Follicular Dendritic Cell Sarcoma

follicular Dendritic st every last(predicate) SarcomaFollicular Dendritic Cell Sarcoma and its paraneoplastic manifestations Re pull inAbstractFollicular Dendritic Cell Sarcoma (FDCS) is a rargon neoplasm arising from dendritic cells. The paraneoplastic phenomena are an underreported aspect of FDCS. Here we present a boldness report of FDCS presenting with autoimmune haemolytic anaemia and pass 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 number one depict by Monda et al who describes a series of 4 cases(1). Being a relatively new entity, its classification body 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 clinical and radiological features. It is not uncommon to misdiagnose these cases as lymphoma due to many kindredities in the morphological features between the two entities. With the emergence of modern immunohistochemistry, the dendritic cell lineage can be confirmed and therefore, there is increasing recognition of this group of disorders. Since the first verbal description in 1986, nearly 350 cases of FDCS have 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 presentation. 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.ComputerizedG2Tomograp hy (CT) scan typically 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(prenominal) similarly than distant metastasis. More than 50% of the cases recur locally by and by wide local excision while only 25% cases fall in distant metastasis. FDCS is considered as a low-grade malignancy by some while separates consider it as an intermediate-grade malignancyG4(6, 7). Liu et al have proposed G5histological criteria for grading the tumor and assessing the risk 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 militant tumor (13) on the other hand, FDCS of the liver and spleen presents like an inflammatory pseudotumor and usually has a di staff predominance. (3)Castlemans affection 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 indisposition whitethorn act as the nidus from which FDCS can evolve.(12)Ebstein-Barr Virus has withal been described in standoff 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 amyloidosis(13)FDCS mostly arises within lymphoid follicles and has a cognize association with Castlemans disease. Hence it was postulated that it arises from lymphoid harbingers. 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 wi th protracted nuclei, delicate, 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 peculiarity 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 continuously strongly positive , while in other dendritic cell neoplasms, this marker is weakly positive.(13) functional excision of the tumor has been attempted in well circumscribed FDCS. Although some reports suggest that they recur in short 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 chemotherapeutic regimen for the same. Both lymphoma and sarcoma directed therapies have been tried. eggbeater regimen is one of the usually 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).G15G16 cuticle communicateA 60-year-old female presented with 2 months history of easy fatiguabilityG17 and low-grade fever. She was detected to have severe anemiaG18 and barmy icterus with difficulty in blood cross matching at a local hospital. She was referred to our fetch for further evaluation. General examination revealed marked pallor and generalized lymphadenopathy. The liverwas palpable 5 cm do wnstairs right costal margin and the spleen was palpable 6 cm below left costal margin. Laboratory evaluation revealed Coombs positive hemolytic anemia, which partially responded to sex hormone therapy. Her Lymph node excision biopsy showed diffuse effacement of nodal architecture with multiple fascicles of spindle cells traversing the lymph node and wrapping around the pre- subsisting 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 exchangeable paraneoplastic manifestations. They are reviewe d below.G19G20Paraneoplastic manifestations of FDCSParaneoplastic 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. duration axillary and cervical lymphadenopathy is the most common presentation of FDCS, PNP has been reported mostly with retroperitoneal 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 undetectable 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 remittal in most of the useable 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 treatment, but there are 2 reports of usage of high immunosuppression to successfully control the PNP(18, 23).II.Myasthenia Gravis (MG)Seven cases of myasthenia gravis have been reported in literature till date. peerless 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, with 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 ready(prenominal) literature, there was n o evidence of CD with FDCS and MG in all but one case.G28G29G30The treatment has been IV immunoglobulin, pyridostigmine, and steroids. near of the authors have reported a good response to therapy with no mortality.G31G32 This is in rapport 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 in the first place detection of the disease(27)III. Autoimmune Hemolytic anaemiaAIHA 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 different 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 ca ncers are usually steroid responsive. G36A search of the literature revealed 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 lump which was diagnosed as FDCS. She did not respond to radiotherapy solo 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 cases of FDCS. Maverakis et al divide paraneoplastic autoimmune disorders broadly into 3 categories (i) Disruption of central tolerance, (ii) peripheral immune dysregulation and (iii) alteration of self-antigensG45(29). The mechanisms proposed for the occurrence of paraneoplastic phenomena in FDCS are so alter that we could find at least one hypothesis under each of these three headings.G46Disruption of primordial 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 possess 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, the 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 simpl y 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 put off I Case reports of FDCS with Para Neoplastic PemphigusNoYearAge/SexCastlemanLocation of FDCSTherapy attachedInterval to PNPStatus of FDCS when PNP occurred outlet and commentsRef.1199966/M+ abdominal muscle surgical operation480 monthsPost-excisionG55Died after 8 days(9)2200464/FAbdominalSurgery18 monthsNoAlive at 7m(33)3200532/M+NASurgery + ChemoNANot in amnestyDied at 3m(10)4200527/FAbdominalNANANANA(34)56200553/F+AbdominalSurgery synchronalNot in cave inDied at 1 year(35)7200860/MLungNil synchronousPost-excisionG56Died at 6m(19)8200867/MAbdominalSurgery1 monthsPost-excisionRelapse at 12mMG+(36)9201068/MAbdominalSurgery1 monthPost-excisionDied at 24mMG +(31)102011NANANANANAR elapsed(11)112011NA+NANANANANA(11)122011NA+NANANANANA(11)13201239/FNASurgeryNANAAlive at 60m(37)14201267/MNASurgerySimultaneousPost-excisionDied after 21mMG +(37)15201268/MAbdominalSurgerySimultaneousPost-excisionDied at 3m simultaneous 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/FLiverSurgery + 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 FDCSN ot in remissionNA(30)4201072/F+MediastinalSurgery7 months prior to FDCSNot in remissionAlive 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