Beitr. Path. Bd. 158,203-211 (1976)
Department of Histopathology, Queen Mary's Hospital London (W. V. Bogomoletz) United Kingdom, Department of Pathological Anatomy (J. Martinez Penuel a V.) and Department of Internal Medicine (J. P. Velilla), Hospital of Navarra, Pamplona, Spain
Eosinophilic Infiltration of the Gastro-Intestinal Tract (Eosinophilic Gastroenteritis) Eosinophiles Infiltrat des Gastrointestinaltraktes (Eosinophile Gastroenteritis) W. V. BOGOMOLETZ, J. P. VELILLA
J. MARTINEZ PENUELA V. and
With 4 Figures· Received November 5, 1975 . Accepted in revised form March
I,
1976
Key words: Eosinophilic infiltration - Gastroenteritis - Diagnosis
Summary Two further cases of eosinophilic infiltration of the gastro-intestinal tract (eosinophilic gastroenteritis) are presented, involving the small intestine of a 73-year old male and the stomach of a 39-year old male. Peripheral blood eosinophilia was present in one case. Clinico-pathological correlations are discussed.
Eosinophilic infiltration of the gastro-intestinal tract (eosinophilic gastroenteritis) is a fairly uncommon condition with protean manifestations. It is characterized histologically by a diffuse eosinophilic infiltrate of a portion of the digestive tract in the absence of gastric and/or intestinal parasitic infestation, vasculitis or neoplasm. Cases are classified, from the pathological viewpoint, into two groups: "diffuse eosinophilic gastroenteritis" and "eosinophilic granulomatous polyp", according to the distribution of the infiltrate. The latter is either widespread with multiple lesions or circumscribed and solitary (Morson and Dawson, 1972). Other criteria used for classification, particularly from the clinical aspect, include eosinophilia in peripheral blood, allergic disorders, response to corticosteroids,
204 .
W. V. Bogomoletz,
J. Martinez Penuel a V. and J. P. Velilla
challenging with specific foods and recurrence (Greenberger and Gryboski, 1973; O'Neill, 1970). In recent years, further interest in eosinophilic infiltration of the gastro-intestinal tract has been sustained by several publications emphasizing its possible relationship with other more lethal disorders such as the "disseminated hypereosinophilic disease" (Manko et al., 197 2). Two further cases of eosinophilic infiltration of small intestine and stomach are reported here, both showing instructive and interesting features.
Report of two cases Case No.
I
A 73-year old male had several hospital admissions for investigations, since 1972, with a clinical diagnosis of probable collagen disease. His main symptoms had been: pyrexia (38 0 C.), aches and pains in the limbs, severe headache of the migraine type, dyspnoea and orthopnoea, palbebral oedema and attacks of bronchial asthma. Numerous laboratory tests had been carried out repeatedly and the most relevant findings were: raised sedimentation rate (from 60 to 80 mm), peripheral blood eosinophilia (5 to 16%) and slightly raised gamma-globulin. Other tests were all within normal limits. Parasites were not identified on repeated stool examination. There was no evidence of malabsorption. A bone marrow biopsy from the iliac crest taken in 1972 had been reported as markedly hypoplastic but showing a slight eosinophilia. A skin biopsy taken in 1974 showed no abnormality of the blood vessels. High doses of corticosteroids were given almost throughout the illness, improving the bronchial asthma and the headaches. In February and April 1974, this patient had two episodes of abdominal distension, treated by gastric aspiration. In June 1974, he was readmitted for a third episode of abdominal distension progressing into a clinical picture of small bowel obstruction, with radiological evidence of small bowel distension with levels. At laparotomy, the small bowel loops were dilated and contained abundant fluid. The distal 30 cms. of ileum were rigid and thickened with a dull serosa. Owing to the poor condition of the patient, no resection was carried out but a latero-Iateral ileo-colic anastomosis was performed and a biopsy was taken from the abnormal ileum. The post-operative course was stormy with suture dehiscence, massive diarrhoea and the patient finally going into shock, with death occurring after a fortnight. A post mortem was not obtained.
Eosinophilic Gastroenteritis .
