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PATHOLOGIC CHANGES IN SO-CALLED CAT-SCRATCH FEVER
REVIEW OF FINDINGS IN LYMPH NODES OF 29 PATIENTS AND CUTANEOUS
LESIONS OF 2 PATIENTS
THEODORE WINSHIP, M.D.
Department of Pathology, Garfield Memorial Hospital, Washington, D. C.
Cat-scratch disease is an infectious process characterized by fever, malaise
and regional lymphadenitis, usually associated with the scratch of a cat. Occasional cases have been reported in which inoculation was apparently by splinters, thorns or some other means. The etiologic agent has not been isolated, but
there is evidence suggesting that the disease is caused by a virus related to the
psittacosis-lymphogranuloma venereum group.
Mollaret and his associates11 described the transmission of cat-scratch disease
to a human volunteer and several monkeys by the intracutaneous inoculation
of an emulsion of an infected human lymph node. However, material from
necrotic nodes has been inoculated into eggs and a large variety of animals by
many routes without transmission of the disease. The cats apparently responsible
for the transmission of the disease were healthy, and they did not react to the
.intradermal injection of a cat-scratch antigen.
There is no reason to believe that cat-scratch disease is a new entity. In the
past, clinicians have confused it with bacterial lymphadenitis, tuberculosis,
infectious mononucleosis, tularemia, parotid tumor, sporotrichosis, lymphoma
and even chondrosarcoma. Pathologists have reported it as a nonspecific infection or have failed to differentiate it from similar granulomatous lesions such
as lymphopathia venereum, tularemia and sporotrichosis.
In 1932, Foshay, of Cincinnati, (cited by Daniels and MacMurray 2 ) was the
first to recognize the disease, encountering it in his studies of tularemia. In
1945, Hanger and Rose, of New York, (cited by Daniels and MacMurray 2 ) discovered that a skin-test antigen could be made from aspirated pus. Debre, 5
of Paris, found that patients suspected clinically of having the disease reacted to
this antigen and, in 1950, published the first report on cat-scratch disease. Greer
and Keefer,6 in 1951, reported the first case in America. In the same year, Daniels
and MacMurray 2 made a detailed study of 12 patients with cat-scratch disease
discovered in Washington, D. C , and recently they published an analysis of 60
cases, many of which were submitted by physicians throughout the country.3
Since 1950, more than 100 cases have been reported from France, Switzerland,
Belgium and this country. 1 , 9 ' 1 0 , 1 2 > 1 3 , 1 5 , 1 6 While most of the patients with this
disease have been white, it has also occurred in the black and yellow races. No
seasonal variation has been noted.
In the typical case there is an initial cutaneous lesion at the site of a cat scratch
Received for publication May 29, 1953.
Dr. Winship is Attending Pathologist.
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or other break in the skin. A primary lesion, consisting of a purple papule surmounted by a vesicle, pustule or crust, develops at the site of inoculation in approximately half of the patients. This is followed, usually in 2 to 3 weeks, by the
appearance of marked swelling and tenderness in the regional lymph nodes, without lymphangitis. The 3 common sites of adenopathy are the axillary and epitrochlear regions, the femoral and inguinal regions, and the cervical region. The
nodes may remain movable and nontender or they may become extremely painful, warm and fixed. Suppuration may or may not ensue, and the disease ma}' last
3 weeks to several months. There is usually fever, malaise and headache, but
occasionally there are no systemic manifestations. There may be a rash that
occurs early, lasts briefly, and is usually macular or papular. Most patients have
a short, mild illness, but in other cases a painful or suppurating lymph node may
persist for months. The recognition of cat-scratch disease assumed greater importance with Stevens'14 report of a patient with cat-scratch encephalitis. Since
then, several similar cases have been described.4
The following studies were made by Daniels and MacMurray on a number of
patients with negative results: agglutinations for Pasturella tularensis, Brucella
abortus and Streptobacillus moniliformis; serologic tests for syphilis; heterophile
antibody test; Frei test with Lygranum; Frei test with human pus; cultures of
pus aspirated from lymph nodes on ordinary mediums and on Sabouraud's
medium; cultures for tubercle bacilli, and cultures of nodes removed at biopsy
for pleuropneumonia-like organisms.
Every known type of therapy, including numerous antibiotics, has been used
in the treatment of cat-scratch disease. No form of therapy has been shown to
be of curative value, though Chloromycetin, aureomycin and terramycin,
when given early, may shorten the course of the disease and prevent suppuration.
