Pulmonary Lymphomatoid Granulomatosis in Seven Dogs (1976-1 987) Clifford R. Berry, DVM, Peter F. Moore, BvSc, PhD, William P. Thomas, DVM, David Sisson, DVM, and Philip D. Koblik, DVM, MS
Seven dogs with pulmonary lymphomatoid granulomatosis were reviewed. The disease occurred in six large-breed and one small-breed dogs. The dogs were five to 14 years old (mean, 8.4; median, 7), and four of seven dogs were males. Three dogs had been previously treated with adulticide therapy for canine dirofilariasis. Clinical histories included a progressive respiratory disease characterized by varying degrees of cough, dyspnea, exercise intolerance, and weight loss. Thoracic radiographic features included hilar lymphadenopathy, pulmonary masses of varying sizes, and mixed pulmonary patterns of lobar consolidation with ill-defined interstitial and alveolar pulmonary infiltrates. Cardiovascular changes compatible with chronic dirofilariasis were present in three dogs. The clinical course was usually progressive and fatal. The survival time ranged from six days to four years (mean, 12.5 mos; median, 3 mos). Gross and histologic features included mass lesions with areas of necrosis that replaced normal pulmonary architecture. Cytologically, these lesions were characterized by infiltration with pleomorphic, angioinvasive mononuclear cells that often resulted in vascular obliteration. The infiltrating cells resembled large lymphoid cells that possessed large hyperchromatic nuclei and small amounts of cytoplasm. Systemic lymphoid neoplasia with peripheral lymphadenopathy was diagnosed in two dogs. In both cases, lymph-node cytology was similar to the cellular infiltrates found in the lungs and consistent with a diagnosis of lymphomatoid granulomatosis. These features are compared with previously reported cases of canine lymphomatoid granulomatosis and those features identified in a similar disease described in man. (Journal of Veterinary Internal Medicine 1990; 4:157-166)
LYMPHOMATOID GRANULOMATOSIS (LYG) is a rare neoplastic pulmonary disorder that has been reported in both the human and dog.'-4 In humans, LYG was originally described by Leibow in 1972 as a disease of unknown etiology, characterized by an angiocentric and angiodestructive pleomorphic infiltrate of an atypical lymphoid cell population.' Other cells seen on histologic examination included small lymphocytes, plasma cells, and occasional histiocytes and eosinophils. Originally LYG was recognized as an entity separate from Wegener's granulomatosis and malignant lymphoma. From the Departments of Radiological Sciences (Berry, Koblik), Pathology (Moore), and Medicine (Thomas), School of Veterinary Medicine, University of California, Davis, California, and the Department of Veterinary Clinical Medicine (Sisson), College of Veterinary Medicine, University of Illinois, Urbana, Illinois. Reprint requests: Clifford R. Beny, DVM, Department of Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.
However, even in early descriptions and case reports, the clinical behavior of some cases of LYG paralleled that of lymphoma, and histologic progression from LYG to a more typical lymphoma was reported.' Human mortality in patients with LYG has been reported between 38%and 85% with a mean survival of 14 month^.^,^ The disease characteristically involves the lungs. Extrapulmonary sites of involvement have been described in 30% of patients and include the central nervous system, kidneys, and integument. Infrequent reports of gastrointestinal, urinary, and multiple-joint involvement have also been do~umented.'-~Current histochemical marker studies suggest that LYG may start as a polyclonal lyrnphoreticular proliferation, which transforms into a non-Hodgkin's form of T-cell lymphoma.10*'Malignant transformation of LYG into an angiocentric pulmonary lymphoma has been documented in 12% to 47% of human patient^.^,"-'^ In the veterinary literature, LYG has been described
'
157
158
Journal of Veterinary Internal Medicine
BERRY ET AL.
