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Review Article
Granulomatous Lymphadenitis
Shigeyuki Asano
In this review, representative types of granulomatous lymphadenitis (GLA) are described. GLA can be classified as
noninfectious GLA and infectious GLA. Noninfectious GLA includes sarcoidosis and sarcoid-like reaction. The cause of
sarcoidosis remains unknown, but it has good prognosis. Sarcoid-like reaction, which is considered to be a biological defense
mechanism, is observed in regional lymph nodes with many underlying diseases. Infectious GLA can be classified as suppura-
tive lymphadenitis (LA) and nonsuppurative LA. Suppurative LA generally shows follicular hyperplasia and sinus histiocytosis
in the early phase. In tularemia and cat scratch disease, monocytoid B lymphocytes (MBLs) with T cells and macrophages
contribute to the formation of granuloma. However, none of the epithelioid cell granulomas of Yersinia LA contains MBLs like
in cat scratch disease. In addition, almost all have a central abscess in granulomas induced by Gram-negative bacteria. In terms
of the lymph nodes, tularemia and cat scratch disease are apt to affect the axillary and cervical regions while Yersinia LA affects
the mesenteric lymph node. Nonsuppurative LA includes tuberculosis and BCG-histiocytosis. These are induced by delayed
allergic reaction of M. tuberculosis. Tuberculosis LA mainly appears in the cervical lymph node. Organisms are histologically
detected by Ziehl-Neelsen staining in the necrotic area. Toxoplasmosis is also a nonsuppurative protozoan infection
(Toxoplasma gondii). In toxoplasma LA, MBLs can also be seen, but round and organized, well-formed granulomas are not
found in this disease. Furthermore, necrosis is not induced and there are no accompanying neutrophils, eosinophils and fibrosis.
GLA described above is associated with characteristic histological findings. An accurate pathological diagnosis using the above
findings can lead to precise treatment. 〔J Clin Exp Hematopathol 52(1) : 1-16, 2012〕
1a 1b
1c 1d
Fig. 1. Sarcoidosis lymphadenitis. (1a) Chest X-p shows bilateral hilar lymph node swel-
ling. (1b) Lymph node is occupied by numerous granulomas that have not coalesced with
each other. There are many plasma cells around each granuloma. (1c) Granuloma is com-
posed of epithelioid cells and multinucleated giant cells. (1d) Asteroid body is observed in
the cytoplasm of multinucleated giant cell.
3a 3b
3c 3d
3e 3f
Fig. 3. Tularemia lymphadenitis. (3a) Variously sized granulomas at the ulcer base
of finger skin (14 days after infection). (3b) Immunostaining of skin lesion. F. tularen-
sis antigens are detected mainly in abscess and necrotic area (14 days after infection)
(anti-F. tularensis antibody). (3c) Markedly swollen axillary lymph node on a cut
section. (3d) Abscess form (12 days after infection). Abscess and necrosis lesion
without epithelioid granuloma in lymph node. Inset : F. tularensis antigens are de-
tected mainly in abscess and necrotic area. (3e) Abscess granulomatous form. Central
abscess and necrosis lesions are surrounded by thickened epithelioid cells. These
granulomas are apt to fuse with each other (27 days after infection). (3f)
Granulomatous form. Large granuloma with central homogenized necrosis and with
radiative pattern of epithelioid cells (81 days after infection).
nail of the cat invade the human skin via the scratch or bite
wound. The annual incidence of CSD has been estimated at have a high titer of seropositivity for Rochalimaea henselae,
9.3 cases per 100,000 people per year in the United States, as in AIDS patients, but low titer for Afipia felis.40 After
although there are no national statistics for Japan.38 genotypic evaluation, the nomenclature, R. henselae, was re-
placed by B. henselae, which was identified as the causative
bacterium.41
History
Parinaud first described only a small subset of CSD ;
Clinical Findings
subsequently, Greer and Keefer published the first report on
CSD in the American literature, in which they described a Erythema (20 to 50%), papules, blisters (vesicular) and
broad spectrum of CSD manifestations.39 Patients with CSD abscess are observed at the injury site within three to ten days
4a 4b
4d
4c
Fig. 4. Cat scratch lymphadenitis. (4a) Follicular hyperplasia and sinus mononucleosis, such
as of immunoblasts, histiocytes and macrophages in the early phase. (4b) Sinus mononucleo-
sis in distended subcapsular sinus. (4c) Imprint feature in the early phase. Many histiocytes,
macrophages and monocytoid B lymphocytes are observed (Giemsa staining). (4d) Large
epithelioid cell granuloma with central abscess and necrosis.
