Lymphomatoid Granulomatosis Report of a Case and Review of the Literature
ROGER C. BONE, M.D.’ MARY VERNON, M.D. RICHARD E. SOBONYA.
M.D.+
HUMBERTO RENDON, M.D. Kansas City, Kansas
From the Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas. Requests for Reprints should be addressed to Dr. Roger C. Bone. Manuscript accepted March 29, 1978. Present address: Pulmonary Division, University of Arkansas Medical Center-V.A. Complex, Little Rock, Arkansas 7220 1. 7 Present address: University of Arizona College of Medicine, Pathology Department, Tucson, Arizona 85724. l
A 24 year old man had a nonproductive cough and chest pain. Chest roentgenogram showed a diffuse infiltrate, and pulmonary function studies showed restrictive lung disease. Extremity weakness, deteriorating mental status and neuropathy progressed as pulmonary findings diminished on corticosteroid therapy. Lung biopsy showed lymphomatoid granulomatosis. The neurologic status deteriorated despite treatment with Cytoxan@, intrathecal methotrexate and brain irradiation. Autopsy showed mass lesions of lymphomatoid granulomatosis in the brain and healed lesions in the lungs. A review of the neurologic and pulmonary findings in reported cases show that diminution of pulmonary disease with progression of neurologic disease manifest by mass lesion is unusual. Since the etiology, prognosis and prevalence of this disease remains undefined, all patients with this disease should be reported on. In 1972, Liebow et al. [l] published the first description of lymphomatoid granulomatosis; noting that the clinical course and histology of this disease differed from that of “limited” Wegener’s granulomatosis and that these two diseases appeared to have different responses to medical therapy. In lymphomatoid granulomatosis, infiltrates and masses of atypical lymphocytes, plasma cells and histocytes involve the lungs and other organs [2]. The atypical cells resemble but are not identical to those seen with lymphoma. The roentgenographic picture of the lung resembles that seen with classic Wegener’s granulomatosis, but the absence of glomerulonephritis, rare involvement of the upper respiratory tract and frequent involvement of the central nervous system and skin in lymphomatoid granulomatosis are distinguishing features. Our report describes a 24 year old patient with lymphomatoid granulomatosis and reviews the literature, with special emphasis on reported treatment modalities. Our patient is unique because of his dramatic initial pulmonary response to corticosteroid therapy. Improvement was seen clinically, roentgenographically and functionally. Serial pulmonary functions and roentgenographic analyses of a patient with biopsy proved lymphomatoid granulomatosis have not been previously reported. Another unusual finding is the demonstration of mass lesions of lymphomatoid granulomatosis in the central nervous system at autopsy. CASE REPORT A 24 year old Mexican-American man was admitted to the University of Kansas Medical Center in April 1974, with complaints of chest pain and
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progressive lower extremity weakness. He had been well until December 1973, when a nonproductive cough developed associated with sharp, midsternal chest pain. A chest roentgenogram taken by his private physician showed a diffuse pulmonary infiltrate. This did not diminish with antibiotic therapy. In March 1974, an open lung biopsy was performed and the specimen was considered to show inflammation and marked necrosis which was nondiagnostic. In early April he experienced a gradual onset of weakness in all extremities, and his pulmonary symptoms continued. At the time of admission in mid-April 1974, he was dyspneic, unable to walk or use his hands effectively due to marked muscle weakness, and was experiencing urinary hesitancy and fecal incontinence. Physical examination showed diffuse rales in the lung and abnormal neurologic findings. Although he was alert and
A
Figure 1. A, chest roentgenogram obtained in April 1974. A diffuse parenchymal infiltrate is present with increased roentgenographic opacity at the left lateral pleural border. 6, chest roentgenogram obtained in November 1974. The chest roentgenogram is normal. The apparent nodule over the right ninth posterior rib is the anterior termination of the fourth rib.
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oriented, there was some impairment of abstraction and memory. Marked motor weakness was present in all extremities In the lower extremities, dorsiflexion was weaker than plantar flexion. Decreased sensation to pinprick was present in a “stocking-glove” distribution. Proprioception was decreased in all extremities. Plantar responses were flexor. Hoffman’s reflex was absent. Decreased rectal sphincter tone was present. Complete blood count, urinalysis and chemistry profile were within normal limits with the exception of a serum cholesterol of 344 mg/lOO ml. Lipoprotein electrophoresis showed a type Ila pattern. Antinuclear antibody and rheumatoid factor were negative. Muscle enzymes, complement, serum lead and serum vitamin 8,s levels were normal. Fungal serologic studies were negative. Skin tests using purified protein derivative (PPD), histoplasmin, coccidioidin and Candida were negative. Serum protein electrophoresis showed an elevated gamma globulin level of 1.5 g (23.1 per cent). Arterial blood gases on admission were pH 7.40, oxygen tension (PO*) 64 mm Hg, carbon dioxide tension (PCOs) 30 mm Hg. Chest roentgenograms showed alveolar and interstitial infiltrates throughout all lobes (Figure 1A). Sinus films were within normal limits. Electromyographic studies showed both upper and lower motor neuron damage. An electroencephalogram was considered diffusely abnormal, but a brain scan was within normal limits. Bone marrow aspiration showed a slight shift to the left in the myeloid elements. Biopsies of skeletal muscle and temporal artery disclosed normal histology. Biopsy of sural nerve showed patchy demyelination with cellular infiltrates. The slides from the previous lung biopsy were obtained and reviewed (Figure 2). The pathologic diagnosis was lymphomatoid granulomatosis. Since muscular weakness was progressing, treatment with prednisolone was instituted (60 mg/day). The patient was unable to void, and an indwelling urinary catheter was inserted. A cystometrogram showed a neurogenic bladder.
Figure 2.
Lung biopsy specimen shows infiltration of artery
and surrounding tissues by lymphoid cells. (Hematoxylin and
eosin stain, magnification X 100 reduced by 3 1 per cent). These showed features of atypia, such as clearing of nuclear chromatin and macronucleoli. A vasculitis consisting of infiltration by the above cells involved both arteries and veins.
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TABLE I --.__
Results of Serial Pulmonary
Predicted Value
Study FVC (Liter) TLC (liter) FEV DLCO'
(mmlmin/mm
Pa02 (mm Hg) PaC02 (mm Hg) Prednisone dose
Function Studies
5.29 6.61 4.34 Hg)
41 WI74
-____ 5/2/74
1.68 4.28 1.66
3.08 4.95 2.92
5/14/74 3.87 5.57 3.49
l/17/74 4.48 5.96 3.80
32.5
10.2
35.7
30.2
33.9
80-100 35-43
64 30 0
93 36 60
97 39 75
88 33 40
(mglday) Single breath method. t Neurologic disease had progressed so that the patient could not hold his breath for the period required to accurately
9/25/74 4.90 6.19 3.90 t a2 34 20
l
Pulmonary function studies showed a severe restrictive defect with a moderate decrease in diffusion capacity (Table I). The five-lobe pulmonary infiltrates decreased (by serial chest films) during treatment with oral corticosteroids (Figure IB). The prednisolone dose was tapered to 50 mg/day. Pulmonary function studies showed improvement (Table I). At home on November 7, the patient experienced tha onset of retrobulbar and cervical spine pain, headache and fever with a temperature of 38. I’C. Aspirin and cold packs to the head provided temporary relief, but these symptoms continued. He was seen in the clinic on November 11. Neurologic examination at that time demonstrated residual lower extremity weakness which was considered unchanged from previous clinic examinations. His complaints were thought to be due to a transient viral infection. On November 15, he was admitted to the hospital with the aforementioned complaints as well as blurred vision, vomiting and dysuria. On physical examination, funduscopic examination disclosed no abnormalities. Meningismus was absent. Decreased motor strength was noted in the lower extremities with the left side being the more severely affected. There was “intermittent jerking” of the lower extremities, as well as
Figure3. Lung microscopy. Caseous material (above) and fibrous wall containing vessel showing healed vasculitis (betweenarrows). Hematoxyln and eosin stain; magnification X 100, reduced by 30 per cent.
