In situ mantle cell neoplasm Definition In situ mantle cell neoplasm (ISMCN) is defined by the presence of cyclin D1-positive B cells usually with CCND1 rearrangement, restricted to slightly or non-expanded mantle zones of lymphoid follicles. ICD-O coding 9673/1 In situ mantle cell neoplasm* ICD-11 coding 2A85.5 & XH8EM2 Mantle cell lymphoma & In situ mantle cell neoplasia Related terminology Acceptable: In situ mantle cell neoplasia Not recommended: in situ mantle cell lymphoma; mantle cell lymphoma-like B cells of uncertain/undetermined significance Subtype(s) None Localization ISMCN is most often found in lymph nodes but may be seen in extranodal lymphoid tissues { 22058203 ; 23280758, 24307917}. Involvement of more than one site does not exclude the diagnosis { 22058203 , 28393378, 33650040}. Clinical features ISMCN is typically an incidental finding in lymph nodes examined for other reasons and is characterized by indolent behaviour { 16935977 ; 18184277 ; 21224472 ; 22058203 }. Occasionally, ISMCN may be identified retrospectively after the diagnosis and/or treatment of overt MCL { 22058203 ; 23023712 } in previous specimens of the patients, or in association with another lymphoma, including chronic lymphocytic leukaemia / small lymphocytic lymphoma { 22058203 }, nodal or extranodal marginal zone lymphoma { 22058203 ; 25596254 }, follicular lymphoma and/or in situ follicular B-cell neoplasm { 18184277 ; 20231612 ; 22058203 ; 25478252 ; 32825940 }. ISMCN occasionally progresses to overt mantle cell lymphoma (MCL), with an overall frequency of less than 10% { 29129357 }. Epidemiology ISMCN is very rare, with a prevalence of 0.35% in unselected reactive lymph nodes { 29129357 }. It affects older adults, with a median age of 66 years, without sex predilection { 22058203 ; 24696721 }. Etiology Unknown Pathogenesis ISMCN represents a colonization the mantle zones of lymphoid follicles by B cells carrying the IG::CCND1 fusion which causes the juxtaposition of the CCND1?gene to an IG locus leading to cyclin D1 over expression. In some cases, an ISMCN pattern is seen in the setting of leukaemic non-nodal mantle cell lymphoma { 33028761 }. Macroscopic appearance Not relevant Histopathology ISMCN generally involves multiple follicles in the same lymph node { 26945339 }. Although other pathological processes may be present, involved lymph nodes or extranodal lymphoid tissues usually show preserved histological architecture, and reactive hyperplasia. The involved follicles show normal appearing or minimally expanded mantle zone without atypical cells. Cyclin D1-positive B cells are typically restricted to the inner mantle zone, with few cells in the outer mantle zone and occasional cells in the interfollicular areas { 22058203 , 24307917 }. Rare cases show intrafollicular spread { 21757601 }. Immunohistochemistry Phenotypically, in addition to cyclin D1, ISMCN shows expression of pan B-cell markers (CD19, CD20, CD79a or PAX5), along with positivity of IgD and BCL2. It is more often negative for CD5 and CD43 compared to overt MCL { 29129357 }. SOX11 expression is variable: its prevalence and significance require further studies { 22058203 ; 24307917 ; 22790016 }. Differential diagnosis ISMCN must be distinguished from MCL with mantle zone growth pattern (MCL-MZGP) { 22058203 ; 31140550 }. This distinction may be difficult, as in some cases of MCL-MZGP there may be ISMCN-like foci { 24307917 ; 24696721 ; 31140550 }. The histopathological differences are summarised in (section 4.3.7.3.) Cytology Usually not discernible on fine needle biopsy. Diagnostic molecular pathology Detection of a CCND1 rearrangement by FISH can confirm the immunophenotypic findings { 29129357 ; 26298543 }. Essential and desirable diagnostic criteria Essential - Preservation of lymphoid architecture without expansion of the mantle zone - Cyclin D1-positive B cells predominantly restricted to the inner layers of mantle zones of lymphoid follicles. - Staging negative for overt MCL. Desirable - Detection of a CCND1 rearrangement in the mantle cells, could be performed in unclear cases. Staging A diagnosis of ISMCN warrants rigorous clinical staging and careful follow-up to exclude overt MCL. Prognosis and prediction Based on the limited number of cases observed, ISMCN is typically a stable disease with an indolent course and favourable clinical course. Only rarely is there a need for therapy { 23999128 }.