after onset or in the very early lesions.43,50,51 vomiting and fever (38~39℃) with flu-like symptoms, which
Immunohistochemical staining with antibodies to B. hen- are somewhat correlated with patient age. Thereafter, diar-
selae in formalin-fixed paraffin-embedded tissue sections can rhea is likely to develop in infants, but terminal ileitis, appen-
specifically identify the bacillus of CSD.44,52 In addition, dicitis and mesenteric lymphadenitis occur in children and
rapid assay for the detection of B. henselae in formalin-fixed youths.58,59 Given the abdominal findings described above,
paraffin-embedded lymph nodes and aspirated pus from these cases are often diagnosed as appendicitis, mesenteric
lymph nodes is available by PCR.43,45,46 lymphadenitis and terminal ileitis. Other symptoms such as
arthritis, erythema nodosum, sepsis, Reiter’s syndrome, men-
ingitis and cutaneous lesions appear in older patients.58,59 On
3) Late phase (granulomatous abscess)
the other hand, Y. pseud. infection is seen in infants and has
In the late phase, coalescence of stellate microabscesses symptoms similar to those of Y. ent. infection. The patients
leads to formation of an irregularly shaped large abscess are younger than those with appendicitis. The diagnosis is
(geographic abscess) (Fig. 4d). Furthermore, the capsule of made by culture of stool, blood, vomit, resected appendix and
lymph node often shows fibrosis or marked inflammation. lymph node. Furthermore, diagnosis also requires serum anti-
The detection rate of bacteria becomes lower than that in the body titer. Therapy is usually not necessary, but tetracycline
previous phase. is useful, and amikacin, chloramphenicol and gentacin are
also effective.61
YERSINIA LYMPHADENITIS (MESENTERIC
LYMPHADENITIS) Histopathology of Lymph Nodes
Bacteria of the genus Yersinia are not detected in normal
1) Lymph nodes
human gut flora, but Yersinia enterocolitica (Y. ent.) and
Yersinia pseudotuberculosis (Y. pseud.), which are Gram- Yersinia lymphadenitis is caused by the bacteria Y. ent.
negative small bacilli, are important human pathogens. and Y. pseud.53 In this disease, lymph nodes of the ileocecal
The disease Yersinia lymphadenitis is characterized by region are often enlarged up to 1.5 cm in size. They do not
acute febrile gastroenteritis, with symptoms that mimic ap- coalesce with each other and show an elastic-soft appearance
pendicitis, and occurs predominantly in infants, children and without distinctive necrosis on cut sections.62
youths. The route of infection is orally, involving infected In the early phase of lymphadenopathy by Y. ent., lympho-
meat, drinking water or other food.53 cytes, immunoblasts and plasma cells are packed within di-
Yersinia bacteria arrive at the mesenteric lymph nodes via lated sinuses. In addition, hyperplastic follicles are often
lymphatic vessels of the intestine after ingestion of infected observed in cortex and paracortex with increases in the cells
material, and form the characteristic lesion. The lymph node described above. These findings coincide with nonspecific
enlarges due to an inflammatory process, resulting in abdomi- reactions.