perform this test.
bilateral unsustained clonus. Plantar response was extensor bilaterally. There was decreased sensation to pinprick in the lower extremities. The patient was unable to stand without assistance. An erythematous, papular, pruritic rash was present. Laboratory values showed complete blood count, blood chemistries and liver function tests to be within normal limits, with the exception of the serum cholesterol level which was elevated to 375 mg/lOO ml. Urinalysis showed 30 to 40 white
Figure 4. Brain at autopsy. Note necrotic lesions of brain stem and pons. (Approximafely 1.3 X natural size.)
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Figure 5. Brain. Vasculitis characterized by infiltration of lymphoid cell with necrosis of brain substance. Hematoxylin and eosin stain; magnification X 100, reduced by 30 per cent.
blood cells/high power field, and urine culture grew Escherichia coli greater than 105/ml. Analysis of cerebrospinal fluid was as follows: glucose 34 mg/lOO ml and protein 290 mg/lOO ml. Serum glucose was 99 mg/lOO ml. The differential white blood cell count was 99 per cent mononuclear with atypical cytology. Repeated antinuclear antibody and lupus erythematosus preparations were negative. The initial diagnosis was that of bacterial or fungal meningitis; however, all cultures of cerebrospinal fluid for fungus and bacteria were negative, as were fungal and viral titers. A therapeutic trial of amphotericin B therapy did not change the patient’s clinical status. Brain scan demonstrated a deep midline mass. Because of the brain scan findings, the atypia of the mononuclear cells in the cerebrospinal fluid, and the negative culture results, the patient was thought to have lymphomatoid granulomatosis involving the central nervous system. A therapeutic trial of increasing the prednisolone dose from 60 mg/kg/day to 100 mg/kg/day had no clinical effect. The administration of cyclophosphamide, 5 mg/ kg/day, was begun on December 7. The patient’s neurologic condition deteriorated, and by December 10, 1974, right-sided cranial nerve palsies developed of the three, four and six cranial nerves. His condition continued to deteriorate with progressive involvement of the fifth cranial nerve on the right side and the third cranial nerve on the left. Cyclophosphamide therapy was discontinued on December 21, and intrathecal methotrexate (10 mg/m2) with citrovorum rescue (6 mg intramuscularly every 4 hours) every other day was begun. By December 24, the intracranial pressure had increased to 400 mm/H20. Because of mild papilledema administration of the intrathecal methotrexate was stopped, after which the neurologic deficits continued to progress. Because the behavior of the pathologic process appeared similar to that of meningeal carcinomatosis, whole brain and upper cervical spine irradiation was begun. Dexamethasone therapy was instituted on December 24 in an attempt to ameliorate the increasing intracranial pressure. After 16 days of dexamethasone therapy, the patient had an episode of
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bloody diarrhea. The dexamethasone dose was decreased, and no more bloody stools occurred although the patient’s condition continued to deteriorate. He was thought to have aspiration pneumonia due to loss of the gag reflex, and was treated with Clindamycin@ and gentamicin. He was transferred to a local hospital to be closer to his family. He died two days after transfer. At autopsy the lungs contained numerous masses with a thick fibrous wall and pasty yellow material. Microscopically, the masses had a wall of collagenous tissue devoid of the characteristic lymphoplasmocytic cells of lymphomatoid granulomatosis (Figure 3). The central part of the lesion was necrotic. Verhoeff’s Van Gieson stain for elastica showed a healed vasculitis involving numerous vessels in the fibrous wall. Histologic stains for bacteria, fungi and acid-fast bacilli on these masses showed no organisms, and culture of these masses for the same microorganisms were sterile. Thus, the pulmonary lesions were considered to be healed lesions of the previously documented lymphomatoid granulomatosis. The brain showed necrosis in the left temporoparietal area, brain stem (measuring 4 by 2 by 1 cm), pons (Figure 4) and cerebellar hemispheres. Microscopically, arteries in the brain were infiltrated by a lymphoplasmocytic infiltrate similar to that described in the original lung biopsy specimen (Figure 5). Lymphoplasmocytic infiltrates consistent with lymphomatoid granulomatosis were seen in abdominal skin, but not in any other site. Lymph nodes showed only cellular depletion. Death was attributed to involvement of the brain stem by le-
sions of lymphomatoid granulomatosis. COMMENTS Lymphomatoid granulomatosis was first described by Liebow et al. [I] in 1972; they characterized this disease of granulomatous lymphoreticular infiltrate as “angiocentric and angiodestructive.” The infiltrate and subsequent vasculitis result in tissue necrosis which often has the gross appearance of a caseating granuloma. In most cases, the disease primarily involves the lungs. Central nervous system involvement is also frequent, occurring in 23 per cent of Liebow’s first 40 patients. Involvement of other organ systems, such as skin [3], skeletal muscle [4], mesentery [4], salivary glands [5], kidney [I], liver [ 11, peripheral nerves [ 11, adrenals [ 11, heart [l] and gastrointestinal tract [4], have been reported. Remarkably, lymph nodes, bone marrow and spleen are rarely involved in this disease process (Table II). The clinical presentation of lymphomatoid granulomatosis depends on the organ symptoms, such as nonproductive cough, fever and dyspnea. In a few patients, the presenting features may be skin rash or central nervous system involvement, with pulmonary involvement developing later. In all reported cases, pulmonary involvement develops at some time. Constitutional complaints, such as weight loss and malaise, are also common. In patients with other presenting complaints, such as skin rash or ataxia, most have roentgenographic evidence of pulmonary involvement.
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TABLE II
Summary of Recent Cases Organ System(s) Involved
Case No.
Age (yr) and Sex
1
53, M
Lung, skin, liver
2
61. M
Lung, kidney liver
Autopsy
. Yes
Presumed Cause of Death
Skin Test Results PPD-mumps coccidioidomycoses PPD-histoplasmosis
Alive at time of publication Sepsis
+, coccidioidomycoses 3
33. M
Lung, brain adrenal, liver
Yes
4
51. F
Skin, breast, lung, subcutaneous fat
Yes
.
Respiratory insufficiency
5
75. M
Limited
DNCB-Candida
Pneumonia
6
54. M
Skin, lung central nervous system by history Skin
7 8
42, M 67, M
Lung Lung, kidney, adrenal, possibly skin
No Yes
9
55, M
Lung
Alive
10
35, M
Lung
Alive
.
11
40, M
Skin, lung
Alive
.
