ISRAEL JOURNAL OF
VETERINARY MEDICINE
VOLUME
54 (3) 1999
JUVENILE MEDIASTINAL LYMPHOMA
A. Kopla and I. Aizenberg
Koret School of Veterinary Medicine, The Hebrew University, Jerusalem
Summary
A 12-month-old, female Weimaraner dog was presented with clinical signs of
regurgitation, polydipsia, polyuria and dyspnea. Laboratory findings showed
hypercalcemia and azotemia. Thoracic radiographs and ultrasound showed enlarged
mediastinal lymph nodes. Cytology of the mediastinal lymph node aspiration sample
was positive for lymphoma.
Introduction
Lymphoma, the most common cancer of the canine haemolymphatic system,
accounts for 5-7% of all canine cancer. (1).
The annual incidence rate for canine lymphoma has been estimated at 6 to
24/100000 population (2, 3). Tumors occur predominately in middle-aged dogs
although young and old dogs may be affected (3). The mean age of dogs with
lymphoma has been variably reported from 5.5 to 9.08 years (3,4,5,6). The annual
incidence rate at specific ages ranges from less than 1.5/100000 in the 0-to-1-year-old
group to over 84/100000 in the 10-to-11-year-old group (2, 3). Though no sex
predilection has been noted, some reports suggest a slightly lower incidence in spayed
females (7). Many breeds have been reported to be at increased risk, but this has been
confirmed for the Boxer and BullMastiff only (8,9).
Four anatomical forms of lymphoma have been recognized; in order of decreasing
incidence these are, multicentric (85% of cases), alimentary (7%), extranodal (6%)
and mediastinal (2%) (10).
The mediastinal form is characterized by enlargement of the cranial mediastinal
lymph nodes and is usually accompanied by pleural effusion (11). Clinical signs due
to mediastinal lymphoma include coughing, dyspnea, orthopnea, dysphagia and
regurgitation (11). In some dogs, constriction of the esophagus at the thoracic inlet or
in the anterior mediastinum may lead to megaesophagus (11).
Another classification of canine lymphoma is the clinical staging as proposed by
the World Health Organization (table 1) (12).
Table 1. Clinical stages of canine lymphoma (12)
Stage I – Involvement limited to a single lymph node, or lymphoid tissue in a single organ (excluding
bone marrow).
Stage II – Involvement of many lymph nodes in regional area ( tonsils).
Stage III – Generalized lymph node involvement.
Stage IV – Liver and/or spleen involvement (±stage III).
Stage V – Manifestations in the blood and involvement of bone marrow and/or other organ systems
(±stages I-IV).
Clinical staging establishes a uniform classification system for the extent of disease
at the time of diagnosis and also enables the clinician to give an accurate prognosis.
Lymphoid tumors can also be classified by immunologic surface markers (11, 19, 20).
Tumors are either of B-or T-cell origin. Cells lacking characteristic surface markers
for B-or T-cell are referred to as null cells.
If untreated, lymphoma is rapidly fatal (16). Chemotherapy is the most effective
treatment for lymphoma. No single drug or drug combination has been found to cure
the disease, but significant remissions have been attained with chemotherapy (16).
Combination chemotherapy is generally more effective than single-agent therapy (16).
The most widely used combination is the "COP" protocol, consisting of
cyclophosphamide, vincristine and prednisone (16).
Several factors are predictive in the response of lymphoma to treatment, including
the clinical stage at the time of diagnosis, the anatomic type, the clinical signs and the
animal's weight (13).
Case report
A 12-month-old, intact female Weimaraner dog was presented at the Koret School
of Veterinary medicine Hebrew University of Jerusalem, with an eleven-day history
of regurgitation, anorexia, polydipsia and polyuria. Antibiotics, antiemetics and
intravenous fluids had been administered by the referring veterinarian, with partial
improvement in clinical signs. A week later, the dog was still anorexic but stopped
regurgitating. A day before referral, the dog started to cough and on the following day
became dyspneic.
Past history - vaccinated (one rabies vaccine, three DHLP+Pv vaccines),
dewormed, eats commercial food and leftovers, lives indoor, walks out only with a
lead, healthy until now.
On physical examination - Temperature-380C, Pulse-80/min, Respiration rate36/min, Weight-24 Kg, cachexia, depression, pale mucous membranes and dyspnea.
Auscultation of the thorax revealed bilateral crackles, mostly on the right side.
Complete blood cell (CBC) count findings were in the normal range (table 2).
Serum biochemistry profile showed: severe hypercalcemia, moderate
hyperphosphatemia, azotemia and a moderately elevated ALP value (table 3).