The following case reports illustrated the clinical aspects of cat-scratch disease, and the accompanying histologic descriptions and photomicrographs show
the associated changes in the lymph nodes.
REPORT OF CASES
Case 1
A 56-year-old woman was scratched on her left wrist by her cat on November 1, 1950.
By November 20, 1950, she had developed tender, enlarged epitrochlear and axillary lymph
nodes. The white blood cell count was 8200, with 56 per cent polymorphonuclear leukocytes
and 34 per cent lymphocytes. She had noted no fever, malaise, chills or other symptoms.
Agglutinations with P. tularensis and S. moniliformis were negative, as was the complement-fixation test with Lygranum for the psittacosis-lymphogranuloma group of viruses.
The Frei test was negative.
An axillary lymph node was removed 40 days after the scratch, and microscopically it
revealed "lesions consistent with tularemia." Histologic examination showed numerous
enlarged hyperactive germinal centers occupying most of the nodal tissue, and only a small
portion of the peripheral sinus was filled with cells. In 1 area, the pericapsular tissue contained lymphocytes and a few neutrophils. Only 2 relatively small abscesses were present,
and neither had a full}' developed peripheral layer of epithelioid cells nor a dense outer
collar of lymphocytes (Fig. 1).
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AVINSHIP
On December 21, the patient was tested with cat-scratch antigen and within 48 hours
developed an area of erythema measuring 4.5 by 3 cm.
The patient has been followed to the present time and is well.
Case 2
Three days after having been scratched on the finger of the right hand by a cat, a 16year-old boy developed a small, crusted lesion at the site of injury. Approximately 3 weeks
later the right epitrochlear nodes became enlarged and tender. At this time the leukocyte
count was normal and there was no fever. Agglutination reactions for typhoid 0, typhoid
H, Salmonella paratyphi A and B, Proteus vulgaris OX 19, Brucella abortus and Pasteu.rella
tularensis were negative.
Fifty days after the scratch epitrochlear nodes were removed. Histologically, the nodes
contained numerous small abscesses characterized by central areas of necrosis and surrounded by a zone composed of epithelioid cells, lymphocytes and polymorphonuclear
neutrophils. Outside this was a dense collar of lymphocytes demarcating the lesion from
the normal lymphoid tissue. A few of the abscesses were elongated, due to coalescence. Scattered hyperplastic follicles were present, most of them in the periphery. The peripheral
sinuses were obliterated by lymphocytes, neutrophils and histiocytes, and the capsule and
pericapsular tissues were infiltrated heavily by similar cells (Fig. 2).
Approximately 3 months after removal of the node the patient was tested with cat-scratch
antigen and reacted positively. He has recovered fully.
Case 3
A 9-year-old boy was scratched on the right hand by a cat. Three weeks later he developed
general malaise and fever. The white blood cell count was 9600, with 35 per cent polymorphonuclear leukocytes and 52 per cent lymphocytes. The right axillary lymph nodes were
enlarged to form a mass 10 by 6 cm. He was treated with penicillin for 4 days, with no response. Following this, an axillary node was removed.
Microscopically, the center of the node was almost completely occupied by large, confluent, pus-filled cavities. Palisading zones of epithelioid cells containing scattered giant
cells were prominent in some areas. There were small peripheral germinal centers which
showed little activity. The capsule was thickened greatly and merged into the pericapsular
tissue, where several small abscesses were present (Fig. 3). Two weeks later, the patient
was tested with cat-scratch antigen and developed a positive reaction. Recovery was gradual but complete.
DISCUSSION
The following pathologic observations regarding cat-scratch disease are based
on the study of tissue from the cutaneous lesions of 2 patients and the involved
lymph nodes from 29 patients with the disease. Four of these patients were
treated at Garfield Memorial Hospital, 7 of the lymph nodes were received from
other hospitals in Washington, D. C , and the remaining cases were submitted
to Daniels and MacMurray from physicians throughout the country.
In only a few instances are sections of the primary skin lesion available for
microscopic study. The dermatologic changes present in cat-scratch disease
described by Hedinger and his associates7 are confirmed in 2 cases in this series.
In well-developed cases, there appears a superficial, circumscribed ulceration
with an underlying inflammatory process extending into the corium. There is a
generalized infiltration of the corium by lymphocytes and polymorphonuclear
leukocytes and a perivascular concentration of these cells. Plasma cells and
FIG. 1 (top). Small abscess in lymph node from Case 1, showingearly changes in a case of
so-called cat-scratch disease. Hematoxylin and eosin stain. X 110.