12
71, M
Skin, lung
No
13
76, M
Lungs
Yes
Respiratory insufficiency
Yes
Pneumonia and pulmonary emboli Respiratory failure Progressive pulmonary disease Alive at time of publication Alive at time of publication Alive at time of publication
PPD-
.
PPD-Candidamumps-DCNB
Myocardial infarction suspected Respiratory insufficiency
Therapy
Reference
Prednisone, [91 cyclophosphamide Cyclophosphamide and 1101 intermittent low-dose prednisone Cyclophosphamide, 1111 vincristine, prednisone Cyclophosphamide, vincristine, prednisone bleomycin Prednisone, 131 cyclophosphamide Vinblastin procarbazine, nitrogen mustard, prednisolone Steroids Chemotherapy
Prednisone, cyclophosphamide Plaquenil, prednisone, nitrogen mustard Prednisone, cyclophosphamide, oncovin Cyclophosphamide and prednisone
[31
151 1121
[81
Digitalis, diuretics, antibiotics, rifampin
NOTE: DNCB = dinitro-chloro-benzene. PPD = tuberculin.
In contrast to Wegener’s granulomatosis, clinical evidence of renal involvement is rare, as glomerulonephritis does not occur. However, renal involvement with granuloma formation does occur in lymphomatoid granulomatosis. Also, the skin manifestations of lymphomatoid granulomatosis differ from those of Wegener’s granulomatosis, which are sharply punched-out ulcers with little cellular infiltrate. Central nervous system symptoms may be the presenting complaint, with or without occult pulmonary disease. The symptoms (ataxia, hemiparesis, dizziness) vary depending on the area involved and the type of involvement. Skin lesions are also a common presenting complaint. The lesions are usually pruritic, nodular or plaque-like and scaly. Ulceration, alopecia and loss of sweating also occur on occasion [3]. One striking feature of lymphomatoid granulomatosis is the parenchymal infiltrates on the chest roentgeno-
gram. Multiple fleeting infiltrates are characteristic, although a diffuse infiltrate resembling a pneumonic process may be present. The lower lung fields are the most frequent site of the lesions, which are most often peripheral and bilateral. Cavitation was seen in 30 per cent of the original patients studied [ 11. Hemorrhage secondary to cavitation was the cause of death in 14 per cent of the original 40 patients. Mass lesions may be seen on intravenous pyleogram and brain scan studies. Other laboratory values are usually normal. Immunoglobulins are sometimes decreased, but this is not a consistent finding [ 11. These mass lesions are usually the result of granuloma. The definitive diagnosis of lymphomatoid granulomatosis is made histologically. Characteristic features of the lesions are plasma cells, lymphocytic cells and large “atypical” mononuclear cells in various stages of maturity infiltrating perivascular tissue. Occlusion by
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TABLE III
Summary of Reported Cases of Central Nervous System Involvement Age
Case
!n!
Organ
No.
Sex
System(s)
1
8. F
.
40. M
4
..
58. F
CNS’,
lungs
Alive
Lung, kidney, liver, tongue, pancreas, skin CNS. skin, lung, kidneys, adrenal peripheral nerves
Yes
Yes, CNS exam excluded
CNS
No
Skin, CNS lungs
Yes
Refer-
Lumbar
Brain Scan
Autopsy
Puncture
EEG
L. orbital Diffusely area enlarged uptake
Therapy
17 WBC: 1 neutrophil, 17 lymphocytes, 4 monocytes; protein 41 mg/lOO ml.; glucose 45 mg/lOO ml.
.
Steroids
ence
[ll Case 19
Prednisone
ill Case
L. frontal lobe infarct
..
Abnormal deep No cells, protein:1 15 mg/ Prednisone 100 ml. glucose 75 midline (brain mg/iOO ml chloride 118 stem) lesion meq/liter “Malignant cells in CSF” CNS-irradiation .. prednisone, tetracycline, irradiation to nodes Prednisone .
;1; Case
24 [fl Case
[ll Case
8
34. M
CNS, lungs
No
..
Lung, lymph node, kidney, CNS, peripheral nervous system Lung, CNS kidney, heart skin, prostate Lung, CNS Skin. CNS
Yes
Lung, CNS adrenal, liver
Yes
Skin, lung, CNS
Limited
..
9 10
67, F 43, M
11
33. M
12
75. M
..
.
..
Prednisone
;1”1 Case 30
[ll Case Prednisone Steroids
No Alive
No cells, protein 34 mg/
..
100 ml., glucose 80 mg/lOO ml.
. .
infiltration of the vessels and subsequent tissue necrosis are frequent findings. With peripheral nerve involvement, the infiltrate is seen surrounding the nerve, and spotty demyelination is present. With skin involvement, the small vessel destruction with a lymphoreticular infiltrate is most often seen surrounding the dermal appendages. Lymphomatoid granulomatosis is often a difficult djsease to diagnose since it presents a confusing clinical picture, and the microscopic appearance seems nonspecific. Metastatic carcinoma and pneumonia are the most common diagnoses. Other common initial diagnoses include other types of pulmonary angiitis, such as Wegener’s granulomatosis, lymphoma and bronchiolitis obliterans. Dermal or mesenteric lesions may be considered “panniculitis.” Central nervous
October 1978
;:1 Case
Yes
.
.
NOTE: CNS = central nervous system; L = left; WBC = white blood cells; CSF = cerebrospinal
714
Prednisone
Cyclophosphamide vincristin, prednisone Prednisone, cyclophosphamide
r”l; Case I”:1
[31
fluid.
system lesions may be confused with primary or metastatic carcinoma, bacterial or fungal abscess, or meningitis. Our case is unique among the reported cases at this time, because granuloma formation due to lymphomatoid granulomatosis was found in the central nervous system at autopsy. One other patient with lymphomatoid granulomatosis and central nervous system symptoms similar to those of our patient has been described, but the central nervous system was not examined at autopsy. Central nervous system disease occurred in 13 of the 53 cases reported to date (Table Ill). In three of the cases with central nervous system involvement at autopsy, the infiltrate was confined to the meninges; in five, there was evidence of encephalitis. Our patient was initially treated with steroids. During
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this time his pulmonary function tests improved markedly (Table I). During steroid therapy, the pulmonary function tests returned to normal and remained so until the second hospital admission, after which central nervous system symptoms prevented cooperation for further pulmonary function testing. It is important to note that while the pulmonary lesions remitted during steroid therapy, central nervous system lesions developed rapidly. Of the 13 cases with central nervous system symptoms, the central nervous system manifestations developed in nine while the patients were being treated with steroids (Table Ill). In the remaining four cases [ l,lO-121, the patients, presented with central nervous system symptoms. Of the eight cases in which the patients were treated with steroids alone [ 1,2,5, lo] 1only two [ 1, lo] experienced significant remission. Both of these patients presented with central nervous system disease. Over-all, three patients were alive at the time of the publication [ 1,4,10]. All patients with cranial nerve involvement died. An initial response with subsequent exacerbation, as was seen with our patient, was seen in nine patients [2,3,5,7-9,l l-131. In six patients, including ours, clearing of pulmonary lesions was followed by the development of central nervous system lesions during treatment [3,4,7-9,131. Although steroid therapy may be associated with remission of pulmonary abnormalities, it certainly does not prevent progression of the central nervous system lesions. One patient other than ours received central nervous system irradiation (Case 4). Good results were reported in this instance. Because our patient underwent irradiation very late in the course of the disease, it is difficult to evaluate irradiation as a treatment modality. Combined chemotherapy was used in four instances [ 3,1 I- 131. Central nervous system deterioration continued in all four instances. The etiology of lymphomatoid granulomatosis is unknown. In the original article, Liebow et al. [l] review the most likely possibilities, including the case of primary malignant reticulosis [7] in a child with WiskottAldrich syndrome, as well as the relationship of the disease to lymphoma and Wegener’s granulomatosis.
