Case identification: J136-96
A previously healthy 44-year old woman presented with low back pain. X-ray showed a calcified mass
beside the left kidney, measuring 5.5 cm. After an observation period of 6 months showing no appreciable
change in the size of the tumor, laparotomy was performed. The mass was situated in front of the upper
pole of left kidney and left adrenal gland, from which it could be separated and excized. The patient
made an uneventful recovery.
Case 2 - Figure 1 - A predominantly diffuse lesion interspersed by occasional hyaline-vascular follicles (left lower field)
Case 2 - Figure 2 - Medium magnification reveals that the diffuse lesion comprises high endothelial venules, spindly cells and lymphocytes. In the left lower filed, there is a hyaline-vascular follicle penetrated by multiple hyalinized venules.
Case 2 - Figure 3 - Higher magnification of hyaline-vascular follicle. The germinal center shows hyalinization and depletion of lymphoid cells. The remaining cells are follicular dendritic cells - some of which exhibit slightly enlarged and atypical nuclei.
Case 2 - Figure 4 - Another hyaline-vascular follicle depleted of lymphoid cells. Some follicular dendritic cells exhibit markedly enlarged nuclei with irregular foldings of the nuclear membrane and coarsened chromatin ("follicular dendritic cell dysplasia").
Case 2 - Figure 5 - Some areas of the diffuse/interfollicular zone look indistinguishable from usual hyaline-vascular Castleman disease.
Case 2 - Figure 6 - However, some areas show in addition short fascicles of plump spindly cells in the diffuse/interfollicular zone.
Case 2 - Figure 7 - Some plump spindly cells have markedly enlarged nuclei, vesicular chromatin and distinct nucleoli.
Case 2 - Figure 8 - Some plump spindly cells have indistinct cell borders, large nuclei and prominent nucleoli. However, mitotic figures are very rare.
There are hyaline-vascular follicles separated by a prominent interfollicular component rich in
venules and lymphocytes, and lacking sinusoids. The hyaline-vascular follicles are often depleted of
lymphoid cells. In some of them, there are enlarged and atypical (dysplastic) follicular dendritic cells
(FDC). The interfollicular zone is very broad, constituting approximately 75% of the lesional area. In
addition, there are atypical plump spindly cells disposed singly or in short fascicles in the
interfollicular zone. The spindly cells have enlarged nuclei, vesicular chromatin and small distinct
nucleoli, but mitotic figures are rare.
On immunohistochemical staining, the hyaline-vascular follicles are formed by small numbers of CD20+ B
cells supported by CD21+/clusterin+ FDC meshworks. The atypical/dysplastic FDCs in the follicles are
also highlighted by CD21 immunostain.
The interfollicular zone is rich in CD3+ T cells, and CD31+/CD34+ high endothelial venules. There are
only small numbers of smooth muscle actin-positive delicate stromal cells. The atypical large cells in
the interfollicular zone are negative for cytokeratin, CD21, CD23, CD35, actin, CD31, CD34 and
factor-VIII-related antigen. These cells are vimentin positive, and only rare ones are immunoreactive
for clusterin. The Ki67 proliferation index is low.
Hyaline-vascular Castleman disease, stroma-rich variant, with interfollicular atypical spindle cell
proliferation of uncertain nature
Hyaline-vascular Castleman disease can affect any age, but most commonly 30-40 years. It presents as
a solitary mass lesion without systemic symptoms. The commonest sites of involvement are:
intrathoracic, neck, axillary, and retroperitoneum. The disease is curable by excision, although the
surgery can be complicated by massive bleeding.
Classical examples of hyaline-vascular Castleman disease should pose no problems in diagnosis.
However, a variety of superimposed cellular atypia or proliferations can cause problems in diagnosis or
terminology. Table 1 lists the spectrum of tumors and tumor-like lesions that can accompany/supervene
from the various cellular components of hyaline-vascular Castleman disease.
Table 1: Tumors or tumor-like lesions accompanying or supervening in hyaline-vascular Castleman disease
|Cell component normally or often present in hyaline-vascular Castleman disease ||Accompanying or supervening tumor or tumor-like lesions|
|Lymphoid cells |
- No increased risk of lymphoma or plasmacytoma
|Plasmacytoid monocytes (plasmacytoid dendritic cells) |
- Kikuchi lymphadenitis-like lesion
|Follicular dendritic cells |
- Follicular dendritic cell dysplasia
- Interfollicular follicular dendritic cell overgrowth
- Follicular dendritic cell tumor
|Other stromal cells |
- Angiolipomatous hamartoma
- Scattered bizarre cells in interfollicular zone
- Vascular hyperplasia
- Vascular neoplasm
- Angiomyoid proliferation/tumor
- Other stromal cell hyperplasias or tumors
Angiolipomatous hamartoma is the simplest. It is usually a
non-circumscribed mass within which the Castleman disease lesion resides.  It comprises mature adipose
cells interspersed with thick-walled blood vessels. This lesion per se is innocuous.
A tumor that shows differentiation into vascular and vascular-related elements may be
superimposed on hyaline-vascular Castleman disease.
It forms a single discrete mass or sometimes
multiple nodules, and focally may merge into the vascular hyperplasia in the interfollicular zone. The
degree of cellular atypia is variable. Some cases, particularly those exhibiting significant nuclear
atypia and mitotic activity, can metastasize.