FIG. 2 (left lower). Well-developed abscess in lymph node from Case 2, showing central
necrotic area and palisading of epithelioid cells. Hematoxylin and eosin stain. X 120.
FIG. 3 (right lower). Large abscess in lymph node from Case 3, showing scattered fibroblasts in zone of epithelioid cells. Hematoxylin and eosin stain. X 110.
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eosinophils are prominent in the early stages of the infection. Histiocytes appear
in increasing numbers as the disease progresses, and giant cells of the foreign
body and Langhans types are seen adjacent to granulomatous areas.
Grossly, the lymph nodes are enlarged and soft and usually are densely adherent to adjacent nodes and to the surrounding tissues. On section, they may be
dark red and homogeneous or they may be necrotic, depending on the stage of
the disease. The initial histologic changes appear at the site of the entrance of
the afferent lymph vessels in the periphery of the node. One or more ill-defined
areas of reticulum-cell hyperplasia appear, associated with a localized infiltration of plasma cells and polymorphonuclear leukocytes. In these areas there soon
develop round or irregular abscesses in which the lymphocytes appear to have
been destroyed. They contain chiefly polymorphonuclear leukocytes and small
particles of debris. The reticulum-cell hyperplasia remains localized in some
instances, but the entire node is affected in other cases. Any follicles (germinal
centers) adjacent to the granulomas promptly enlarge and become very active.
The peripheral sinuses quickly fill with inflammatory cells, and by the time small
abscesses are developed the pericapsular tissue is involved in the inflammatory
process and occasionally abscesses form in the tissue surrounding the node.
Shortly after the development of the peripheral lesions, similar but usually larger
granulomas begin to form in the medullary portion of the node. Not until the
abscesses are well developed do the epithelioid cells become apparent. These
large, clear cells form a well-defined collar about the periphery of the abscess.
Frequently, the lymphoid cells immediately surrounding the epithelioid ring
appear more dense than those elsewhere in the node because of the heavy infiltration of plasma cells and polymorphonuclear leukocytes in that zone.
Giant cells were found in 25 of the 29 nodes examined. They were often in the
outer zone of the rim of epithelioid cells, but in some instances large, mononuclear
giant cells were scattered throughout the entire node, and in 1 case they were
found in the extracapsular tissue. The majority of giant cells were multinucleated
and similar to Langhans cells or foreign-body-giant cells. Many, however, simulated the Sternberg cells of Hodgkin's disease. Blood vessels were not damaged,
but in the pericapsular tissue they were surrounded frequently by inflammatory
cells. Vessels within the granulomas were usually completely destroyed, but those
unrelated to the granulomas remained intact and did not show the endarteritis
that is said to accompany tularemia.
Wilder stains show the usual distribution of reticulum in the node except in
well-developed abscesses where it is minimal or absent. No organisms are demonstrated by the use of acid-fast, gram or periodic acid-Schiff stains. Hyaline material similar to that found in tuberculosis was absent in this series. The process
of healing may be demonstrated by the use of Masson stains. After the abscesses
have been present from 4 to 8 weeks, fibroblasts appear in the layer of epithelioid
cells surrounding the abscesses in the lymph nodes. A solid ring of fibrous tissue
results, encroaching on the abscess cavities and eventually producing a solid
fibrous scar.
Giemsa stains show numerous, large, usually elongated macrophages containing
PATHOLOGY OF CAT-SCRATCH DISEASE
10.17
purple inclusion bodies, which are very small and may fill the cell nucleus and the
cytoplasm. Mollaret and his associates11 considered the intracellular inclusion
granules which are present in all cases of cat-scratch disease to be of value in
establishing the diagnosis but others are skeptical of any such specificity. Because of these different opinions, a careful search was made of Giemsa-stained
sections of lesions from proved cases of bacterial adenitis, tuberculosis, tularemia,
lymphopathia venereum and sporotrichosis. Small intracellular inclusion bodies
were found in the slides from each disease. Thus it appears that the presence of
inclusion granules in the lymph nodes of patients with cat-scratch disease is of
no diagnostic significance.
In this series of cases, the enlargement of the regional lymph nodes occurred
4 to 30 days after the initial inoculation. I t was found that nodes involved clinically for only 7 days sometimes could not be distinguished histologically from
nodes enlarged for 40 days. In 1 case, lymph nodes received after 2 ! days of enlargement were identical histologically with those from the same patient after
3.1 days, except for the slightly increased size of the abscesses in the latter nodes.