GRANIJLOMATOSIS--BONE
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It is interesting that so many cases of central nervous system disease develop during steroid treatment. Perhaps this points in the direction of lymphoproliferative disease rather than hypersensitivity, although the vascular lesions are very similar to those of hypersensitivity reactions. Possibly, lymphomatoid granulomatosis is an acquired abnormality of the lymphocyte in a susceptible host such as in Sjogren’s syndrome [6,14]. Evidence for this includes the absence of delayed hypersensitivity as evidenced by nonreactivity to skin test antigens including dinitrochloro-benzene (Table II) and the response of the lung lesions to corticosteroids. As in Sjogren’s syndrome, lyphomatoid granulomatosis can terminate in a neoplastic disease. Electron microscopic studies have shown lymphomatoid granulomatosis to be different from other known abnormalities of the lymphoreticular system, with some similarity to “hair-cell” leukemia [8]. Other diseases, such as Mediterranean lymphoma and mycosis fungoides, can have years of symptoms with a biopsy showing nonspecific lymphoid and plasma cell infiltrates before it assumes the usual features of a neoplastic disease. Renal homotransplantation can be followed by lymphoreticular proliferation with involvement of the central nervous system [ 15-l 71. Possibly antigenic exposure in an immunosuppressed host alters cell membrane and produces an autoimmune disease [6]. With continued immunosuppression, neoplastic disease may result. Spontaneous disease in animals, such as the Aleutian mink disease [ 18-201 and immune complex disease of NZB mice [ 2 l-231, is associated with atypical lymphoreticular proliferation and angiitis [23,26]. Experimental models of diffuse granulomatous disease are now available [24,25]. These models may increase our understanding of the pathogenesis of lymphomatoid granulomatosis. Further investigation may help to define whether lymphomatoid granulomatosis is a reactive granulomatosis or a malignant lymphoma of the large lymphoid type [ 131. Possible causes and appropriate treatment for this disease are thus far speculative, and this is a fruitful area for future investigations [26,27].
REFERENCES 1. 2.
3. 4.
Liebow AA, Carrington CR, Friedman PJ: Lymphomatoid granulomatosis. Hum Pathol 3: 457, 1972. Saldana MJ, Patchefsky AS, Israel HI, et al.: Pulmonary angiitis and granulomatosis. The relation between histological features, organ involvement, and response to treatment. Hum Pathol 8: 391. 1977. MacDonald DM, Sarkany I: Lymphomatoid granulomatosis. Clin Exp Dermatol 1: 163, 1976. Mazhar M, McShane KL, Barret FA: Lymphomatoid granulomatosis. Reoort of a case. Rockv Mt Med J 73: 203, 1976. ’
5.
6.
7.
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Weisbrot IM: Lymphomatoid granulomatosis of the lung, associated with a long history of benign lympho-epithelial lesions of the salivary glands and lymphoid interstitial pneumonitis. Report of a case. Am J Clin Pathol 66: 792, 1976. Liebow AA: The J. Burns Amberson Lecture: Pulmonary Angiitis and Granulomatosis. Am Rev Respir Dis 108: 1, 1973. Brand MD, Marinkovich VA: Primary malignant reticulosis of the brain in Wiskott-Aldrich Syndrome. Arch Dis Child 44: 536, 1969.
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8.
9. 10. 11. 12.
13.
14.
15. 16.
17.
18.
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Kays Fu Ys, Minors, N, Brady JW: Lymphomatoid granulomatosis of the skin. Light microscopic and ultra structural studies. Cancer 34: 1675, 1974. Scully R: Case records of the Massachusetts General Hospital. N Engl J of Med 293: 292, 1975. Scully R: Case records of the Massachusetts General Hospital. N Engl J of Med 294: 1052, 1976. Hammar S, Mennemeyer R: Lymphomatoid granulomatosis in a renal transplant recipient. Hum Pathol 7: 6, 1976. Lee SC, Roth LM, Brasher RE: Lymphomatoid granulomatosis: A clinico-pathologic study of four cases. Cancer 38: 846, 1976. Damjanov IJ: Lymphomatoid granulomatosis of We lung associated with active tuberculosis. 2 Erkr Atmungsorgane (143): 56, 1975. Anderson LG, Tala N: The spectrum of benign to malignant lymphoproliferation in Sjogren’s syndrome. Clin Exp Immunol 10: 199.1972. Schnek SA, Penn I: Cerebral neoplasms associated with renal transplantation. Arch Neurol 22: 226, 1970. Doak PB, Montgomeric JZ, Noth JDD, et al.: Reticulum cell sarcoma after renal homotransplantation and azathioprine and prednisone therapy. Br Med J 4: 746. 1968. Pierce JC, Madge GE, Lee HM, et al.: Lymphoma: a complication of renal allotransplantation in man. JAMA 219: 1593, 1972. Porter DD, Larsen A: Virus-host Interactions in Aleutian disease of mink. Perspect Virol 6: 173, 1968.
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19.
20.
21.
22.
23. 24.
25.
26.
27.
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Porter DD, Larsen A, Porter HG: Pathogenesis of Aleutian disease of mink. I. In vivo replication and host antibody response to viral antigens. J Exp Med 130: 575, 1969. Eklund CM, Hadlow WJ, Kennedy RC, et al.: Aleutian disease of mink: properties of the etiologic agent and the host responses. J Infect Dis 118: 510, 1968. East J, Branca M: Autoimmune reactions and malignant changes in germ-free New Zealand black mice. Clin Exp lmmunol4: 621, 1969. Mellors RC: Autoimmune disease in NZB/Bl mice. II. Autoimmunity and malignant lymphoma. Blood 27: 435, 1966. East J: Viruses and autoimmunity. VOX Sang 16: 318, 1968. Davis CR, Min B, Rochester DF, et al.: Histochemical and electron microscopic studies on induced granulomatosis disease in dog lung. Am J Pathol 83a: 82, 1976. Lavietes MH, Min G, Hagstrom WC, et al.: Diffus pulmonary granulomatosis disease in the dog: relation between pressure-volume behavior and morphologic features. Am Rev Respir Dis 116: 907, 1977. Israel HL, Patchefsky AS. Saldona MJ: Wegener’s granulomatosis, lymphomatoid granulomatosis, and benign lymphocytic angiitis and granulomatosis of lung. Ann Intern Med 87: 691, 1977. Fauci AS: Granulomatosis vasculiticles: distinct but not related entities. Ann Intern Med 87: 782. 1977.
ROGER C. BONE, M.D.’ MARY VERNON, M.D. RICHARD E. SOBONYA.