When the interfollicular zone is broad, accounting for >50% of the lesional area, the
term "stroma-rich variant" can be applied.  In some cases, there can be large zones devoid of
follicles. In contrast to the various types of superimposed cellular proliferations, the cellular
composition should be morphologically identical to the interfollicular zone of the classical
cases, i.e. high endothelial venules and small lymphocytes, in the absence of atypical cells and
unexplained spindly cells. In cases in which the venules appear prominent and closely packed (resembling
a hemangioendothelioma),  a designation such as "vascular hyperplasia" is justified, provided that such
hypervascular area merges into the interfollicular zone, does not form a discrete mass, and does not
exhibit cellular atypia.
This variant is of no clinical significance. The main problem is that the diagnosis of
Castleman disease might not be thought of at all due to paucity of hyaline-vascular follicles.
FDC dysplasia and scattered bizarre cells in interfollicular zone
In some examples of hyaline-vascular Castleman disease, occasional cells within the
follicles exhibit large bizarre nuclei. While most of these atypical cells appear to be FDC, the
possibility that occasional bizarre cells represent endothelial cells cannot be totally ruled out. The
significance of these cells is currently unclear, although it has been suggested that these cells might
be the precursors for the development of FDC tumors. The current evidence suggests that there is no
Rare bizarre large cells can also be occasionally found in the interfollicular zone. The
nature of these cells is often difficult to determine. Two possibilities include residual FDC from
regressed follicles and endothelial cells. There is currently no evidence that this lesion has a
malignant potential. The most important work-up is to rule out a Hodgkin lymphoma.
Various spindle cell proliferations: hyperplasia versus neoplasia
A variety of cellular proliferations (with or without frank cytologic atypia) can
supervene on hyaline-vascular Castleman disease. It is often difficult to determine if the process is
hyperplastic or neoplastic, and for the latter the malignant potential. When the lesion forms a discrete
expansile mass (whether circumscribed or infiltrative), it is reasonable to assume that the process is
neoplastic. However, even in the absence of an expansile mass, a neoplastic process cannot be ruled out
(in which case the non-committal term "proliferation" may be applied). So far, all cases of angiomyoid
proliferation/tumor have pursued a benign cause, while FDC proliferations/tumors are potentially
malignant (with recurrence or metastasis in a proportion of cases).
The malignant potential of
other stromal cell proliferations is currently unknown. Thus thorough immunohistochemical evaluation
should be performed to determine the nature of the cellular proliferation as far as possible.
Angiomyoid proliferation/tumor is characterized by compact, haphazard or focally
storiform proliferation of spindly cells, usually without forming long fascicles. There are some admixed
small blood vessels with solid lumina. Nuclear atypia is absent. On immunostaining, most spindly cells
are immunoreactive for smooth-muscle actin, while the rich component of ramified small blood vessels with
compressed lumens can be highlighted by CD34. 
FDC proliferation/tumor is characterized by spindly or ovoid cells growing
predominantly in a storiform or fascicular pattern, and sprinkled with small lymphocytes. The tumor
cells often have indistinct cell borders and distinct nucleoli. Nuclear atypia is variable, but often
present to some extent. Immunostaining for FDC markers such as CD21 or CD35 is positive. The FDC
proliferation can be present at the time of presentation of Castleman disease, or can develop
Other stromal cell proliferationsare characterized by proliferation of cells of
other types (such as histiocytic/fibrohistiocytic) or cells that cannot be characterized (such as the
- Tsang WY, Chan JK, Dorfman RF, Rosai J. Vasoproliferative lesions of the lymph node. Pathol Annu 1994;29:63-133.
- Gerald W, Kostianovsky M, Rosai J. Development of vascular neoplasia in Castleman's disease. Report of seven cases. Am J Surg Pathol 1990;14:603-14.
- Chan JK, Tsang WY, Ng CS. Follicular dendritic cell tumor and vascular neoplasm complicating hyaline-vascular Castleman's disease. Am J Surg Pathol 1994;18:517-25.
- Danon AD, Krishnan J, Frizzera G. Morpho-immunophenotypic diversity of Castleman's disease, hyaline- vascular type: with emphasis on a stroma-rich variant and a new pathogenetic hypothesis. Virchows Arch A Pathol Anat Histopathol 1993;423:369-82.
- Lin O, Frizzera G. Angiomyoid and follicular dendritic cell proliferative lesions in Castleman's disease of hyaline-vascular type: a study of 10 cases (published erratum appears in Am J Surg Pathol 1998;22:139). Am J Surg Pathol 1997;21:1295-306.
- Ruco LP, Gearing AJ, Pigott R, Pomponi D, Burgio VL, Cafolla A, et al. Expression of ICAM-1, VCAM-1 and ELAM-1 in angiofollicular lymph node hyperplasia (Castleman's disease): evidence for dysplasia of follicular dendritic reticulum cells. Histopathology 1991;19:523-8.
- Chan JK. Proliferative lesions of follicular dendritic cells: an overview, including a detailed account of follicular dendritic cell sarcoma, a neoplasm with many faces and uncommon etiologic associations. Adv Anat Pathol 1997;4:387-411.
- Izumi M, Mochizuki M, Kuroda M, Iwaya K, Mukai K. Angiomyoid proliferative lesion: an unusual stroma-rich variant of Castleman's disease of hyaline-vascular type. Virchows Arch 2002;441:400-5.
- Chan JK, Fletcher CD, Nayler SJ, Cooper K. Follicular dendritic cell sarcoma. Clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized. Cancer 1997;79:294-313.
- Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM. Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies. Histopathology 2001;38:510-8.
- Chan JK, Luk SC, Ho PL. Stroma-rich Castleman's disease with superimposed Kikuchi's lymphadenitis-like changes. Int J Surg Pathol 1997;4:197-202.
- Kurotaki H, Kaimori M, Nagai K. Recurred Castleman's disease containing a fibrohistiocytic nodular lesion with vascular occlusion. Acta Pathol Jpn 1993;43:603-7.