Aspiration Cytopathology of Lymph Nodes and Lymphoproliferative Neoplasms
Case 2 -
Suppurative Granulomatous Lymphadenitis
Paul E. Wakely, Jr.
A 12 y/o girl is seen in the clinic with a 1.5 cm. right axillary node which was
noted by her mother 3 weeks earlier. The mass has increased slightly despite antibiotic therapy. There
are no skin lesions.
|smears contain several small loosely clustered granulomas scattered in a background of many neutrophils.|
|granulomas characterized by epithelioid histiocytes with elongated often slightly indented nuclei, and a moderate-abundant amount of cytoplasm.|
Diagnosis: Suppurative Granulomatous Lymphadenitis
In this particular case it was discovered that the family had recently
purchased a kitten, and it is inferred that this example of suppurative granulomatous lymphadenitis is
secondary to Cat-Scratch Disease(Bartonella
|CSD is most common cause of suppurative granulomatous lymphadenitis in North America.|
|children to early adulthood|
|self-limited disease; symptoms 6-8 weeks after contact|
|resolves over a period of months in most patients|
|tender regional lymphadenopathy: >nodes in inguinal, axillary, and cervical neck region are most often affected.|
|negative cat history in up to 50% of cases - diagnosis: culture and serum immunofluorescent Ab test|
|Other organisms that can produce an identical cytologic(and tissue) picture to CSD:|
| ||tularemia (Franciscella tularensis),|
| ||lymphogranuloma venereum (Chlamydia trachomatis),|
| ||yersinia (Y. enterocolitica or Y. pseudotuberculosis),|
| ||certain fungi,|
| ||less common: tuberculosis.|
Smears are moderate to highly cellular; contain neutrophils, a variable degree of
background necrosis, and occasional multinucleated giant cells. Granulomas are found in varying numbers;
sometimes obscured by the acute inflammation and karyorrhectic debris that exists on the smears. Early
stages of the disease may display few granulomas and easily mistaken for reactive hyperplasia. Unless
the organism is isolated, the cytologic diagnosis is presumptive, not definitive. Histochemical staining
(Steiner & Steiner stain) of smears to identify the organism is possible yet insensitive. Molecular
methods can unequivocally diagnose the infection in tissue sections, and is possible on DNA taken from
smears or cells collected by FNAB.(Avidor. AJCP 2001;115:900) Since these aspirates may
appear purulent to the naked eye, one should always submit a portion of aspirate for culture.
Granulomas are recognized in smears as either loose or tightly clustered collections of
epithelioid histiocytes. To avoid confusing granulomas with a collection of non-epithelioid histiocytes,
macrophages, or lymphohistiocytic aggregates one must concentrate on the nuclear features.
Note: The key feature of epithelioid histiocyte nuclei is an elongated
almost elliptical or spindle shape unlike conventional histiocyte or macrophage nuclei which are rounded.
Often, a slight smooth indentation is present on one side of the nucleus producing an outline that has
been variously described as "footprint, C-shape, or boomerang shape".
Thesenuclei are hypochromic and may have small nucleoli or no visible nucleoli. Nuclei
may project away from the granuloma center in a "starburst" pattern. Epithelioid histiocytes have a
moderate to sometimes large amount of finely granular cytoplasm.
The differential diagnosis of CSD includes:
| non-caseating granulomatous lymphadenitis(as is seen in sarcoidosis),|
| suppurative granulomatous lymphadenitis due to other organisms as listed above, and|
| granulomatous inflammation as a component of Hodgkin lymphoma, or some T-cell lymphomas.|
Smears of sarcoidosis contain granulomas with or without multinucleated giant cells. A
polymorphous lymphocytic population as described for a hyperplastic lymph node may or may not be present.
Unlike cat-scratch disease or other causes of suppurative lymphadenitis a neutrophilic infiltrate is
absent in smears of sarcoidosis. As in tissue pathology, the diagnosis of sarcoid is one of exclusion.