M.D.+
HUMBERTO RENDON, M.D. Kansas City, Kansas
From the Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas. Requests for Reprints should be addressed to Dr. Roger C. Bone. Manuscript accepted March 29, 1978. Present address: Pulmonary Division, University of Arkansas Medical Center-V.A. Complex, Little Rock, Arkansas 7220 1. 7 Present address: University of Arizona College of Medicine, Pathology Department, Tucson, Arizona 85724. l
A 24 year old man had a nonproductive cough and chest pain. Chest roentgenogram showed a diffuse infiltrate, and pulmonary function studies showed restrictive lung disease. Extremity weakness, deteriorating mental status and neuropathy progressed as pulmonary findings diminished on corticosteroid therapy. Lung biopsy showed lymphomatoid granulomatosis. The neurologic status deteriorated despite treatment with Cytoxan@, intrathecal methotrexate and brain irradiation. Autopsy showed mass lesions of lymphomatoid granulomatosis in the brain and healed lesions in the lungs. A review of the neurologic and pulmonary findings in reported cases show that diminution of pulmonary disease with progression of neurologic disease manifest by mass lesion is unusual. Since the etiology, prognosis and prevalence of this disease remains undefined, all patients with this disease should be reported on. In 1972, Liebow et al. [l] published the first description of lymphomatoid granulomatosis; noting that the clinical course and histology of this disease differed from that of “limited” Wegener’s granulomatosis and that these two diseases appeared to have different responses to medical therapy. In lymphomatoid granulomatosis, infiltrates and masses of atypical lymphocytes, plasma cells and histocytes involve the lungs and other organs [2]. The atypical cells resemble but are not identical to those seen with lymphoma. The roentgenographic picture of the lung resembles that seen with classic Wegener’s granulomatosis, but the absence of glomerulonephritis, rare involvement of the upper respiratory tract and frequent involvement of the central nervous system and skin in lymphomatoid granulomatosis are distinguishing features. Our report describes a 24 year old patient with lymphomatoid granulomatosis and reviews the literature, with special emphasis on reported treatment modalities. Our patient is unique because of his dramatic initial pulmonary response to corticosteroid therapy. Improvement was seen clinically, roentgenographically and functionally. Serial pulmonary functions and roentgenographic analyses of a patient with biopsy proved lymphomatoid granulomatosis have not been previously reported. Another unusual finding is the demonstration of mass lesions of lymphomatoid granulomatosis in the central nervous system at autopsy. CASE REPORT A 24 year old Mexican-American man was admitted to the University of Kansas Medical Center in April 1974, with complaints of chest pain and
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progressive lower extremity weakness. He had been well until December 1973, when a nonproductive cough developed associated with sharp, midsternal chest pain. A chest roentgenogram taken by his private physician showed a diffuse pulmonary infiltrate. This did not diminish with antibiotic therapy. In March 1974, an open lung biopsy was performed and the specimen was considered to show inflammation and marked necrosis which was nondiagnostic. In early April he experienced a gradual onset of weakness in all extremities, and his pulmonary symptoms continued. At the time of admission in mid-April 1974, he was dyspneic, unable to walk or use his hands effectively due to marked muscle weakness, and was experiencing urinary hesitancy and fecal incontinence. Physical examination showed diffuse rales in the lung and abnormal neurologic findings. Although he was alert and
A
Figure 1. A, chest roentgenogram obtained in April 1974. A diffuse parenchymal infiltrate is present with increased roentgenographic opacity at the left lateral pleural border. 6, chest roentgenogram obtained in November 1974. The chest roentgenogram is normal. The apparent nodule over the right ninth posterior rib is the anterior termination of the fourth rib.
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oriented, there was some impairment of abstraction and memory. Marked motor weakness was present in all extremities In the lower extremities, dorsiflexion was weaker than plantar flexion. Decreased sensation to pinprick was present in a “stocking-glove” distribution. Proprioception was decreased in all extremities. Plantar responses were flexor. Hoffman’s reflex was absent. Decreased rectal sphincter tone was present. Complete blood count, urinalysis and chemistry profile were within normal limits with the exception of a serum cholesterol of 344 mg/lOO ml. Lipoprotein electrophoresis showed a type Ila pattern. Antinuclear antibody and rheumatoid factor were negative. Muscle enzymes, complement, serum lead and serum vitamin 8,s levels were normal. Fungal serologic studies were negative. Skin tests using purified protein derivative (PPD), histoplasmin, coccidioidin and Candida were negative. Serum protein electrophoresis showed an elevated gamma globulin level of 1.5 g (23.1 per cent). Arterial blood gases on admission were pH 7.40, oxygen tension (PO*) 64 mm Hg, carbon dioxide tension (PCOs) 30 mm Hg. Chest roentgenograms showed alveolar and interstitial infiltrates throughout all lobes (Figure 1A). Sinus films were within normal limits. Electromyographic studies showed both upper and lower motor neuron damage. An electroencephalogram was considered diffusely abnormal, but a brain scan was within normal limits. Bone marrow aspiration showed a slight shift to the left in the myeloid elements. Biopsies of skeletal muscle and temporal artery disclosed normal histology. Biopsy of sural nerve showed patchy demyelination with cellular infiltrates. The slides from the previous lung biopsy were obtained and reviewed (Figure 2). The pathologic diagnosis was lymphomatoid granulomatosis. Since muscular weakness was progressing, treatment with prednisolone was instituted (60 mg/day). The patient was unable to void, and an indwelling urinary catheter was inserted. A cystometrogram showed a neurogenic bladder.
Figure 2.
Lung biopsy specimen shows infiltration of artery
and surrounding tissues by lymphoid cells. (Hematoxylin and
eosin stain, magnification X 100 reduced by 3 1 per cent). These showed features of atypia, such as clearing of nuclear chromatin and macronucleoli. A vasculitis consisting of infiltration by the above cells involved both arteries and veins.
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LYMPHOMATOID GRANULOMATOSIS-BONE ET AL.
TABLE I --.__
Results of Serial Pulmonary
Predicted Value
Study FVC (Liter) TLC (liter) FEV DLCO'
(mmlmin/mm
Pa02 (mm Hg) PaC02 (mm Hg) Prednisone dose
Function Studies
5.29 6.61 4.34 Hg)
41 WI74
-____ 5/2/74
1.68 4.28 1.66
3.08 4.95 2.92
5/14/74 3.87 5.57 3.49
l/17/74 4.48 5.96 3.80
32.5
10.2
35.7
30.2
33.9
80-100 35-43
64 30 0
93 36 60
97 39 75
88 33 40
(mglday) Single breath method. t Neurologic disease had progressed so that the patient could not hold his breath for the period required to accurately
9/25/74 4.90 6.19 3.90 t a2 34 20
l
Pulmonary function studies showed a severe restrictive defect with a moderate decrease in diffusion capacity (Table I). The five-lobe pulmonary infiltrates decreased (by serial chest films) during treatment with oral corticosteroids (Figure IB). The prednisolone dose was tapered to 50 mg/day. Pulmonary function studies showed improvement (Table I). At home on November 7, the patient experienced tha onset of retrobulbar and cervical spine pain, headache and fever with a temperature of 38. I’C. Aspirin and cold packs to the head provided temporary relief, but these symptoms continued. He was seen in the clinic on November 11. Neurologic examination at that time demonstrated residual lower extremity weakness which was considered unchanged from previous clinic examinations. His complaints were thought to be due to a transient viral infection. On November 15, he was admitted to the hospital with the aforementioned complaints as well as blurred vision, vomiting and dysuria. On physical examination, funduscopic examination disclosed no abnormalities. Meningismus was absent. Decreased motor strength was noted in the lower extremities with the left side being the more severely affected. There was “intermittent jerking” of the lower extremities, as well as
Figure3. Lung microscopy. Caseous material (above) and fibrous wall containing vessel showing healed vasculitis (betweenarrows). Hematoxyln and eosin stain; magnification X 100, reduced by 30 per cent.