only in dog^.^-^ Lucke's original description of a pulmonary disease involving three young dogs has been recently expanded upon in two review articles so that a total of 13 cases in the dog have been reported in the literat~re.~" The purpose of the current retrospective study was to describe radiographic findings, clinical features, and histopathology of seven dogs with LYG. Criteriafor Selection of Cases
Records from the Veterinary Medical Teaching Hospital, University of California, Davis (VMTHUCD), were reviewed for dogs with a diagnosis of pulmonary lymphoid neoplasia, lymphomatoid granulomatosis, and eosinophilic granuloma from December 1976 through July 1987. Twenty-one cases were identified based on biopsy or necropsy reports. Further review of biopsy or necropsy histopathology using specific criteria for LYG resulted in the selection of seven cases for complete study. Histopathologic criteria to be met for inclusion in the study included angiocentric pleomorphic lymphoid infiltrate, evidence of angiodestruction, and neoplastic characteristics (frequent mitotic figures, anaplastic cellular characteristics, and metastasis to regional lymph nodes) of the cellular infiltrate. Special stains (acid-fast and brown and brenn stains) were used to rule out infectious etiologies and specific cell populations (such as toluidene blue for mast cells). In five cases, cytoplasmic lysozymal immunoreactivity was used as a histiocytic marker, based on a previously described te~hnique.'~ The remaining 14 dogs were eliminated from the study based on histopathologic findings. These dogs had similar radiographic and clinical features to the LYG group. However, these dogs represented a heterogeneous group of diseases, which included eosinophilic granuloma, spindle cell sarcoma, amelanotic melanoma, and heartworm induced granulomas. Clinical Evaluation. Clinic records were reviewed for signalment, chief presenting complaint, clinical signs, physical examination findings, and laboratory data. In all cases, thoracic radiographs were also reviewed.
Poodle. Four of seven dogs were males. The age range was between five and 14 years (mean, 8 . 4 median, 7). Chief Complaint/Physical Examination
The primary complaint at presentation and physical examination findings were related to the respiratory system. Most commonly, a nonproductive dry cough (6 dogs) of several months' duration with progressive respiratory distress (6) was reported. Anorexia (4) and weight loss (3) were other common primary complaints. Physical examination findings were nonspecific, but fever (4) and increased lung sounds, particularly heard caudodorsally (6), were most common. In one dog, the primary complaint was submandibular swelling caused by a peripheral lymphadenopathy. In this dog, no other abnormalities on physical examination were detected. A split-second heart sound was detected in two dogs and one dog had ascites. Laboratory Data
Six dogs had negative serum titers to Coccidioides immitis. Three of six dogs had positive indirect fluorescent antibody (IFA) tests for heartworm microfilarial antibodies. Three dogs had been treated for adult heartworms using standard thiacetarsamide* adulticide protocol within two to eight months (mean, 5.6 mos; median, 7 mos) before presentation with LYG. Leucocytosis (mean, 25,80O/pI; median, 22,6OO/pl; range, 11,500-52,000/p1) was present in six dogs. An eosinophilia (mean, 9,263/p1; median, 3,7891~1;range, 1,200-22,8OO/pl) and basophilia (mean, 1,4 12/pI; median, 1,60O/pl; range, 800-1,837/~1) were present in three dogs with either a history of heartworm disease (2) or with a positive heartworm microfilaria test (1) at the time of presentation for LYG. Arterial hypoxemia (mean, 59 mmHg; median, 65.0 mmHg; range, 51-67 mmHg) was identified in three dogs, two of which were two and seven months postadulticide therapy, respectively. No consistent abnormalities in serum chemistries or urinalyses were noted. Thoracic Radiographic Findings
Results The signalment, chief presenting complaint, physical examination findings, thoracic radiographic features, and clinical outcomes are summarized in Table 1Signalment
Six of the seven dogs were large breeds, represented by German Shepherd (l), Malamute ( I), German Shorthair Pointer (I), Golden Retriever (l), Great Dane (I), and Doberman Pinscher (1). The small-breed dog was a
Thoracic radiographs revealed a hilar lymphadenopathy ( 5 ) with associated caudal lobar bronchial compression, and discrete intrapulmonary masses (6) ranging radiographically from 1 to 7 cm in diameter (Figs. IA, lB, 2A, and 2B). Lobar consolidation (Figs. 3A and 3B), other ill-defined pulmonary masses, alveolar, and diffuse interstitial pulmonary infiltrates (7) were also common findings. Radiographic evidence of a cranial mediastinal mass (2) and sternal lymphadenopathy (2) was ~~~
* Caparsolate CEVA, Abbott Laboratories, North Chicapo, IL.
