphadenopathy, 17 presented in extranodal sites including the liver, spleen, bowel and pancrease. With such a range of patient histories no definitive cause has been linked to FDCS. There has, however, been some evidence that previous exposure to the Epstein Barr Virus or diagnosis of Castleman’s Disease can increase your risk of developing FDCS. This link is not statistically significant. These connections were made due to the FD cell proliferation seen in both Castleman’s Disease and FDCS and the established link between Epstein Barr Virus and lymphoma.Symptoms of FDCS vary, and are largely dependent on the part of the body the tumor develops. The most common symptom is painless swelling in lymph nodes. This symptom alone, however, is nonconclusive as it is associated with many other diseases including the common cold. Other symptoms include cough, sore throat, difficulty swallowing, weight loss and tiredness. In cases that present in extranodal sites outside of the head and neck region, organ specific symptoms are observed.
Staining
Proliferation of FDC cells is characteristic of many neoplastic conditions including follicular hyperplasia, follicular lymphomaFollicular lymphoma
Follicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells , which has at least a partially follicular pattern...
, nodular lymphocyte predominate Hodgkin’s disease and angioimmunoblastic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Angioimmunoblastic T-cell lymphoma is a mature T-cell lymphoma with systemic characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells and high endothelial venules and systemic involvement...
. Despite finally being recognized as its own disease in 1986, diagnosis of FDCS is still difficult. FDC cells are large, contain two nuclei, and form clusters with lymphocytes making them difficult to distinguish in staining. These cells are best visualized with immunostaining using the FDC markers CD21, CD35, R4/23, clusterin, and KiM4p. Marker analysis has also led to debate over the origin of the cell type; it coexpresses CD45, a leukocyte common antigen, and CD15, a monocyte common antigen. Because of the debate and difficulty of staining, pathologic diagnosis often requires morphologic, cytochemical and electron microscope analysis as well.
Cellular Mutations
Biological mutations of the FDCS tumor have been exploited for diagnostic purposes. Characteristically FDCS have mircotubuloreticular structures (MTRS) and increased levels of intracellular clusterinClusterin
Clusterin is a 75 - 80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis...
. MTRS contribute to microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
formation of many structures including the mitotic spindle during cell division. This contributes to many of the hallmarks of cancer including proliferative signaling, growth activation, and replicative immortality. Clusterin is a heterodimeric protein that aids in the clearance of cellular debris and is involved with apoptosis. Clusterin can be stained to help distinguish FDCS and is involved in the many important cancer hallmarks including resistance to cell death and evading growth suppressors.
CHOP
Ironically, the largest problem in treating FDCS is the lack of patients. At the time of its discovery information on the effect of chemotherapy and radiation on FDCS was nonexistent. The best physicians could do was try existing chemotherapeutic agents. With no evidence of the clinical benefit of chemotherapy, many of the first cases were treated solely with complete resection and/or radiation. However, 12 of 31 patients who had surgery alone as primary treatment relapsed. Of the patients who received surgery and radiation 2 of 8 relapsed. It became apparent that better treatment options were necessary. Being so similar to lymphomas, physicians began using a common leukemia and non-Hodgkin’s lymphoma chemotherapy regimen on FDCS patients: CHOPCHOP
CHOP is the acronym for a chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. CHOP consists of:* Cyclophosphamide, an alkylating agent which damages DNA by binding to it and causing cross-links...
.
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, Doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
, Oncovin, and Prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
(CHOP). They all exploit different pathways common in cancer cells. Cyclophosphamide slows or stops cell growth cells. It targets cells that are rapidly dividing which include cancer cells that are self-sufficient in growth signals and insensitive to antigrowth signals. More importantly, the biological actions of cyclophosphamide are dose-dependent. At high doses it is very cytotoxic; its metabolite phosphoromide adds an alkyl group to the N7 position on guanine resulting in arrested growth and cell death. The metabolite is only formed in cells with low levels of cytoplasmic aldehyde dehydrogenase (ALDH) resulting in relatively low chemotherapy toxicity in other non-cancer cells like bone marrow. It is also an immunosuppressant and decreases the inflammatory response. At low doses, while it is less cytotoxic, it shows some anti-angiogenic properties. The mechanism is not fully understood but it is thought that it interferes with the VEGF growth factors produced in and around the tumor microenvironment.
Doxorubicin interferes with cell growth and replication by intercalating in DNA. This stops topoisomerase II from relaxing the DNA strands and inhibiting transcription. Recent studies have also shown that doxorubicin may be involved in the Akt pathway. An important hallmark of cancer, Akt is part of the cell survival pathways by inhibiting apoptosis. There is also evidence that Akt is involved in angiogenesis and vascular maturation. Activation of PI3-kinase/Akt mediates VEGF production in cells. Therefore doxorubicin has a dual role in cancer treatment: it inhibits cell survival (causes apoptosis), and decreases angiogenesis.
Oncovin, more commonly known as vincristine, is a mitotic inhibitor. It binds to tubulin dimers, inhibiting the assembly of microtubule structures like the cytoskeleton and mitotic spindle. Although this drug still cannot strictly target cancer cells, cancer cells have a higher average turnover of microtubules making them more susceptible to the cytotoxicity of oncovin. Prednisone, the last drug in the CHOP combination therapy is a corticosteroid that acts as an immunosuppressant decreasing inflammation.
Although some results were seen in FDCS patients treated with CHOP, they were far from consistent. Using a chemotherapy regimen designed for another cancer is an archaic “guess-and-check” way of treating a disease. In 2008 the largest review of FDCS was published as a retrospective analysis on 98 patients and the authors recommended that surgery with no adjuvant treatment be the standard for FDCS treatment. Patients treated with surgery alone had a recurrence rate of 40% and those treated with adjuvant therapy after surgery did not have a significantly different recurrence rate. Radiation and/or chemotherapy had no significant effect in improving patients’ disease-free survival. With developments in our understanding of the hallmarks of cancer, however, novel approaches to specifically targeting and treating FDCS are being developed.
(PEG)-liposomal doxorubicin
One such development is in the delivery of doxorubicin. While it is an effective inducer of apoptosis, doxorubicin is quickly filtered out of the body. By loading a PEG-liposome with doxorubicin the circulation time and localization to tumors greatly increases. Cancerous tumors characteristically have extensive angiogenesis and leaky vasculatures, which causes the PEG-liposomes to naturally accumulate in the tumor. This also allows for patients to receive lower and fewer doses of the drug and experience fewer side effects. This is also being attempted with nanoparticles but has not been tested on FDCS. In 2008 COP plus (PEG)-liposomal doxorubicin went into a clinical trial for an FDCS patient to replace the CHOP regimen, and after 5 years the patient remains in CR.Taxotere and gemcitabine