perform this test.
bilateral unsustained clonus. Plantar response was extensor bilaterally. There was decreased sensation to pinprick in the lower extremities. The patient was unable to stand without assistance. An erythematous, papular, pruritic rash was present. Laboratory values showed complete blood count, blood chemistries and liver function tests to be within normal limits, with the exception of the serum cholesterol level which was elevated to 375 mg/lOO ml. Urinalysis showed 30 to 40 white
Figure 4. Brain at autopsy. Note necrotic lesions of brain stem and pons. (Approximafely 1.3 X natural size.)
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Figure 5. Brain. Vasculitis characterized by infiltration of lymphoid cell with necrosis of brain substance. Hematoxylin and eosin stain; magnification X 100, reduced by 30 per cent.
blood cells/high power field, and urine culture grew Escherichia coli greater than 105/ml. Analysis of cerebrospinal fluid was as follows: glucose 34 mg/lOO ml and protein 290 mg/lOO ml. Serum glucose was 99 mg/lOO ml. The differential white blood cell count was 99 per cent mononuclear with atypical cytology. Repeated antinuclear antibody and lupus erythematosus preparations were negative. The initial diagnosis was that of bacterial or fungal meningitis; however, all cultures of cerebrospinal fluid for fungus and bacteria were negative, as were fungal and viral titers. A therapeutic trial of amphotericin B therapy did not change the patient’s clinical status. Brain scan demonstrated a deep midline mass. Because of the brain scan findings, the atypia of the mononuclear cells in the cerebrospinal fluid, and the negative culture results, the patient was thought to have lymphomatoid granulomatosis involving the central nervous system. A therapeutic trial of increasing the prednisolone dose from 60 mg/kg/day to 100 mg/kg/day had no clinical effect. The administration of cyclophosphamide, 5 mg/ kg/day, was begun on December 7. The patient’s neurologic condition deteriorated, and by December 10, 1974, right-sided cranial nerve palsies developed of the three, four and six cranial nerves. His condition continued to deteriorate with progressive involvement of the fifth cranial nerve on the right side and the third cranial nerve on the left. Cyclophosphamide therapy was discontinued on December 21, and intrathecal methotrexate (10 mg/m2) with citrovorum rescue (6 mg intramuscularly every 4 hours) every other day was begun. By December 24, the intracranial pressure had increased to 400 mm/H20. Because of mild papilledema administration of the intrathecal methotrexate was stopped, after which the neurologic deficits continued to progress. Because the behavior of the pathologic process appeared similar to that of meningeal carcinomatosis, whole brain and upper cervical spine irradiation was begun. Dexamethasone therapy was instituted on December 24 in an attempt to ameliorate the increasing intracranial pressure. After 16 days of dexamethasone therapy, the patient had an episode of
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bloody diarrhea. The dexamethasone dose was decreased, and no more bloody stools occurred although the patient’s condition continued to deteriorate. He was thought to have aspiration pneumonia due to loss of the gag reflex, and was treated with Clindamycin@ and gentamicin. He was transferred to a local hospital to be closer to his family. He died two days after transfer. At autopsy the lungs contained numerous masses with a thick fibrous wall and pasty yellow material. Microscopically, the masses had a wall of collagenous tissue devoid of the characteristic lymphoplasmocytic cells of lymphomatoid granulomatosis (Figure 3). The central part of the lesion was necrotic. Verhoeff’s Van Gieson stain for elastica showed a healed vasculitis involving numerous vessels in the fibrous wall. Histologic stains for bacteria, fungi and acid-fast bacilli on these masses showed no organisms, and culture of these masses for the same microorganisms were sterile. Thus, the pulmonary lesions were considered to be healed lesions of the previously documented lymphomatoid granulomatosis. The brain showed necrosis in the left temporoparietal area, brain stem (measuring 4 by 2 by 1 cm), pons (Figure 4) and cerebellar hemispheres. Microscopically, arteries in the brain were infiltrated by a lymphoplasmocytic infiltrate similar to that described in the original lung biopsy specimen (Figure 5). Lymphoplasmocytic infiltrates consistent with lymphomatoid granulomatosis were seen in abdominal skin, but not in any other site. Lymph nodes showed only cellular depletion. Death was attributed to involvement of the brain stem by le-
sions of lymphomatoid granulomatosis. COMMENTS Lymphomatoid granulomatosis was first described by Liebow et al. [I] in 1972; they characterized this disease of granulomatous lymphoreticular infiltrate as “angiocentric and angiodestructive.” The infiltrate and subsequent vasculitis result in tissue necrosis which often has the gross appearance of a caseating granuloma. In most cases, the disease primarily involves the lungs. Central nervous system involvement is also frequent, occurring in 23 per cent of Liebow’s first 40 patients. Involvement of other organ systems, such as skin [3], skeletal muscle [4], mesentery [4], salivary glands [5], kidney [I], liver [ 11, peripheral nerves [ 11, adrenals [ 11, heart [l] and gastrointestinal tract [4], have been reported. Remarkably, lymph nodes, bone marrow and spleen are rarely involved in this disease process (Table II). The clinical presentation of lymphomatoid granulomatosis depends on the organ symptoms, such as nonproductive cough, fever and dyspnea. In a few patients, the presenting features may be skin rash or central nervous system involvement, with pulmonary involvement developing later. In all reported cases, pulmonary involvement develops at some time. Constitutional complaints, such as weight loss and malaise, are also common. In patients with other presenting complaints, such as skin rash or ataxia, most have roentgenographic evidence of pulmonary involvement.
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LYMPHOMATOID GRANULOMATOSIS--BONE ET AL.
TABLE II
Summary of Recent Cases Organ System(s) Involved
Case No.
Age (yr) and Sex
1
53, M
Lung, skin, liver
2
61. M
Lung, kidney liver
Autopsy
. Yes
Presumed Cause of Death
Skin Test Results PPD-mumps coccidioidomycoses PPD-histoplasmosis
Alive at time of publication Sepsis
+, coccidioidomycoses 3
33. M
Lung, brain adrenal, liver
Yes
4
51. F
Skin, breast, lung, subcutaneous fat
Yes
.
Respiratory insufficiency
5
75. M
Limited
DNCB-Candida
Pneumonia
6
54. M
Skin, lung central nervous system by history Skin
7 8
42, M 67, M
Lung Lung, kidney, adrenal, possibly skin
No Yes
9
55, M
Lung
Alive
10
35, M
Lung
Alive
.
11
40, M
Skin, lung
Alive
.