Hilar LN pulmonary masses, necropsy: spleen involvement
Progressive enlargement of pulmonary masses
Seven months post-HW treatment, thoracic biopsy
None, thoracic biopsy
Two months postheartworm treatment, thoracic biopsy
Left caudal lobectomy
Mixed alveolar/interstitiaI pattern with ill-defined mass lesions, sternal and hilar lymphadenopathy
Multiple pulmonary masses that have a bilateral distribution with hilar lymph-node enlargement and resultant bronchial compression, CMM present Multiple bilateral pulmonary masses with areas of ill-defined consolidation, hilar LN with bronchial compression Left caudal lobe consolidation with bronchial distortion, hilar lymph-node enlargement
IFA mff antibody negative, WBC, 12,7OO/pl; Fibrinogen, 500 mg/dl; Pa02, 65 mmHg; C. immitis negative IFA mff antibody positive, WBC, 30,20O/pI; Eosinophils, 22,80O/pl; Fibrinogen, 400 mg/dl; Basophils, l,600/pl; Pa02, 61 mmHg; C. immitis negative IFA mff antibody, negative, WBC, 1 1,50O/pl;C. immitis negative
IFA mff antibody positive, WBC, 33,4OO/pl; Eosinophils, 1,20O/pl; Basophils, 1,837/p1; Pa02, 43.5; C. immitis negative ELISA adult heartworm antigen negative; WBC, 15,OOO/pl; C. immitis negative
Cough, dyspnea, anorexia. fever, increased lung sounds, weight loss
Dyspnea, nonproductive cough, anorexia, split S2, increased lung sounds
Lethargy, fever, weight loss, dyspnea, cough, anorexia
Lethargy, cough, fever, dyspnea, increased lung sounds
Cough (nonproductive), increased lung sounds
9-yr M Doberman Pinscher
5-yr M German Shorthair Pointer
6-yr FS Golden Retriever
I-yr M Malamute
14-yr FS Poodle
~
Hilar LN and pulmonary masses
Thoracic biopsy only
Multiple, bilateral pulmonary masses. Hilar lymphadenopathy and CMM present
Knotts and IFA rnff antibody negative, C. immitis negative
Peripheal lymph node enlargement (submandibular swelling)
12-yr FS Great Dane
Hilar LN, diffuse pulmonary involvement within one month
Hilar LN and pulmonary masses
Prednisone Euthanatized after 18 months due to cancer cachexia.
Hilar LN, peripheral LN, no necropsy
Prednisone, open thoracic biopsy, popliteal lymph-node biopsy
Multiple pulmonary masses with bilateral distribution, hilar lymphadenopathy and cranial mediastinal mass, alveolar/interstitia1 pattern
IFA mff antibody positive, WBC, 52,00O/pl; Eosinophils, 3,789/p1; Basophils, SOO/pI; Fibrinogen, 600 mg/dl; C. immitis negative
Weight loss, anorexia, fever, ascites, cough, split S2, harsh lung sounds, dyspnea
7-yr M German Shepherd
~
Prednisone, 20 days
COAP, six days
COAP, three months
COAP, six days postthoracotomy
COAP, 18 months
Four years postlobectom y: treated for lymphoma with COAP and died within two weeks
Four years later: systemic lymphoma
Lung lobectomy, heartworm disease treated eight months before systemic lymphoma diagnosis
Left caudal lobe mass and pulmonary artery enlargement four years later, hilar LN, alv/int densities noted diffusely.
Laboratory Abnormalities
Treatment and Survival
Chief Complaint/PE
Metastatic Spread
Signalment
Treatment
PE = physical examination; M = male; FS = female spayed; split S2 = splitting of second heart sound; hilar LN = hilar lymphadenopathy; CMM = cranial mediastinal mass; COAP = combination chemotherapy for lymphoma (see text); rnff antibody = D.immitis microfilaria antibodies; C. immitis = IFA coccidioidomycosis-negative: a h = alveolar; int = interstitial.