nal pain. In progression and later phases, thickened edematous cap-
In this disease, there are no specific findings except for sule occasionally contains lymphocytes, immunoblasts and
swelling of mesenteric lymph nodes, even though acute ap- plasma cells. In addition, the same kinds of cells are ob-
pendicitis or terminal ileitis can be shown. served in extended sinuses (Fig. 5a, 5b). Later, many epithe-
lioid cell granulomas (EPGs) emerge in the germinal centers
and they are predominantly nonsuppurative (Fig. 5c, 5d).63
History
Some EPGs show suppuration of the centers of granulomas
This group of bacteria was described under different (central microabscesses) (Fig. 5e). These lesions eventually
names, such as Bacterium enterocoliticum,54 Pasteurella X55 enlarge to form round microabscesses, but no giant cells.
and germe X,56 from 1939 to the early 1960s. The first Y. ent. EPGs are composed of histiocytes with or without epithelioid
infections in humans were described in 194957 as infections cell features along with scattered small T lymphocytes and
with Pasteurella pseudotuberculosis. Since then, there have plasmacytoid monocytes.64 EPGs of this type of lymphadeni-
been many reports on Y. ent. infection in Western Europe and tis do not contain MBLs like in cat scratch disease and lym-
the United States.58-60 phogranuloma venereum.65 Gram-negative acid-fast diplo-
bacilli may be identified in the lesions.53,58,59,62,66
On the other hand, lymphadenopathy induced by Y. pseud.
Clinical Findings
is quite similar to that of Y. ent. infection in the initial phase.53
The incubation period is 24 to 48 hours after the onset of In the progression phase, Y. pseud.-infected lymph nodes
ingestion. The most common symptoms of Y. ent. infection show massive neutrophil infiltration, and later, there are scat-
are diarrhea (80%), lower right quadrant pain (50%), nausea, tered microabscess lesions with central pus formation sur-
5c 5d
5e
Fig. 5. Yersinia lymphadenitis. (5a & 5b) Edematous thickening capsule (C) and markedly
dilated subcapsular sinuses (SS) contain innumerable lymphocytes, immunoblasts and plasma
cells. (5c) Many epithelioid cell granulomas appear in the germinal centers and are predomi-
nantly nonsuppurative. (5d) Enlargement of granuloma with nonsuppurative lesion. (5e)
Granuloma with microabscess formation.
rounded by plump histiocytes (suppurative granulomas) iden- gional lymph nodes show typical EPGs.
tical to those seen in cat scratch disease,53,58,66,67 a feature that
is rare with Y. ent.
TUBERCULOUS LYMPHADENITIS
Tuberculosis is a chronic airborne infectious disease in-
2) Appendix and terminal ileum
duced by M. tuberculosis. In Japan recently, tuberculosis has
In this disease, the wall of the appendix is thickened and been ranked as only the 20th most common cause of mortal-
the mucosa is edematous. Appendical lesions contain trans- ity, so it has been relatively ignored. However, cases are still
mural, mixed inflammatory infiltrates with numerous lym- conspicuous and outbreaks are occasionally reported. The
phoid follicles and EPGs. EPGs are predominantly non- major problem for tuberculosis is the severity of illness in
suppurative. In addition, they are usually surrounded by association with the global spread of AIDS. Tuberculosis has
small T lymphocytes and plasmacytoid monocytes. EPGs do become remarkable as a reemerging infectious disease not
not contain MBLs like regional lymph nodes.64 However, only in developing countries but worldwide.68,69
some cases show mild hemorrhage and catarrh, although re-
6a 6b
6c
Fig. 6. Tuberculous lymphadenitis. (6a) Many granulomas fuse, resulting in large irregular
nodules with central coagulation necrosis. (6b) Langhans giant cells in epithelioid granuloma.
(6c) Ziehl-Neelsen staining shows rod-shaped M. tuberculosis.
10
In the early phase of tuberculous lymphadenitis, the must be surgically resected, but follow up is necessary for
lymph node shows elastic hard tumor like nonspecific lym- those smaller than 3 cm.
phadenitis. Inflammatory cells gradually infiltrate and peri- In children with congenital immune deficiencies82 and in
adenitis appears over time. patients with HIV infection and AIDS, suppurative lymphade-
After the formation of abscesses in the lymph node, they nitis and tuberculosis sometimes develop.80
enlarge and gradually change to caseous necrosis and soften.