Table 2 - Haemogram findings on the day of arrival and after one week of treatment.
Table 3 - Biochemistry findings on the day of arrival and after one week of treatment .
Thoracic survey radiographs showed (figure 1) big soft tissue masses in the cranial
mediastinum that pressed the trachea dorsally and a large mass above the base of the
heart compatible with the cranial lymph node.
Figure 1 - Thoracic right lateral survey radiograph at the day of arrival, showing radiodense cranial
mediastinal masses pressing the trachea dorsally and undefined cardiac silhouelte.
Barium contrast esophogram was done by giving barium paste to the dog. On this
radiograph (figure 2) the esophagus is pressed dorsally by the mass. The radiological
diagnosis was a mediastinal mass.
Figure 2 - Barium contrast esophogram, right lateral view, at the day of arrival, showing the
esophagus pressed dorsally by the mediastinal masses and especially by the mass above the base of the
heart, which is compatible with the cranial lymph node.
For descriptive purposes, the mediastinum is divided in to several regions (11).
Since each region contains anatomic-structures which are unique, the anatomic
subdivision can help us determine the lesions. In this case the mass was present in the
cranioventral region of the mediastinum. The differential diagnosis of mediastinal
masses based on radiographic signs has been reviewed in detail (24,25). Since the
anatomic location of the mediastinal masses is compatible with the location of the
mediastinal lymph nodes, the masses were suspected to be enlarged lymph nodes.
Further diagnostic procedures were done in order to make a conclusive diagnosis.
On thoracic ultrasound, echogenic masses were imaged in the cranial mediastinum
(Figure 3). The masses were suspected as enlarged and non-homogenic lymph nodes.
Ultrasound guided fine needle aspiration samples were taken from the mediastinal
masses and were submitted for cytology.
Figure 3 - Thoracic ultrasound at the day of arrival, showing mediastinal masses around the aorta
(AO).
On cytology, the predominant finding was a monomorphic population of medium
sized (2-3 RBC’s in size) lymphocytes with high nucleus:cytoplasm ratio and no
apparent nucleoli. Intact cells had granular to fenestrated nuclear chromatin pattern. A
few lymphocytes had idented nuclei. The cytoplasm stained basophilic and often
contained a clear zone, compatible with Golgi zone. There were many
lymphoglandular bodies, occasional mitotic figures, few eosinophils and rare
neutrophils. No plasma cells and no small well-differentiated lymphocytes were
present. The cytology diagnosis was lymphoma (the distinction between hyperplasia
and neoplasia is based on findings of predominantly medium and large cells of a
monomorphic population), likely B-cell (based on findings of the Golgi zone and
lymphoglandular bodies), although the distinction between the type of lymphocyte
involved is strictly with markers for histological evaluation.
Based on clinical description, radiographs, ultrasound and cytology results, the
diagnosis was mediastinal lymphoma.
Treatment - a day later, the dog started treatment according to the "COP" protocol:
1. Vincristine - 0.75 mg/m2 IV once a week.
2. Cyclophosphamide - 200 mg/m2 PO SID four days a week.
3. Prednisone - 30 mg PO SID for a week.
A week after the treatment started, the dog came for a checkout. The owner
reported anorexia, depression, weakness, regurgitation twice during the week and
breathing improvement. On physical examination - Weight-19.4 Kg (4.6 Kg weight
loss in 10 days), pale and dry mucous membranes. Blood samples were taken for CBC
and biochemistry, CBC findings were normal (table 2). Biochemistry findings showed
(table 3) : calcium total value returned to normal, severe azotemia and
hyperphosphatemia, severe elevated ALP, moderately elevated liver enzymes (ALT,
AST), hyperbilirubinemia, severely elevated muscles enzymes (LDH, CPK) and
moderate hyperlipidemia (elevated cholesterol and triglyceride). Urinalysis findings
showed (table 4) hematuria and proteinuria.
Table 4 - Urinalysis findings
Urine sample was taken by cystocentesis.
Thoracic radiographs were done again (Fig. 4) and showed that most of the masses
disappeared and the trachea was not elevated and almost in the normal position.
Figure 4 - Thoracic right lateral survey radiograph after a week of treatment, showing disappearance of
most of the mediastinal masses.
Thoracic U/S was done again and showed that most of the enlarged mediastinal
lymph nodes had disappeared, although an enlarged mediastinal lymph node (2.8 cm
diameter) could still be imaged. Abdominal U/S showed enlarged and diffuse
echogenickidneys. Other abdominal organs were normal. The dog was treated with 1
liter LRS IV and 0.75 mg/m2 vincristine IV.
The dog was sent home with the same treatment protocol. A week later the dog died
at home. The owners refused necropsy.
