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California Tumor Tissue Registry’s
Case of the Month
CTTR COTM www.cttr.org Vol 9:5
February, 2007
A 66-year old Caucasian male presented with an enlarged left-supraclavicular lymph node.
Excisional biopsy of the mass was performed.
Microscopically, the lymph node architecture was obscured by a mixed inflammatory cell
infiltrate of small lymphocytes, eosinophils, plasma cells, histiocytes and occasional granulocytes
along with numerous granulomata (Fig. 1). Large numbers of multinucleated giant cells as well
as mononucleated, binucleated and multinucleated histiocyte-like Reed-Sternberg (RS) cells and
variants were seen (Figs. 2,3). These had moderate to abundant amphophilic cytoplasm and
demonstrated distinctive eosinophilic macronucleoli (insets - Figs 2,3). They marked for CD15
(membrane and para-nuclear dot-like staining) and CD30 (Fig. 4), but neither decorated for CD45
nor CD20.
Diagnosis: “Mixed Cellularity Hodgkin Lymphoma (MCHL) with Granulomatous
Lymphadenitis Including Overwhelming Multinucleated Giant Cell
Reaction”
Angie Pham, M.D., Jun Wang, M.D., Donald R. Chase, M.D
Department of Pathology, Loma Linda University and Medical Center
California Tumor Tissue Registry
(CTTR submission by John Svirbely, M.D.)
Hodgkin Lymphoma (HL) accounts for 30% of all lymphomas typically presenting as painless
adenopathy of cervical and/or supraclavicular lymph nodes. It may occasionally arise in axillary
or inguinal regions. Constitutional symptoms such as fever, night sweats, and/or weight loss
occur but are less frequent. The disease has two distinct categories.
Classic Hodgkin Lymphoma (CHL) includes:
 nodular sclerosis (NSHL),
 mixed cellularity (MCHL),
 lymphocyte predominant (LPHL), and
 lymphocyte depleted (LDHL)
Non-Classic Hodgkin Lymphoma (NCHL) includes:
 nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL).
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MCHL, illustrated in our case, comprises approximately 20-25% of HL and has a median
presentation age of 37 years. It usually occurs in males (approximately 70%) and unlike NSHL,
lacks a bimodal age distribution.
Microscopically, MCHL typically obliterates the nodes follicular architecture. The distinctive
feature is the presence of Reed-Sternberg cells (RS), usually binucleated cells with prominent
eosinophilic macronucleoli. They are seen in a background milieu of inflammatory cells
consisting of eosinophils, neutrophils, plasma cells and histiocytes.
Granulomata in HL
Curiously, both Hodgkin Lymphoma and Non-Hodgkin Lymphoma may present with a
granulomatous lymphadenopathic microscopic appearance in either lymph node(s) or other
organs, and it has been suggested that this change may portend a better prognosis. The change is
morphologically non-specific as to etiology and may be caused by a myriad of etiologies related
to the tumor process or separate from it. It may also obscure underlying clues to a diagnosis of
lymphoma. Our presentation case shows an overwhelming granulomatous reaction with many
multinucleated giant cells nearly obscuring diagnostic RS cells and variants.
The granulomata of HL are described as being epithelioid histiocytes with associated Langhans or
foreign-body type giant cells. Although asteroid bodies, Schaumann bodies or birefringent
crystals are typically not found within the cytoplasm of the giant cells (as might be seen in
sarcoidosis) a morphologic diagnosis is problematic and an attempt to explain the granulomatous
inflammation should be made whenever possible.
Granulomatous Lymphadenitis can be:
non-infectious, including:
 sarcoidosis, foreign body reaction, secondary draining carcinoma, lymphoma,
or
infectious, including:
 tuberculosis, histoplasmosis, toxoplasmosis, brucellosis, tularemia,
leishmaniasis, syphilis.
In developing countries, infectious causes especially tuberculosis are the most likely, but in the
West, the more common causes are non-infectious, especially sarcoidosis.
Non-infectious Causes of Granulomatous Lymphadenitis (other than lymphoma):
Sarcoidosis affects adults between the ages of 20 to 40 years and has a male to female ratio of
2:1. Blacks are nearly 10 times more frequently affected than whites. The disease is felt to be
autoimmune and it tends to involve multiple organs most frequently the lungs, eyes, skin and
lymph nodes. Although mediastinal and hilar lymph nodes are usually affected, generalized
lymphadenopathy is possible. The characteristic granuloma is non-necrotic, composed of
uniform epithelioid histiocytes, Langhans giant cells and small lymphocytes. The granulomata
are sharply marginated (“punched out”). Cytoplasmic abnormalities such as Schaumann bodies,
asteroid bodies, and calcium oxalate crystals may be present. But since these histologic findings
may also occur in other disorders, ancillary studies are usually done including a Kviem test, a
skin test, and possibly an angiotensin-converting enzyme level. The results, however, must be
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correlated with the biopsy findings and the clinical setting. The diagnosis of sarcoidosis is one of
exclusion.
