Follicular Dendritic Cell Sarcoma

Follicular Dendritic cubicle SarcomaFollicular Dendritic Cell Sarcoma and its paraneoplastic manifestations ReviewAbstractFollicular Dendritic Cell Sarcoma (FDCS) is a r are neoplasm arising from dendritic cells. The paraneoplastic phenomena are an underreported aspect of FDCS. Here we present a teddy report of FDCS presenting with auto tolerant haemolytic anaemia and commit done a detailed review of all its paraneoplastic manifestations.Follicular Dendritic Cell Sarcoma (FDCS) is a rare malignancy, which arises from the follicular dendritic cells. It was first described by Monda et al who describes a series of 4 cases(1). Being a relatively new entity, its classification remains a subject of controversy. It has been variously described as lymphoma, sarcoma and histiocytic neoplasm. It has been grouped under histiocytic and dendritic cell neoplasms by the WHO 2008 classification(2)There is considerable under-reporting of thisG1 entity as it usually presents with unremarkable clini cal and radiological features. It is non uncommon to misdiagnose these cases as lymphoma due to m any convertibleities in the morphological features between the two entities. With the emergence of modern immunohistochemistry, the dendritic cell lineage can be confirmed and on that pointfore, there is increasing acquaintance of this group of disorders. Since the first description in 1986, nearly 350 cases of FDCS consent been reported(3) including 11 cases from our country(4)FDCS generally presents as a slow growing, well draw painless mass with a median size of 5 cm(2). Constitutional symptoms are not usually seen at intro. Young to middle-aged adults are affected, without any sex predilection. Over fifty percent of the cases are nodal with cervical and axillary lymph nodes being the most common sites(2). The common extranodal sites include tonsils, nasopharynx, palate,entire gastrointestinal tract, pancreas, liver, peritoneum, and lungs.ComputerizedG2Tomography (CT) scan typ ically shows morphological aspects of an expansive mass with an increasingly inhomogeneous enhancement, directly proportional to lesion size (due to central necrosis, hemorrhage, and cystic changes with a patchy pattern) (5)G3Local recurrence in FDCS is more akinly than distant metastasis. More than 50% of the cases recur locally aft(prenominal) wide local excision while only 25% cases overhaul distant metastasis. FDCS is considered as a low-grade malignancy by some while new(prenominal)(a)s consider it as an intermediate-grade malignancyG4(6, 7). Liu et al have proposed G5histological criteria for grading the tumor and assessing the guess of recurrence.G6(8). G7G8Variations in clinical behavior of FDCS are described in the literature. At one end of the spectrum, FDCS presenting with multifocal abdominal or pelvic mass behaves like an belligerent tumor (13) on the other hand, FDCS of the liver and spleen presents like an inflammatory pseudotumor and usually has a female predo minance. (3)Castlemans disease has been found to be associated with FDCS in a few patients(9-11). It has been proposed that the dysplastic changes and FDC proliferation which occur in Castlemans disease may act as the nidus from which FDCS can evolve.(12)Ebstein-Barr Virus has also been described in tie beam with FDCS especially when the liver or spleen is involved. CD21 expression on the FDC cells has been suggested to be the entry point for EBV in affected cells.(7) FDCS has also been reported to be associated with secondary coil amyloidosis(13)FDCS mostly arises within lymphoid follicles and has a known acquaintance with Castlemans disease. Hence it was postulated that it arises from lymphoid forerunners. But studies by Krautler et al suggest that they may arise from prevascular stomal precursor cells, which express platelet-derived growtG9h factor beta(14)FDCS has a distinct picture on histopathology a storiform arrangement of spindle-shaped cells with elongated nuclei, del icate, dispersed chromatin and pale eosinophilic cytoplasm. Lymphocytes are seen scattered among the tumor cells and they may also be seen gathered around blood vessels,creating a cuffing pattern. Another characteristic pattern is a concentric whorl.FDCS is specifically immunopositive to CD21, CD35, and/or CD23, vimentin, fascin, HLA-DR, EMA, D2-40, clusterin, and CXCL13. It shows variable positivity to CD68, CD45, CD3, and CD20.G10(7) a unique point in IHC of FDCS is expression of clusterin which is almost always strongly positive , while in other dendritic cell neoplasms, this marker is weakly positive.