~
Dog
Thoracic Radiographic Features
TABLE I . Summary of Case Histories and Findings in Seven Dogs With Lymphomatoid Granulomatosis
Seven dogs with pulmonary lymphomatoid granulomatosis were reviewed. The disease occurred in six large-breed and one small-breed dogs. The dogs were five to 14 years old (mean, 8.4; median, 7), and four of seven dogs were males. Three dogs had been previously treated with adulticide therapy for canine dirofilariasis. Clinical histories included a progressive respiratory disease characterized by varying degrees of cough, dyspnea, exercise intolerance, and weight loss. Thoracic radiographic features included hilar lymphadenopathy, pulmonary masses of varying sizes, and mixed pulmonary patterns of lobar consolidation with ill-defined interstitial and alveolar pulmonary infiltrates. Cardiovascular changes compatible with chronic dirofilariasis were present in three dogs. The clinical course was usually progressive and fatal. The survival time ranged from six days to four years (mean, 12.5 mos; median, 3 mos). Gross and histologic features included mass lesions with areas of necrosis that replaced normal pulmonary architecture. Cytologically, these lesions were characterized by infiltration with pleomorphic, angioinvasive mononuclear cells that often resulted in vascular obliteration. The infiltrating cells resembled large lymphoid cells that possessed large hyperchromatic nuclei and small amounts of cytoplasm. Systemic lymphoid neoplasia with peripheral lymphadenopathy was diagnosed in two dogs. In both cases, lymph-node cytology was similar to the cellular infiltrates found in the lungs and consistent with a diagnosis of lymphomatoid granulomatosis. These features are compared with previously reported cases of canine lymphomatoid granulomatosis and those features identified in a similar disease described in man. (Journal of Veterinary Internal Medicine 1990; 4:157-166)
LYMPHOMATOID GRANULOMATOSIS (LYG) is a rare neoplastic pulmonary disorder that has been reported in both the human and dog.'-4 In humans, LYG was originally described by Leibow in 1972 as a disease of unknown etiology, characterized by an angiocentric and angiodestructive pleomorphic infiltrate of an atypical lymphoid cell population.' Other cells seen on histologic examination included small lymphocytes, plasma cells, and occasional histiocytes and eosinophils. Originally LYG was recognized as an entity separate from Wegener's granulomatosis and malignant lymphoma. From the Departments of Radiological Sciences (Berry, Koblik), Pathology (Moore), and Medicine (Thomas), School of Veterinary Medicine, University of California, Davis, California, and the Department of Veterinary Clinical Medicine (Sisson), College of Veterinary Medicine, University of Illinois, Urbana, Illinois. Reprint requests: Clifford R. Beny, DVM, Department of Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.
However, even in early descriptions and case reports, the clinical behavior of some cases of LYG paralleled that of lymphoma, and histologic progression from LYG to a more typical lymphoma was reported.' Human mortality in patients with LYG has been reported between 38%and 85% with a mean survival of 14 month^.^,^ The disease characteristically involves the lungs. Extrapulmonary sites of involvement have been described in 30% of patients and include the central nervous system, kidneys, and integument. Infrequent reports of gastrointestinal, urinary, and multiple-joint involvement have also been do~umented.'-~Current histochemical marker studies suggest that LYG may start as a polyclonal lyrnphoreticular proliferation, which transforms into a non-Hodgkin's form of T-cell lymphoma.10*'Malignant transformation of LYG into an angiocentric pulmonary lymphoma has been documented in 12% to 47% of human patient^.^,"-'^ In the veterinary literature, LYG has been described
'
157
158
Journal of Veterinary Internal Medicine
BERRY ET AL.