Discussion
The results of the complete blood count are usually not diagnostic for lymphoma
(11). The total leukocyte count is generally in the high normal range with a left shift
and a moderate monocytosis (11). The erythron is normal or there may be a mild to
moderate depression anemia (11). Thrombocytopenia may be observed in 50% of the
cases (11).
Serum biochemistry profile at the day of arrival showed severe hypercalcemia,
moderate hyperphosphatemia and azotemia. Hypercalcemia may complicate
lymphoma in approximately 10% of the cases. (11). Signs associated with
hypercalcemia include polydipsia, polyuria and muscle weakness, as in this case (11).
Hypercalcemia is caused by the production of physiologically active substances
associated with the tumor; these stimulate bone resorption (11). This is also the
explanation for the moderate hyperphosphatemia. High concentrations of intrarenal
calcium cause direct effects on renal tubular function and haemodynamics, and also
have an indirect effect, by the presence of renotropic factors that interact specifically
with the parathyroid hormone receptor in the kidney (18). The hypercalcemic
nephropathy is the explanation for the azotemia in this case. The serum chemistry
profile also showed moderatly elevated ALP, which is probably the result of bone
resorption or bone growth in young animals.
After a week of treatment, multiple abnormalities were found in the serum
biochemistry profile. Calcium total value returned to normal, probably as a result of
effective treatment which destroyed tumor cells. Hypercalcemic nephropathy and
reduced glomerular filtration rate can explain the severe azotemia and
hyperphosphatemia. Elevated ALP and liver enzymes (ALT, AST) values can be
explained by glucocorticoid therapy or by liver lymphoid infiltration.
Hyperbilirubinemia can be the result of hepatobiliary metastases. Muscle damage due
to anorexia and severe cachexia, can explain the elevation in AST, CPK and LDH
values. Hyperlipidemia is probably the result of anorexia.
Urinalysis results showed hematuria and proteinuria. This is probably related to the
use of cyclophosphamide, which causes irritation and sterile hemorrhagic cystitis
(16).
Clinical staging of this case of lymphoma is complicated by the lack of bone
marrow specimens. Since immunologic surface markers were not checked, it cannot
be decided whether this case was a B-cell lymphoma, although the cytology findings
were characteristic. According to the literature, the multicentric and alimentary forms
account for most lymphoid neoplasia and appear to be predominantly of B-cell origin,
while mediastinal and cutaneous lymphomas are primarily tumors of malignant Tcells. (19, 20).
After a week of treatment, thoracic x-ray and ultrasound showed a great decrease in
the size of the mediastinal lymph node, yet a week later the dog died. The death can
be due to lack of specificity of drugs utilized (although the decrease in the size of the
tumors does not support this assumption), development of resistance by the cancer
cells, drug toxicity and immunosuppression induced by the chemotherapeutic agents
(22). Cyclophosphamide, prednisone and vincristine have variable potencies as
immunosuppressive agents, vincristine being the weakest of the three (23). Studies on
the antibody response of dogs given cyclophosphamide, prednisone and vincristine at
doses approximated those which were used in the present study, revealed no
significant effect on humoral antibody production, although a suppressive effect on
cell-mediated immunity cannot be excluded (23). Immunosuppression can lead to
leukopenia, bacterial septicemia and septic shock. In a prospective study that was
conducted on 100 naturally occurring canine lymphomas, it was found that bacterial
sepsis and drug toxicity were the main causes of death (14). The development of
septic shock follows the triggering of three main mechanisms: host cell activation,
multiple organ failure and release of secondary mediators. Tumor necrotizing factor
(TNF) is one of the most potent pro-inflammatory agents that are generated during
bacterial sepsis. A massive release of TNF can cause necrosis of tumor cells and
systemic effects such as fever, synthesis of acute-phase proteins, intravascular
coagulation and suppression of hematopoiesis (21).
In the prospective study that was mentioned above, it was found that among many
chemotherapy regimens, the highest percent remissions (79%) and the longest mean
remission durations (184 days) were achieved with combined vincristinecyclophosphamide-prednisone therapy, regardless of clinical stage or cell type (14). In
this case, remission was not achieved but the treatment led to a decrease in the size of
tumors.
Mediastinal lymphoma is the least common form of canine lymphoma, which occur
mainly in middle-aged dogs. This case is a rare of lymphoma, which demonstrates
mediastinal lymphoma in a very young dog with typical clinical signs and diagnostic
procedures.
Acknowledgements
We wish to thank Dr. Ana Maria Anug PathoVet, Diagnostic Veterinary Pathology
Services, for reading the cytology results.
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