(13)Surgical excision of the tumor has been attempted in well circumscribed FDCS. Although some reports suggest that they recur shortly afterward(15). Pooled data analysis confirms that surgery remains a good option for localized disease(3, 16). In view of the rarity of FDCS, there is no standard chemotherapeutical regimen for the same. Both lymphoma and sarcoma directed therapies have been tried. CHOP regimen is one of the ordinarily used with variable results. G11G12CHOP therapy has been postulated to have an indirect action on FDCS by some authors. It has been postulated that CHOP therapy depletes the B lymphocytes leading to a reduction in the growth factors for FDCSG13(17). Other regimens which have been tried include ABVD, EPOCH, ICE, and cisplatin/epirubicin(13). Gemcitabine and cisplatin in combination with imatinib(18)and single-agent rituximabG14are the other reported regimens with some activity against FDCS(19).G15G16Case ReportA 60-year-old female presented with 2 months history of easy fatiguabilityG17 and low-grade fever. She was detected to have severe anemiaG18 and haywire icterus with difficulty in blood cross matching at a local hospital. She was referred to our institute for further evaluation. General examination revealed marked pallidity and generalized lymphadenopathy. The liverwas palpable 5 cm below right costal margin and the splee n was palpable 6 cm below left costal margin. Laboratory evaluation revealed Coombs positive hemolytic anemia, which partially responded to steroid therapy. Her Lymph node excision biopsy showed diffuse effacement of nodal architecture with multiple fascicles of spindle cells traversing the lymph node and swathe around the pre-existing vessels admixed with many eosinophils and plasma cells (Figure 1a-c). Immunohistochemistry for CD20, CD3, S100, CD 45 and PD-1 were negative, whereas CD23 showed strong membranous positivity in these spindle cells (Figure 1d-i). The histopathological examination was suggestive of Follicular dendritic cell sarcoma. Due to the disseminated involvement by FDCS and associated autoimmune hemolytic anemia, she was treated with CHOP chemotherapy. Both disease and anemia responded to therapy. There are numerous case reports of FDCS presenting with similar paraneoplastic manifestations. They are reviewed below.G19G20Paraneoplastic manifestations of FDCSParane oplastic manifestations are a constellation of signs and symptoms that are not directly caused by the malignancy(20). All paraneoplastic manifestations reported with FDCS are of an autoimmune nature. Although they appear similar to classic autoimmune diseases, paraneoplastic autoimmune disorders tend to be more aggressive. Their management too is centered in part on the underlying malignancy (AI) A systematic search was performed on Medline and the paraneoplastic manifestations reported with FDCS in English Literature were identified. (table 1)I. Paraneoplastic Pemphigus (PNP)PNP usually presents secondary to an underlying malignancy, mainly Chronic Lymphocytic leukemia, Non Hodgkins Lymphoma, Thymoma and Castlemans disease(21). PNP is the most commonly reported paraneoplastic manifestation with FDCS. There are 22 cases reports in English literature till date. While axillary and cervical lymphadenopathy is the most common presentation of FDCS, PNP has been reported mostly with retro peritoneal FDCS. The clinical course of PNP is at variation with the relatively benign course of FDCS and most authors have reported death soon after detection of PNP. An association with the hyaline vascular variant of G21Castlemans disease has been described in 27% of these cases.Reports of other malignancies associated with paraneoplastic syndromes suggest that it is associated with an antitumor response. The underlying malignancy remained indiscernible for up to a year after the paraneoplastic syndrome first manifested due to this effect. It has been suggested that the immune response against the paraneoplastic antigen in the tumor, slows down the growth of the tumor(22). The status of FDCS is not in remission in most of the available reports. Thus, there is no evidence to suggest an antitumor effect in patients presenting with PNP.Resection of the underlying FDCS along with oral steroids for the PNP has been the usual sermon, exactly there are 2 reports of usage of higher i mmunosuppression to successfully control the PNP(18, 23).II.Myasthenia Gravis (MG)Seven cases of myasthenia gravis have been reported in literature till date. genius case was also reported to be associated with Castlemans diseaseInterestingly, four of the seven cases also had paraneoplastic pemphigus. A similar presentation has been reported with another malignancy involving the immune system. Thymoma has a well-known association with MG. Less commonly, it has also been reported with PNP and there is even a report of Thymoma presenting with both MG and PNP. The authors have suggested that the linkage is indirect, finished a triad, which also includes the tumor rather than a direct relation. G22G23G24G25 A similar linkage may explain the cases of FDCS with MG and PNP. Alternatively, CD which G26has known association with both these conditions could be the missing linkG27(24-26). But among available literature, there was no evidence of CD with FDCS and MG in all but one case.G28G29G 30The treatment has been IV immunoglobulin, pyridostigmine, and steroids. close of the authors have reported a good response to therapy with no mortality.G31G32 This is in resonance with the findings of MG with other disorders. Thymoma associated with MG is found to have a better prognosis than thymoma without MG. This has partly been attributed to earlier detection of the disease(27)III. Autoimmune Hemolytic AnemiaAIHA is a well-known phenomenon in lymphoproliferative disorders. Among the solid organ cancers, a majority of the available literature is with Kaposi sarcoma, lung, kidney and colorectal caG33ncers. It may occur prior to, concurrent with cancer or well after the end of G34treatment (28). Two various responses to therapy have been documented with paraneoplastic AIHA. Some cases are steroid resistant