The histology of tuberculous lymphadenitis is characterized
Histopathology of Lymph Nodes83
by central caseous necrosis surrounded by epithelioid cell
layer and sporadic Langhans giant cells (Fig. 6a, 6b). In BCG-lymphadenopathy is usually smaller than tubercu-
addition, in the outermost layer can be seen lymphocytes and lous lymphadenopathy. Follicular hyperplasia and sinus his-
fibroblasts, but no plasma cells are observed. This node is tiocytes are observed as in nonspecific lymphadenitis in the
called tuberculous nodule, type IV allergic reactions against early phase. Later, micronodules of epithelioid granulomas
M. tuberculosis. Tuberculous lymphadenitis is distinguished without necrosis and epithelioid cell granuloma with central
from sarcoidosis lymphadenitis by the presence of central coagulation necrosis are observed (Fig. 7a, 7b). Langhans
caseous necrosis. giant cells rarely appear.
In this phase, Ziehl-Neelsen staining occasionally shows
short rod-shaped bacteria (M. tuberculosis) in the coagulation
TOXOPLASMA LYMPHADENITIS (PIRINGER-
necrosis (Fig. 6c). Organisms are now most easily detected
KUCHINKA LYMPHADENITIS)
by PCR. Finally, healing occurs with calcification.76
Toxoplasmosis is a common zoonosis caused by
Toxoplasma gondii ; it is found worldwide, and is prevalent
BCG-LYMPHADENITIS (BCG-HISTIOCYTOSIS)
in warm and humid climates, but infrequent in cold and dry
Immunization of BCG (Bacillus Calmette-Guérin) vac- areas.84
cine, as an immunostimulant, is very useful for preventing the
dissemination of Mycobacterium tuberculosis from the pri-
mary complex. BCG is conventionally re-injected for
tuberculin-test-negative patients, but according to the revision
of the Tuberculosis Prevention Law, from 2005, infants under
6 months should be immunized only once without tuberculin
test. BCG is a version of Mycobacterium bovis with attenu-
ated virulence, and is the weakest strain globally. After vac-
cination of BCG, the bacillus moves to regional lymph node
and arrives at systemic organs within several hours.
Although tuberculous lesions in systemic organs such as re- 7a
gional lymph nodes, liver and spleen can appear, there may be
spontaneous healing without specific lesions.77,78 Redness
and suppuration at the inoculation site within ten days of
vaccination may indicate tuberculosis infection. About three
months later, the lesion heals with desquamation, crusting and
scar.
Clinical Findings
The side effects of BCG-vaccination can include localized
ulcer, abscess formation and regional lymph node enlarge- 7b
ment. In terms of the lymph nodes, they are usually affected
in axillary and cervical regions and swell up to two to three Fig. 7. BCG-lymphadenitis. (7a)
cm in size. Side effects are observed more frequently in cases Epithelioid cell granulomas with central co-
of intradermal vaccination than percutaneous one.79 agulation necrosis are observed. (7b) Old
The incidence of side effects is 0.73 to 2.2% in vaccinated granuloma with central liquefaction necrosis.
children. Younger children are more susceptible to infection,
and lymphadenopathy occurs from one week to 9 months
after vaccination.80,81 BCG lymphadenopathy of over 3 cm
11
8a 8b
8c 8d
Fig. 8. Toxoplasma lymphadenitis (Piringer-Kuchinka lymphadenopathy). (8a) The charac-
teristic features such as reactive follicular hyperplasia, cluster of epithelioid cells and patches
of monocytoid B lymphocyte (MBL) proliferation are seen in lymph node. (8b) Enlarged
follicles with reactive germinal centers include increased centroblasts, mitosis and macro-
phages containing tingible bodies. (8c) Imprint smear shows MBLs with clear cytoplasm and
darkly stained nuclei are observed (Giemsa staining). (8d) Mononuclear cells, macrophages
and elongated epithelioid cells are observed by imprint smear (Giemsa staining).
12
13
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