Whether these findings were due to differences in the virulence of the infecting organism or to the differences in the resistance of the host, could not be determined.
Antigen for the skin test may be prepared,2 according to the method devised
by Hanger and Rose, using pus aspirated from a suppurating lymph node in a
patient with known cat-scratch disease. The material is diluted 1 part to 5 parts
with isotonic sodium chloride solution and heated at 56 C. for 1 hour on 2 successive days. The intradermal test is performed by injecting 0.1 ml. of the material and is read in 48 hours. A positive reaction is similar to a tuberculin
reaction. It consists of a papule 0.5 to .1.0 cm. in diameter, surrounded by an
erythematous area 3 to 5 cm. in diameter.
Additional laboratory procedures are helpful in establishing a diagnosis of
cat-scratch disease if antigen for skin testing is not available. Nonspecific lymphadenitis can be excluded by the absence of bacteria in cultures. Cultures of aspirated pus from the lesions of cat-scratch disease will not grow tubercle bacilli,
and stains for tubercle bacilli are negative. The caseous material present in
tuberculous lymph nodes is not seen in the histologic section of lymph nodes of
cat-scratch disease. The Hotchkiss-McManus stain may be helpful in distinguishing between sporotrichosis and cat-scratch disease.s Lymphopathia venereum can be excluded by the use of the Frei test. A negative agglutination for
Pasturella lularensis will eliminate the possibility of tularemia.
SUMMARY
So-called cat-scratch disease is an infectious process probably caused by a
virus which is introduced, in most cases, by the scratch of a cat.
The disease appears to have no significant geographic, racial or seasonal incidence.
A well-developed lesion characteristically consists of multiple abscesses composed of necrotic centers surrounded by a zone of epithelioid cells and scattered
giant cells.
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The histologic appearance of the skin lesions and lymph nodes, while not
pathognomonic, is suggestive of cat-scratch disease but may be mistaken for
tularemia, lymphopathia venereum or sporotrichosis.
Acknowledgment. I wish to express my gratitude to Dr. Worth B. Daniels and Dr. Frank
G. MacMurray for the opportunity of studying the pathologic material from their large
series of cases and to the physicians throughout the country who contributed the tissue
studied. I am grateful to Dr. Worth B. Daniels, Jr., for the pathologic data on 4 cases. I
wish to thank Dr. Hugh Grady of the Armed Forces Institute of Pathology for the slides
from cases of tularemia, lymphopathia venereum and sporotrichosis. I am indebted to
Mr. John T. McCawley for the photomicrographs.
REFERENCES
1. BENNETT, I. L., JR., AND MELTON, J. T.: Cat scratch disease. J.M.A. Georgia, 40: 466469, 1951.
2. DANIELS, W. B., AND MACMURRAY, F. G.: Cat-scratch disease. Arch. Int. Med., 88:
736-751, 1951.
3. DANIELS, W. B., AND MACMURRAY, F. G.: Cat scratch disease; nonbacterial regional
lymphadenitis; report of 60 cases. Ann. Int. Med., 37: 697-713, 1952.
4. DEBRE, R.: Accidents nerveux de la maladie des griffes du chat. Bull. Acad. nut. m&L,
24-26: 454, 1952.
5. DEBRE, R., LAMY, M., JAMMET, M. L., COSTIL, L., AND MOZZICONACCI, P.: La maladie
des griffes de chat. Bull, et mem. Soc. med. d. hop. de Paris, 66: 76-79, 1950.
6. GREER, W. E. R., ANDKEEFER, C. F.: Cat-scratch fever; disease entitv. New England J.
Med., 244: 545-548, 1951.
7. HEDINGER, VON C , USTERI, C , WEGMANN, T., AND WORTMANN, F.: Der kutane Pri-
maraffekt der sogenannten Katzenkratzkrankheit, einer benignen Viruslymphadenitis. Dermatologica, 104:101-107, 1952.
8. KLIGMAN, A. M., MESCON, H., AND DELAMATER, E. D.: The Hotchkiss-McManus stain
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9. LANGE, H. L.: Cat scratch fever, a report of 3 cases. J. Pediat., 39: 431-435, 1951.
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sarcoma of the neck. Am. J. Surg., 84: 483-485, 1952.
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lymphoreticulose benigne d'inoculation. Presse med., 59: 681-682, 1951.
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14. STEVENS, H.: Cat scratch fever encephalitis. Am. J. Dis. Child., 84: 218-222, 1952.
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