12
71, M
Skin, lung
No
13
76, M
Lungs
Yes
Respiratory insufficiency
Yes
Pneumonia and pulmonary emboli Respiratory failure Progressive pulmonary disease Alive at time of publication Alive at time of publication Alive at time of publication
PPD-
.
PPD-Candidamumps-DCNB
Myocardial infarction suspected Respiratory insufficiency
Therapy
Reference
Prednisone, [91 cyclophosphamide Cyclophosphamide and 1101 intermittent low-dose prednisone Cyclophosphamide, 1111 vincristine, prednisone Cyclophosphamide, vincristine, prednisone bleomycin Prednisone, 131 cyclophosphamide Vinblastin procarbazine, nitrogen mustard, prednisolone Steroids Chemotherapy
Prednisone, cyclophosphamide Plaquenil, prednisone, nitrogen mustard Prednisone, cyclophosphamide, oncovin Cyclophosphamide and prednisone
[31
151 1121
[81
Digitalis, diuretics, antibiotics, rifampin
NOTE: DNCB = dinitro-chloro-benzene. PPD = tuberculin.
In contrast to Wegener’s granulomatosis, clinical evidence of renal involvement is rare, as glomerulonephritis does not occur. However, renal involvement with granuloma formation does occur in lymphomatoid granulomatosis. Also, the skin manifestations of lymphomatoid granulomatosis differ from those of Wegener’s granulomatosis, which are sharply punched-out ulcers with little cellular infiltrate. Central nervous system symptoms may be the presenting complaint, with or without occult pulmonary disease. The symptoms (ataxia, hemiparesis, dizziness) vary depending on the area involved and the type of involvement. Skin lesions are also a common presenting complaint. The lesions are usually pruritic, nodular or plaque-like and scaly. Ulceration, alopecia and loss of sweating also occur on occasion [3]. One striking feature of lymphomatoid granulomatosis is the parenchymal infiltrates on the chest roentgeno-
gram. Multiple fleeting infiltrates are characteristic, although a diffuse infiltrate resembling a pneumonic process may be present. The lower lung fields are the most frequent site of the lesions, which are most often peripheral and bilateral. Cavitation was seen in 30 per cent of the original patients studied [ 11. Hemorrhage secondary to cavitation was the cause of death in 14 per cent of the original 40 patients. Mass lesions may be seen on intravenous pyleogram and brain scan studies. Other laboratory values are usually normal. Immunoglobulins are sometimes decreased, but this is not a consistent finding [ 11. These mass lesions are usually the result of granuloma. The definitive diagnosis of lymphomatoid granulomatosis is made histologically. Characteristic features of the lesions are plasma cells, lymphocytic cells and large “atypical” mononuclear cells in various stages of maturity infiltrating perivascular tissue. Occlusion by
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TABLE III
Summary of Reported Cases of Central Nervous System Involvement Age
Case
!n!
Organ
No.
Sex
System(s)
1
8. F
.
40. M
4
..
58. F
CNS’,
lungs
Alive
Lung, kidney, liver, tongue, pancreas, skin CNS. skin, lung, kidneys, adrenal peripheral nerves
Yes
Yes, CNS exam excluded
CNS
No
Skin, CNS lungs
Yes
Refer-
Lumbar
Brain Scan
Autopsy
Puncture
EEG
L. orbital Diffusely area enlarged uptake
Therapy
17 WBC: 1 neutrophil, 17 lymphocytes, 4 monocytes; protein 41 mg/lOO ml.; glucose 45 mg/lOO ml.
.
Steroids
ence
[ll Case 19
Prednisone
ill Case
L. frontal lobe infarct
..
Abnormal deep No cells, protein:1 15 mg/ Prednisone 100 ml. glucose 75 midline (brain mg/iOO ml chloride 118 stem) lesion meq/liter “Malignant cells in CSF” CNS-irradiation .. prednisone, tetracycline, irradiation to nodes Prednisone .
;1; Case
24 [fl Case
[ll Case
8
34. M
CNS, lungs
No
..
Lung, lymph node, kidney, CNS, peripheral nervous system Lung, CNS kidney, heart skin, prostate Lung, CNS Skin. CNS
Yes
Lung, CNS adrenal, liver
Yes
Skin, lung, CNS
Limited
..
9 10
67, F 43, M
11
33. M
12
75. M
..
.
..
Prednisone
;1”1 Case 30
[ll Case Prednisone Steroids
No Alive
No cells, protein 34 mg/
..
100 ml., glucose 80 mg/lOO ml.
. .
infiltration of the vessels and subsequent tissue necrosis are frequent findings. With peripheral nerve involvement, the infiltrate is seen surrounding the nerve, and spotty demyelination is present. With skin involvement, the small vessel destruction with a lymphoreticular infiltrate is most often seen surrounding the dermal appendages. Lymphomatoid granulomatosis is often a difficult djsease to diagnose since it presents a confusing clinical picture, and the microscopic appearance seems nonspecific. Metastatic carcinoma and pneumonia are the most common diagnoses. Other common initial diagnoses include other types of pulmonary angiitis, such as Wegener’s granulomatosis, lymphoma and bronchiolitis obliterans. Dermal or mesenteric lesions may be considered “panniculitis.” Central nervous
October 1978
;:1 Case
Yes
.
.
NOTE: CNS = central nervous system; L = left; WBC = white blood cells; CSF = cerebrospinal
714
Prednisone
Cyclophosphamide vincristin, prednisone Prednisone, cyclophosphamide
r”l; Case I”:1
[31
fluid.
system lesions may be confused with primary or metastatic carcinoma, bacterial or fungal abscess, or meningitis. Our case is unique among the reported cases at this time, because granuloma formation due to lymphomatoid granulomatosis was found in the central nervous system at autopsy. One other patient with lymphomatoid granulomatosis and central nervous system symptoms similar to those of our patient has been described, but the central nervous system was not examined at autopsy. Central nervous system disease occurred in 13 of the 53 cases reported to date (Table Ill). In three of the cases with central nervous system involvement at autopsy, the infiltrate was confined to the meninges; in five, there was evidence of encephalitis. Our patient was initially treated with steroids. During
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LYMPHOMATOID
this time his pulmonary function tests improved markedly (Table I). During steroid therapy, the pulmonary function tests returned to normal and remained so until the second hospital admission, after which central nervous system symptoms prevented cooperation for further pulmonary function testing. It is important to note that while the pulmonary lesions remitted during steroid therapy, central nervous system lesions developed rapidly. Of the 13 cases with central nervous system symptoms, the central nervous system manifestations developed in nine while the patients were being treated with steroids (Table Ill). In the remaining four cases [ l,lO-121, the patients, presented with central nervous system symptoms. Of the eight cases in which the patients were treated with steroids alone [ 1,2,5, lo] 1only two [ 1, lo] experienced significant remission. Both of these patients presented with central nervous system disease. Over-all, three patients were alive at the time of the publication [ 1,4,10]. All patients with cranial nerve involvement died. An initial response with subsequent exacerbation, as was seen with our patient, was seen in nine patients [2,3,5,7-9,l l-131. In six patients, including ours, clearing of pulmonary lesions was followed by the development of central nervous system lesions during treatment [3,4,7-9,131. Although steroid therapy may be associated with remission of pulmonary abnormalities, it certainly does not prevent progression of the central nervous system lesions. One patient other than ours received central nervous system irradiation (Case 4). Good results were reported in this instance. Because our patient underwent irradiation very late in the course of the disease, it is difficult to evaluate irradiation as a treatment modality. Combined chemotherapy was used in four instances [ 3,1 I- 131. Central nervous system deterioration continued in all four instances. The etiology of lymphomatoid granulomatosis is unknown. In the original article, Liebow et al. [l] review the most likely possibilities, including the case of primary malignant reticulosis [7] in a child with WiskottAldrich syndrome, as well as the relationship of the disease to lymphoma and Wegener’s granulomatosis.