only in dog^.^-^ Lucke's original description of a pulmonary disease involving three young dogs has been recently expanded upon in two review articles so that a total of 13 cases in the dog have been reported in the literat~re.~" The purpose of the current retrospective study was to describe radiographic findings, clinical features, and histopathology of seven dogs with LYG. Criteriafor Selection of Cases
Records from the Veterinary Medical Teaching Hospital, University of California, Davis (VMTHUCD), were reviewed for dogs with a diagnosis of pulmonary lymphoid neoplasia, lymphomatoid granulomatosis, and eosinophilic granuloma from December 1976 through July 1987. Twenty-one cases were identified based on biopsy or necropsy reports. Further review of biopsy or necropsy histopathology using specific criteria for LYG resulted in the selection of seven cases for complete study. Histopathologic criteria to be met for inclusion in the study included angiocentric pleomorphic lymphoid infiltrate, evidence of angiodestruction, and neoplastic characteristics (frequent mitotic figures, anaplastic cellular characteristics, and metastasis to regional lymph nodes) of the cellular infiltrate. Special stains (acid-fast and brown and brenn stains) were used to rule out infectious etiologies and specific cell populations (such as toluidene blue for mast cells). In five cases, cytoplasmic lysozymal immunoreactivity was used as a histiocytic marker, based on a previously described te~hnique.'~ The remaining 14 dogs were eliminated from the study based on histopathologic findings. These dogs had similar radiographic and clinical features to the LYG group. However, these dogs represented a heterogeneous group of diseases, which included eosinophilic granuloma, spindle cell sarcoma, amelanotic melanoma, and heartworm induced granulomas. Clinical Evaluation. Clinic records were reviewed for signalment, chief presenting complaint, clinical signs, physical examination findings, and laboratory data. In all cases, thoracic radiographs were also reviewed.
Poodle. Four of seven dogs were males. The age range was between five and 14 years (mean, 8 . 4 median, 7). Chief Complaint/Physical Examination
The primary complaint at presentation and physical examination findings were related to the respiratory system. Most commonly, a nonproductive dry cough (6 dogs) of several months' duration with progressive respiratory distress (6) was reported. Anorexia (4) and weight loss (3) were other common primary complaints. Physical examination findings were nonspecific, but fever (4) and increased lung sounds, particularly heard caudodorsally (6), were most common. In one dog, the primary complaint was submandibular swelling caused by a peripheral lymphadenopathy. In this dog, no other abnormalities on physical examination were detected. A split-second heart sound was detected in two dogs and one dog had ascites. Laboratory Data
Six dogs had negative serum titers to Coccidioides immitis. Three of six dogs had positive indirect fluorescent antibody (IFA) tests for heartworm microfilarial antibodies. Three dogs had been treated for adult heartworms using standard thiacetarsamide* adulticide protocol within two to eight months (mean, 5.6 mos; median, 7 mos) before presentation with LYG. Leucocytosis (mean, 25,80O/pI; median, 22,6OO/pl; range, 11,500-52,000/p1) was present in six dogs. An eosinophilia (mean, 9,263/p1; median, 3,7891~1;range, 1,200-22,8OO/pl) and basophilia (mean, 1,4 12/pI; median, 1,60O/pl; range, 800-1,837/~1) were present in three dogs with either a history of heartworm disease (2) or with a positive heartworm microfilaria test (1) at the time of presentation for LYG. Arterial hypoxemia (mean, 59 mmHg; median, 65.0 mmHg; range, 51-67 mmHg) was identified in three dogs, two of which were two and seven months postadulticide therapy, respectively. No consistent abnormalities in serum chemistries or urinalyses were noted. Thoracic Radiographic Findings
Results The signalment, chief presenting complaint, physical examination findings, thoracic radiographic features, and clinical outcomes are summarized in Table 1Signalment
Six of the seven dogs were large breeds, represented by German Shepherd (l), Malamute ( I), German Shorthair Pointer (I), Golden Retriever (l), Great Dane (I), and Doberman Pinscher (1). The small-breed dog was a
Thoracic radiographs revealed a hilar lymphadenopathy ( 5 ) with associated caudal lobar bronchial compression, and discrete intrapulmonary masses (6) ranging radiographically from 1 to 7 cm in diameter (Figs. IA, lB, 2A, and 2B). Lobar consolidation (Figs. 3A and 3B), other ill-defined pulmonary masses, alveolar, and diffuse interstitial pulmonary infiltrates (7) were also common findings. Radiographic evidence of a cranial mediastinal mass (2) and sternal lymphadenopathy (2) was ~~~
* Caparsolate CEVA, Abbott Laboratories, North Chicapo, IL.