Only isolation of a specific organism can distinguish cat-scratch disease from the other
infectious causes of suppurative granulomatous lymphadenitis.
Lymph Node FNA in the HIV Infected Patient
The principal diagnostic categories causing lymphadenopathy in these patients are a form
of reactive hyperplasia (HIV lymphadenopathy), various infectious diseases, and malignant lymphoma.
|persistent lymph node enlargement that is not secondary to infectious, neoplastic, or other well-defined condition.|
|initially, explosive follicular hyperplasia followed by regressive changes, and eventual lymphocyte depletion.|
|Although reports to the contrary exist in the literature, no one has conclusively demonstrated that the histologic alterations described for HIV-associated lymphadenopathy can be appreciated, or diagnosed with any degree of certainty from the evaluation of aspirates - an inability cytologically to gauge the explosive follicular hyperplasia with follicle lysis and thin mantle zones of type A phase, the follicular involution, partial lymphocyte depletion, and Castleman-like changes of type B phase, or the small depleted follicles and marked paracortical vascular hyperplasia of type C phase. Most aspirates have a cytologic picture that mimics that of a reactive lymph node. Occasional multinucleated polykaryocytes may be found, but are non-specific. Even though the number of capillary segments may be increased in smears from the later phases of this lymphadenopathy these correlate poorly with the degree of vascularity seen in tissue sections.|
In North America, Mycobacterial infection is a common cause
of lymphadenopathy in HIV infected individuals. Most examples of Mycobacterial lymphadenitis show some degree of inflammation - neutrophils,
lymphocytes, or plasma cells - on the smear in addition to granulomas. Caseation necrosis is not always
present. Granulomas may be scarce or even absent in the smears of many HIV+ and other immunosuppressed
patients infected with Mycobacteria. One should carefully examine these
smears for evidence of the "negative image" phenomenon [images produced by a resistance of the lipid coat
of acid-fast bacilli to stain with Diff-Quik or any other Romanowsky type of stain]. This creates a
"negative image" by which the tubercle bacilli appear as short optically clear rods/striations surrounded
by stained proteinaceous or necrotic material.] These rods may exist extracellularly or within
macrophages. Intracellularly, these appear as multiple linear striations giving the cytoplasm a
"crinkled tissue paper" appearance mimicking the storage cells of Gaucher disease. Some authors have
dubbed these striated cells pseudo-Gaucher cells. Das has categorized the aspirates of patients with
myobacterial infection into 3 types:
Table 16. FNAB of Mycobacterial Lesions
|Type I – Granulomas without Necrosis|
|Type II – Granulomas with Necrosis|
|Type III – Necrosis without Granulomas (with or without neutrophils).|
Note: It is important to stain smears for
acid-fast bacilli and fungi in any immune suppressed patient where necrosis and/or a neutrophilic
infiltrate are present regardless of whether granulomas are seen.
This is best done with unstained smears, but stained smears can also be de-stained and then re-stained
Cryptococcus lymphadenitis is also rather common in aspirates
from immunosuppressed patients, and like Mycobacteria may mimic an acute
bacterial lymphadenitis. Other more unusual organisms (at least in North America) that can appear in
lymph node aspirates of HIV+ patients include Leishmania, Histoplasma, and Pencillium marneffei.
HIV-related malignant lymphomas:
| highly aggressive tumors that remain resistant to treatment|
| vast majority are B-cell, often extranodal, and stage III or IV at time of presentation.|
| most common histologic subtypes: Diffuse Large B-cell Lymphoma, and Burkitt Lymphoma, Primary Effusion Lymphoma|
Granulomatous lymphadenitis caused by Toxoplasmosis is difficult if not impossible to
diagnose by FNA. The small collections of parafollicular epithelioid histiocytes that stand out in
tissue sections are rarely appreciated in aspirates unless the condition is florid because these
histiocytes are widely scattered on smears. When found in aggregates they are only very loosely
assembled and of course their paracortical location is lost in smears. Also one cannot evaluate
subcapsular and trabecular sinuses for monocytoid B cells in smears as is possible in tissue sections.