GRANIJLOMATOSIS--BONE
ET AL.
It is interesting that so many cases of central nervous system disease develop during steroid treatment. Perhaps this points in the direction of lymphoproliferative disease rather than hypersensitivity, although the vascular lesions are very similar to those of hypersensitivity reactions. Possibly, lymphomatoid granulomatosis is an acquired abnormality of the lymphocyte in a susceptible host such as in Sjogren’s syndrome [6,14]. Evidence for this includes the absence of delayed hypersensitivity as evidenced by nonreactivity to skin test antigens including dinitrochloro-benzene (Table II) and the response of the lung lesions to corticosteroids. As in Sjogren’s syndrome, lyphomatoid granulomatosis can terminate in a neoplastic disease. Electron microscopic studies have shown lymphomatoid granulomatosis to be different from other known abnormalities of the lymphoreticular system, with some similarity to “hair-cell” leukemia [8]. Other diseases, such as Mediterranean lymphoma and mycosis fungoides, can have years of symptoms with a biopsy showing nonspecific lymphoid and plasma cell infiltrates before it assumes the usual features of a neoplastic disease. Renal homotransplantation can be followed by lymphoreticular proliferation with involvement of the central nervous system [ 15-l 71. Possibly antigenic exposure in an immunosuppressed host alters cell membrane and produces an autoimmune disease [6]. With continued immunosuppression, neoplastic disease may result. Spontaneous disease in animals, such as the Aleutian mink disease [ 18-201 and immune complex disease of NZB mice [ 2 l-231, is associated with atypical lymphoreticular proliferation and angiitis [23,26]. Experimental models of diffuse granulomatous disease are now available [24,25]. These models may increase our understanding of the pathogenesis of lymphomatoid granulomatosis. Further investigation may help to define whether lymphomatoid granulomatosis is a reactive granulomatosis or a malignant lymphoma of the large lymphoid type [ 131. Possible causes and appropriate treatment for this disease are thus far speculative, and this is a fruitful area for future investigations [26,27].
REFERENCES 1. 2.
3. 4.
Liebow AA, Carrington CR, Friedman PJ: Lymphomatoid granulomatosis. Hum Pathol 3: 457, 1972. Saldana MJ, Patchefsky AS, Israel HI, et al.: Pulmonary angiitis and granulomatosis. The relation between histological features, organ involvement, and response to treatment. Hum Pathol 8: 391. 1977. MacDonald DM, Sarkany I: Lymphomatoid granulomatosis. Clin Exp Dermatol 1: 163, 1976. Mazhar M, McShane KL, Barret FA: Lymphomatoid granulomatosis. Reoort of a case. Rockv Mt Med J 73: 203, 1976. ’
5.
6.
7.
October 1978
Weisbrot IM: Lymphomatoid granulomatosis of the lung, associated with a long history of benign lympho-epithelial lesions of the salivary glands and lymphoid interstitial pneumonitis. Report of a case. Am J Clin Pathol 66: 792, 1976. Liebow AA: The J. Burns Amberson Lecture: Pulmonary Angiitis and Granulomatosis. Am Rev Respir Dis 108: 1, 1973. Brand MD, Marinkovich VA: Primary malignant reticulosis of the brain in Wiskott-Aldrich Syndrome. Arch Dis Child 44: 536, 1969.
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~~wHotdATol0
8.
9. 10. 11. 12.
13.
14.
15. 16.
17.
18.
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~~~ANUL~MATO~IS--B~NE ET AL.
Kays Fu Ys, Minors, N, Brady JW: Lymphomatoid granulomatosis of the skin. Light microscopic and ultra structural studies. Cancer 34: 1675, 1974. Scully R: Case records of the Massachusetts General Hospital. N Engl J of Med 293: 292, 1975. Scully R: Case records of the Massachusetts General Hospital. N Engl J of Med 294: 1052, 1976. Hammar S, Mennemeyer R: Lymphomatoid granulomatosis in a renal transplant recipient. Hum Pathol 7: 6, 1976. Lee SC, Roth LM, Brasher RE: Lymphomatoid granulomatosis: A clinico-pathologic study of four cases. Cancer 38: 846, 1976. Damjanov IJ: Lymphomatoid granulomatosis of We lung associated with active tuberculosis. 2 Erkr Atmungsorgane (143): 56, 1975. Anderson LG, Tala N: The spectrum of benign to malignant lymphoproliferation in Sjogren’s syndrome. Clin Exp Immunol 10: 199.1972. Schnek SA, Penn I: Cerebral neoplasms associated with renal transplantation. Arch Neurol 22: 226, 1970. Doak PB, Montgomeric JZ, Noth JDD, et al.: Reticulum cell sarcoma after renal homotransplantation and azathioprine and prednisone therapy. Br Med J 4: 746. 1968. Pierce JC, Madge GE, Lee HM, et al.: Lymphoma: a complication of renal allotransplantation in man. JAMA 219: 1593, 1972. Porter DD, Larsen A: Virus-host Interactions in Aleutian disease of mink. Perspect Virol 6: 173, 1968.
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19.
20.
21.
22.
23. 24.
25.
26.
27.
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Porter DD, Larsen A, Porter HG: Pathogenesis of Aleutian disease of mink. I. In vivo replication and host antibody response to viral antigens. J Exp Med 130: 575, 1969. Eklund CM, Hadlow WJ, Kennedy RC, et al.: Aleutian disease of mink: properties of the etiologic agent and the host responses. J Infect Dis 118: 510, 1968. East J, Branca M: Autoimmune reactions and malignant changes in germ-free New Zealand black mice. Clin Exp lmmunol4: 621, 1969. Mellors RC: Autoimmune disease in NZB/Bl mice. II. Autoimmunity and malignant lymphoma. Blood 27: 435, 1966. East J: Viruses and autoimmunity. VOX Sang 16: 318, 1968. Davis CR, Min B, Rochester DF, et al.: Histochemical and electron microscopic studies on induced granulomatosis disease in dog lung. Am J Pathol 83a: 82, 1976. Lavietes MH, Min G, Hagstrom WC, et al.: Diffus pulmonary granulomatosis disease in the dog: relation between pressure-volume behavior and morphologic features. Am Rev Respir Dis 116: 907, 1977. Israel HL, Patchefsky AS. Saldona MJ: Wegener’s granulomatosis, lymphomatoid granulomatosis, and benign lymphocytic angiitis and granulomatosis of lung. Ann Intern Med 87: 691, 1977. Fauci AS: Granulomatosis vasculiticles: distinct but not related entities. Ann Intern Med 87: 782. 1977.