Hilar LN pulmonary masses, necropsy: spleen involvement
Progressive enlargement of pulmonary masses
Seven months post-HW treatment, thoracic biopsy
None, thoracic biopsy
Two months postheartworm treatment, thoracic biopsy
Left caudal lobectomy
Mixed alveolar/interstitiaI pattern with ill-defined mass lesions, sternal and hilar lymphadenopathy
Multiple pulmonary masses that have a bilateral distribution with hilar lymph-node enlargement and resultant bronchial compression, CMM present Multiple bilateral pulmonary masses with areas of ill-defined consolidation, hilar LN with bronchial compression Left caudal lobe consolidation with bronchial distortion, hilar lymph-node enlargement
IFA mff antibody negative, WBC, 12,7OO/pl; Fibrinogen, 500 mg/dl; Pa02, 65 mmHg; C. immitis negative IFA mff antibody positive, WBC, 30,20O/pI; Eosinophils, 22,80O/pl; Fibrinogen, 400 mg/dl; Basophils, l,600/pl; Pa02, 61 mmHg; C. immitis negative IFA mff antibody, negative, WBC, 1 1,50O/pl;C. immitis negative
IFA mff antibody positive, WBC, 33,4OO/pl; Eosinophils, 1,20O/pl; Basophils, 1,837/p1; Pa02, 43.5; C. immitis negative ELISA adult heartworm antigen negative; WBC, 15,OOO/pl; C. immitis negative
Cough, dyspnea, anorexia. fever, increased lung sounds, weight loss
Dyspnea, nonproductive cough, anorexia, split S2, increased lung sounds
Lethargy, fever, weight loss, dyspnea, cough, anorexia
Lethargy, cough, fever, dyspnea, increased lung sounds
Cough (nonproductive), increased lung sounds
9-yr M Doberman Pinscher
5-yr M German Shorthair Pointer
6-yr FS Golden Retriever
I-yr M Malamute
14-yr FS Poodle
~
Hilar LN and pulmonary masses
Thoracic biopsy only
Multiple, bilateral pulmonary masses. Hilar lymphadenopathy and CMM present
Knotts and IFA rnff antibody negative, C. immitis negative
Peripheal lymph node enlargement (submandibular swelling)
12-yr FS Great Dane
Hilar LN, diffuse pulmonary involvement within one month
Hilar LN and pulmonary masses
Prednisone Euthanatized after 18 months due to cancer cachexia.
Hilar LN, peripheral LN, no necropsy
Prednisone, open thoracic biopsy, popliteal lymph-node biopsy
Multiple pulmonary masses with bilateral distribution, hilar lymphadenopathy and cranial mediastinal mass, alveolar/interstitia1 pattern
IFA mff antibody positive, WBC, 52,00O/pl; Eosinophils, 3,789/p1; Basophils, SOO/pI; Fibrinogen, 600 mg/dl; C. immitis negative
Weight loss, anorexia, fever, ascites, cough, split S2, harsh lung sounds, dyspnea
7-yr M German Shepherd
~
Prednisone, 20 days
COAP, six days
COAP, three months
COAP, six days postthoracotomy
COAP, 18 months
Four years postlobectom y: treated for lymphoma with COAP and died within two weeks
Four years later: systemic lymphoma
Lung lobectomy, heartworm disease treated eight months before systemic lymphoma diagnosis
Left caudal lobe mass and pulmonary artery enlargement four years later, hilar LN, alv/int densities noted diffusely.
Laboratory Abnormalities
Treatment and Survival
Chief Complaint/PE
Metastatic Spread
Signalment
Treatment
PE = physical examination; M = male; FS = female spayed; split S2 = splitting of second heart sound; hilar LN = hilar lymphadenopathy; CMM = cranial mediastinal mass; COAP = combination chemotherapy for lymphoma (see text); rnff antibody = D.immitis microfilaria antibodies; C. immitis = IFA coccidioidomycosis-negative: a h = alveolar; int = interstitial.
~
Dog
Thoracic Radiographic Features
TABLE I . Summary of Case Histories and Findings in Seven Dogs With Lymphomatoid Granulomatosis