and respond to treatment of the primary malignancy. While, AIHA present along with metastaticG35 cancers are usually steroid responsive. G36A search of the literature revea led that G37ours is only the second case of AIHA with FDCS reported. Conry et al. had reported a 36-year-old African-G38G39AmericanG40 female who had presented with AIHA not responding to steroids or splenectomy. She presented 1 year later with the abdominal toughie which was diagnosed as FDCS. She did not respond to radiotherapy alone but had a good response to chemotherapy with gemcitabine and docetaxG41el(17). Experience in this case and our case may be insufficient to label AIHA as a paraneoplastic manifestation of FDCS, but several plausible mechanisms of occurrence of AIHA exist in patients of FDCS. And FDCS has known association with other autoimmune paraneoplastic syndromes. So with increased awareness of this association, we hope that more such cases will be documented. G42G43Proposed mechanisms for development of autoimmunityG44Castlemans disease is known to be associated with PNP. Several authors have suggested that a preexisting Castlemans may be the cause of PNP in cas es of FDCS. Maverakis et al divide paraneoplastic autoimmune disorders broadly into 3 categories (i) Disruption of central tolerance, (ii) peripheral immune dysregulation and (iii) vicissitude of self-antigensG45(29). The mechanisms proposed for the occurrence of paraneoplastic phenomena in FDCS are so varied that we could find at least one hypothesis under each of these three headings.G46Disruption of fundamental tolerance1.Hartert et al and Kim et al have reported immature T cell proliferation, which is not characteristic of FDCS, in those presenting with Myasthenia Gravis. The resulting immune dysregulation may be lead to paraneoplastic phenomena (30, 31).2. Spreading epitope phenomenon states that cytokines produced by the tumor induce immunoglobulin production, which in turn leads to paraneoplastic phenomena(32). G47Peripheral immune dysregulationG481. B7 is a ligand which required for activation of T cells. Most antigen presenting cells have a low expression of B7 ligand, th e only exception being the dendritic cell. The B7 expression on NHL cellsG49 has been proposed as the mechanism underlying autoimmune phenomena seen in them(29). FDCS which arises from dendritic cells may also have a similar mechanism.Alteration of self-antigensG501.Antibodies directed against the tumor may cross-react with epidermG51al antigens in the case of PNP(32). Shared antigens between FDCS and erythrocytes like CD 35 may be the link in case of Autoimmune Hemolytic AnemiaConclusionThe paraneoplastic phenomena are an underreported aspect of FDCS. The clinical scenario is not uniform among all FDCS with paraneoplastic phenomena. While PNP is associated with poor prognosis, the available reports on AIHA and MG suggest a relatively benign course. There are only 2 cases of AIHA reported with FDCS. Although the mechanism for the development of AIHA in FDCS has been proposed, there is a possibility that it is simply a G52case of 2 unrelated diseases occurring together. In the times to come, better recognition of this entity amongst pathologists may lead to an identification of a larger number of patients. Thereby our understanding of this rare neoplasm and its even rareG53G54r complication of PNS will improve duck I Case reports of FDCS with Para Neoplastic PemphigusNoYearAge/SexCastlemanLocation of FDCSTherapy addictedInterval to PNPStatus of FDCS when PNP occurredOutcome and commentsRef.1199966/M+AbdominalSurgery480 monthsPost-excisionG55Died after 8 days(9)2200464/FAbdominalSurgery18 monthsNoAlive at 7m(33)3200532/M+NASurgery + ChemoNANot in remissionDied at 3m(10)4200527/FAbdominalNANANANA(34)56200553/F+AbdominalSurgery concurrentNot in remissionDied at 1 year(35)7200860/MLungNilSimultaneousPost-excisionG56Died at 6m(19)8200867/MAbdominalSurgery1 monthsPost-excisionRelapse at 12mMG+(36)9201068/MAbdominalSurgery1 monthPost-excisionDied at 24mMG +(31)102011NANANANANARelapsed(11)112011NA+NANANANANA(11)122011NA+NANANANANA(11)13201239/FNASurgeryNANAAlive at 60 m(37)14201267/MNASurgerySimultaneousPost-excisionDied after 21mMG +(37)15201268/MAbdominalSurgerySimultaneousPost-excisionDied at 3mSynchronous thyroid and renal cancer(38)16201361/F+Abdominal + multiple sitesSurgery + Chemo36 monthsNot in remissionDied(39)17201328/M+AbdominalChemoSimultaneousNot in remissionNA(40)18201320/M+Rt pelvisChemosimultaneousNot in remissionDied at 1m(41)19201446/F colorfulSurgery + Chemo6 monthsNot in remissionDied at 12m(23)20201420/MRt parahilarSurgery + ChemoNilPost-excisionAlive at 12m(42)21201526/F+NANANANAAliveMG+(43)Case reports of FDCS with Myasthenia GravisNoYearAge/SexCastlemanLocation of FDCSTherapy givenInterval to MGStatus of FDCS when MG occurredOutcome and commentsRef.1200867/MAbdominalSurgery1 monthsPost-excisionRelapse at 12 mPNP+(36)2201068/MAbdominalSurgerySimultaneousPost-excisionDied at 24mPNP+(31)3201039/FMediastinalSurgery36 months prior to FDCSNot in remissionNA(30)4201072/F+MediastinalSurgery7 months prior to FDCSNot in remissionAl ive at 8m(25)5201159/FAxillarySurgery1.5 monthsPost-excisionNA(44)6201267/MNASurgerySimultaneousPost-excisionDied after 21mPNP+(37)7201526/F+NANANANAAlivePNP+(43)Case reports of FDCS with Auto Immune Hemolytic AnemiaNoYearAge/SexCastleman