Discovery of the parasitic cysts of T. gondii is rare in aspirates as well
as in tissue. Serological testing is necessary to confirm the diagnosis in most cases. Other causes of
lymphadenopathy that cannot be diagnosed with absolute certainty from FNA are in Table 7.
Aspirates of acute bacterial lymphadenitis are hypercellular and composed of nearly a pure
population of neutrophils which are easily recognized. These may be mixed with lymphocytes. If an
abscess exists, pus will be noted either in the hub or barrel of the syringe during the FNA. One should
routinely submit part of any obvious purulent material for culture. Even if a patient is being treated,
this should be done because the organism may be resistant to the antibiotic the patient is receiving.
Culture of the aspirate may correctly identify the sensitivity of the organism leading to a change in
antibiotic therapy - an event we have witnessed, but only infrequently.
The smears of Mycobacterial infection in immunodeficient patients can mimic those of acute
lymphadenitis as discussed above.
Table 17. Rosai-Dorfman Disease [Sinus Histiocytosis With Massive Lymphadenopathy]
| principally young children to teenagers, but wide age spectrum|
| massive painless bilateral cervical lymphadenopathy are affected in the vast majority.|
| can also occur extra-nodally.|
| accompanying symptoms include fever, joint pain, night sweats, and even weight loss - all of which can clinically mimic lymphoma.|
| polyclonal hypergammaglobulinemia, and leukocytosis.|
| IP: S-100, CD68, CD30, alpha 1 anti-chymotrypsin|
The most striking feature in tissue sections is a marked expansion of lymph node sinuses
filled with histiocytes that have engulfed lymphocytes (lymphophagocytosis), and to a lesser extent
plasma cells, neutrophils, and red cells. Unfortunately, this sinusoidal architecture is not recognized
in smears even though histiocytes are numerous. Smears may appear to represent reactive hyperplasia
having a range of lymphocytes, large numbers of histiocytes and D&L aggregates.
Key feature: aggregates of lymphocytes within cytoplasm of histiocytes.
The principal differential diagnosis of R-D disease in smears is a florid histiocytosis in an
otherwise reactive lymph node. Other much less common causes of lymphophagocytosis are:
Table 18. Causes of Lymphophagocytosis
| Sinus Histiocytosis|
| Rosai-Dorfman Disease|
| Virus Associated Hemophagocytosis Syndrome|
| Bacterial Associated Lymphadenitis|
A diagnostic pitfall is to misinterpret lymphocyte engulfment as D&L aggregates and
vice versa. The collections of engulfed cytoplasmic lymphocytes may be so numerous that the underlying
histiocyte nucleus is obscured and the diagnosis overlooked.In typical D&L aggregates lymphocytes
overlie and commingle with non-epithelioid histiocytes, but are not engulfed by them. One can be much more certain of lymphophagocytosis if a thin halo surrounds the engulfed
lymphocytes. Unlike TBMs there is no apoptosis by these engulfed lymphocytes.Unequivocal diagnosis
requires positive immunostaining of these unique histiocytes for S-100, and this can be performed
directly on smears. Recall however that dendritic cells are also S100 positive.
Another much less likely lesion that enters into the differential diagnosis is
Langerhans cell histiocytosis (LCH). While nuclei of R-D disease are
hypochromic, rounded and contain little if any indentation, those of LCH posses an irregular often
reniform border, lack nucleoli, commonly display linear grooves, and parenthetically contain no engulfed
lymphocytes in their cytoplasm. Since LCH cells are also S-100 positive, they may be a source of
confusion if one does not carefully examine the nuclear detail. Additionally, LCH cells are CD1a
positive while those of R-D disease are not.
References for All Cases