The two issues of interest in this unique case of HVCD relate to the nature and significance of the multifocal T-lymphoblastoid proliferation and the striking ‘organoid’ FDC proliferation.
The T-lymphoblastoid element had an immunophenotype corresponding to the common thymocyte stage of cortical thymocyte differentiation [19, 20]. In the absence of any thymic epithelial elements to suggest entrapped normal thymus, this finding is usually strongly indicative of a pathological proliferation of T lymphoblasts. Whether in this case the population represents a hyperplastic, heterotopic/choristomatous or neoplastic proliferation (T-lymphoblastic lymphoma) remains unclear. Rare case reports and a recent case series  support the concept of an indolent T-lymphoblastic proliferation, although the origin of non-lymphomatous immature T cells outside the thymus remains obscure. In contrast to a reported case of FDC sarcoma and immature T cell proliferation , in which infiltrating immature T cells were admixed with atypical follicular dendritic sarcoma cells, in our case the T-lymphoblastic population formed multiple discrete aggregates between the compartmentalised expansile FDC nodules. There was no admixture of the two cell types and no significant disruption of architecture by either cell population. The presence of tumour-like aggregates of T lymphoblasts has been noted in two cases of CD with follicular dendritic cell tumour in the recent cases series , with all other aggregations being patchy in distribution. The microenvironment in which the T lymphoblasts proliferate in this case includes small CD31+ venules, PDCs, polyclonal plasma cells and larger CD68+ histiocytes. Plasmacytoid dendritic cells and polyclonal plasma cells would be unusual in typical cases of T-lymphoblastic lymphoma; thus, their presence might argue that the T-lymphoblastic proliferation is non-neoplastic.
In our case, owing to degraded DNA (ex paraffin-embedded material), we could not determine whether the T lymphoblasts are monoclonal or polyclonal heterotopic collections. It should be noted that all previous reports of indolent T-lymphoblastic proliferations outside the thymus have lacked monoclonality [12–18]. One may speculate that a microenvironment may exist whereby circulating T progenitors are entrapped and become T lineage-committed outside the normal thymic microenvironment. Early studies into the pathogenesis of CD demonstrated overexpression of inducible adhesion molecules including vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) . Within the normal thymus, intimate contact with VCAM-1-positive stroma is required for migration of double-negative (subcapsular zone) thymic lymphocytes. Subsequently, double-positive (cortical) thymocytes no longer require contact with stromal VCAM-1, although they undergo positive selection under the influence of ICAM-1 stromal signalling [19, 20]. It could be proposed that in this instance of HVCD, an alteration in the microenvironment, including altered stromal signalling, may have lead to the attraction of T progenitors and positive selection recapitulating T cell differentiation in the thymic cortical microenvironment.
Plasmacytoid dendritic cells are implicated in a wide variety of immune functions. These cells respond to a variety of DNA and RNA viruses by secreting copious amounts of interferon-α and to a lesser extent other cytokines including IL-6, IL-8 and TNF-β . Interleukin-6 in particular is postulated to drive CD via a dysfunctional local cytokine network . The presence of PDCs adjacent to areas of T-lymphoblastic proliferation raises the possibility that a local cytokine milieu mediated by PDCs may be responsible for these T-lymphoblastic expansions, though to our knowledge the presence of significant PDCs has not been studied in other cases of reported indolent T-lymphoblastic expansions. Although the pathogenesis underlying Castleman lymphadenopathy remains poorly understood, recent models emphasise the role of the virus HHV-8 in some cases, whilst an unidentified viral agent with lower pathogenicity may be relevant in cases lacking HHV-8 infection .
The second component of interest in this case is the organoid proliferation of follicular dendritic cells. FDCs have been implicated in the pathogenesis of CD. A recent publication suggests that in multicentric CD, FDCs may drive disease by presenting an HHV-8-associated antigen . HVCD has been associated with FDC abnormalities shared by FDC sarcoma including overexpression of EGFR . Whilst stroma-rich changes may characterise some forms of HVCD, there are no clear criteria to distinguish between FDC hyperplasia and FDC sarcoma, and it is conceivable that an “in situ” form of FDC sarcoma may exist. Sequential biopsies from a reported case of FDC sarcoma arising in HVCD showed an initially expansile growth of FDC networks without architectural disruption or cellular atypia , somewhat similar to the changes in our case. A recent publication describes folliculocentric B cell-rich FDC sarcoma , but the morphology described, which in particular includes cellular atypia, sheet-like overgrowth and loss of some FDC markers, is quite distinct from our case. The issue of FDC dysplasia and distinction from FDC hyperplasia is difficult, particularly in the setting of HVCD . In our case, mantle zone B cells remained closely admixed with the expanded FDC networks and the FDC proliferation remained compartmentalised in nature and also lacked destructive or sheet-like overgrowth. Furthermore, there was no nuclear atypia and the proliferation index was extremely low. Collectively, these features strongly favour florid FDC hyperplasia rather than FDC sarcoma.
The final intriguing aspect of this case is the strong probability of a familial predisposition to HVCD. The patient’s mother and aunt have had histologically confirmed HVCD diagnosed more than 10 years ago, although the original diagnostic material is not available for our review. This possible familial association would be a unique occurrence as, to our knowledge, an inherited predisposition to CD has not been previously described.
In summary, we report a patient with HVCD in the context of a possible underlying familial predisposition and the lesion complicated by multifocal T-lymphoblastic and florid FDC proliferation, both latter components were most likely benign in nature. The pathogenesis of CD, as currently understood, suggests that there may be an underlying inherited subtle immune dysfunction in this patient’s family. One may speculate that in a dysregulated immunological environment, an unknown infectious agent or agents have led to the development of HVCD. Subsequently, a microenvironment mimicking the normal thymic cortex, and an inappropriate cytokine milieu possibly facilitated by accumulations of PDCs, may have resulted in the interesting combination of an indolent T-lymphoblastic proliferation and the striking FDC overgrowth. At most recent follow-up, 30 months after biopsy, the patient remains disease free, and whilst he should be followed closely, the long-term outlook we suggest should be guardedly optimistic, with little likelihood of progression to T-lymphoblastic lymphoma or follicular dendritic sarcoma.