Benign lymph nodes draining carcinoma may develop granulomatous reactions secondary to the
infusion of necrobiotic byproducts. Similar reactions may also be due to foreign body reactions
to contrast media.
Infectious Causes of Granulomatous Lymphadenitis
Infectious granulomatous lymphadenitis has been described as having two distinctive granuloma
morphologies:

non-suppurative, hypersensitivity-type granulomata:
histiocytes, with small round B cells located at the periphery

suppurative granulomata:
neutrophils, histiocytes, and monocytoid B cells present both at the
periphery and in the center of the granuloma
Tuberculosis. This classic type of suppurative infectious granulomatous lymphadenitis is typified
by epithelioid granulomata having central caseating necrosis. Since necrosis is present, there may
also be development of a draining sinus to the skin or through a mucosal lining. Most commonly,
the cervical region (scrofula) is affected. Acid fast stain, cultures, or polymerase chain reaction
are necessary to confirm presence of organisms.
Atypical mycobacteria cause granulomatous lymphadenitis typically of lateral cervical lymph
nodes. Microscopically, the granulomas are nearly identical to those of tuberculosis but show
more neutrophils with formation of an abscess. Other clues to suggest nontuberculous
mycobacterial etiology include ill-defined, irregularly shaped or serpinginous granuloma. An
acid-fast stain may demonstrate the bacilli, and confirmation by PCR or cultures should identify
the organisms.
Fungal infections of a lymph node may show suppurative, non-supportive or both kinds of
granulomata. Histoplasmosis shows a the basic reactive changes seen in stimulated lymph nodes,
but also shows regions of necrosis and diffuse hyperplasia of sinus histiocytes. Blastomycosis,
coccidioidomycosis, sporotrichosis, paracoccidioidomycosis, as well as opportunistic fungi
(cryptococcosis, aspergillosis, mucormycosis, and candidiasis) are capable of causing fungal
lymphadenitis. The organisms can be confirmed by GMS stain, cultures and molecular testing.
Toxoplasmosis lymphadenitis will usually present with irregular granulomata composed of
epithelioid histiocytes, marked follicular hyperplasia with small granulomas within the
hyperplastic follicles, and monocytoid B cells distending the cortical and marginal sinuses.
Toxoplasmosis usually involves the posterior cervical nodes of young women. Since
morphologic and molecular diagnosis of toxoplasmosis is difficult, the diagnosis should be
confirmed with serologic tests.
Bartonella henselae, the bacteria responsible for cat-scratch disease, is the most common cause of
suppurative lymphadenitis. Regional lymph nodes, mostly axillary or cervical, are usually
involved showing follicular hyperplasia with monocytoid B cell proliferation within the sinuses
and paracortical regions. Small suppurative granulomata are located adjacent to or within the
monocytoid B cell aggregates. Later stages show stellate microabscesses with palisading
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epithelioid histiocytes surrounding central necrotic fibrinoid material intermixed with neutrophils.
Langhans-type giant cells are generally not present, but peripherally located mature plasma cells
and immunoblasts may be seen. Clusters or chains of bacilli, which are most commonly found in
the capillary walls, macrophages lining the lymph node sinuses, and areas of necrosis, are
highlighted with the Warthin-Starry silver stain. The disease usually affects children and young
adults, with an equal male to female ratio. Antibodies to the organism and amplification of DNA
are helpful in the diagnosis.
Other possible causes of granulomatous lymphadenopathy include syphilis, leprosy,
lymphogranuloma venereum and Brucellosis, all of which must be confirmed with special stains,
molecular or serologic tests.
Suggested Reading:
O’Connell M, Schimpff S, Kirschner R, Abt A, Wiernik P. Epithelioid Granulomas in Hodgkin
Disease: A favorable prognostic sign? JAMA. 233: 886-889, 1975.
Abrams J, Pearl P, Moody M, Schimpff S. Epithelioid Granulomas Revisited: Long-Term
Follow-Up in Hodgkin’s Disease. Am J Clin Oncol (CCT). 11(4): 456-460, 1988.
Braylan R, Long J, Jaffe E, Greco FA, Orr S, Berard C. Malignant Lymphoma Obscured by
Concomitant Extensive Epithelioid Granulomas. Cancer 39: 1146-1155, 1977.
Pak H, Friedman N. Pseudosarcoid Granulomas in Hodgkin’s Disease Hum Pathol 12(9): 832837, 1981.
Silverberg S, DeLellis R, Frable W, LiVolsi V, Wick M . Silverberg’s Principles and Practice of
Surgical Pathology and Cytopathology. Elsevier, Inc. 2006.
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