205
Histological examination of the biopsy revealed the following features: this full-thickness piece of small intestine showed a diffuse infiltration by sheets of mature eosinophils of all the various layers from the mucosa, right through the muscularis propria and into the serosa (Fig. I). The muscle bundles of the muscularis propria were dissociated by this eosinophilic infiltrate (Fig. 2). Histiocytes, lymphocytes and scattered neutrophils were also present, admixed to the eosinophils. The villous pattern of the mucosa was within normal limits as far as villi height and crypts depth were concerned, but the villi appeared somewhat bloated by the excess of eosinophils. Some fatty infiltration was present in the submucosa. There was no evidence of granulomatous lesions, vasculitis or neoplasia. The histopathological diagnosis was that of diffuse eosinophilic enteritis.
Case
NO.2
A 39-year old male was admitted in June 1974 for surgery, with a 6 years history and fairly typical clinical features of chronic peptic ulceration of stomach. His symptoms had been well controlled by medical treatment in the form of alkalis but had worsened recently. At no time had there been any episode of bleeding from the gastro-intestinal tract. This patient was noted to be allergic to penicillin and had complained for many years of Raynaud's phenomenon. Clinical examination and laboratory tests did not reveal any other significant abnormality; in particular, there was no peripheral blood eosinophilia. Radiological investigations showed an ulcer on the lesser curve. A Billroth I gastrectomy was carried out. The post-operative course was uneventful. Macroscopically, the partial gastrectomy specimen showed two ulcers (1.5 cm and 0.5 cm in diameter respectively) with smooth edges, situated on either side of the lesser curve (Fig. 3). A few slightly enlarged lymphnodes were identified along the lesser and greater curves. Histology of the two gastric lesions showed identical features (Fig. 4): the mucosa, submucosa and superficial portion of the muscle wall were ulcerated and partly replaced by granulation tissue. This granulation tissue was heavily and diffusely infiltrated by large numbers of eosinophils. Sheets of eosinophils also extended widely through the full-thickness of the muscle wall, spreading into the serosa. In addition, the deep portion of the muscle wall showed features suggestive of a chronic peptic ulcer: fibrosis, neuromatous hyperplasia and endarteritis obliterans. The mucosal edges of these two ulcers consisted of pyloric mucosa modified by chronic inflammation with patches of intestinal metaplasia. Sections of body mucosa taken at random showed no significant abnormality and, in particular,
206 .
W. V. Bogomolerz, ]. Martinez Penuel a V. and]. P. Velilla
Fig. I. (Case No. J) Full thickness section of the small intestinal biopsy showing a diffuse and transmural infiltration by eosinophils. X 37.5.
Eosinophilic Gastroenteritis . 20 7
Fig. 2. (Case No.1) Bundles of smooth muscle fibres from the muscularis propria ot small intestine, markedly dissociated by the dense and diffuse eosinophilic infiltration . X 150.
208 .
W. V. Bogomoletz,
J. Martinez Penuela V.
and
J. P. Velilla
no eosinophil infiltration. The lymphnodes examined from lesser and greater curves showed reactive hyperplasia and contained large numbers of eosinophils. A histopathological diagnosis of two ulcerated lesions of eosinophilic gastritis was suggested, although the possibility of chronic peptic ulceration with superimposed eosinophil infiltration was also entertained (see discussion) .
Discussion A number of classifications of eosinophilic infiltration of the gastrointestinal tract have been proposed (Ureles et al., 1952; Higgins et al., 1966; O'Neill, 1970), but sometimes cases cannot be easily fitted into one or the other of the schemes proposed. Our Case No. I presented with a background of "collagen disease" and had extensive investigations, but no satisfactory clinical diagnosis was made during this patient's lifetime. A slight peripheral blood eosinophilia,
ulcers situated on either side of the lesser curve ("kissing ulcers"). Fig. 3. (Case No.2) Mucosal aspect of the partial gastrectomy specimen showing twO
Eosinophilic Gastroenteritis .
20 9
Fig. 4. (Case No.2) Full thickness section of one gastric ulcer showing diffuse eOSlllOphilic infiltration of all layers. X 37.5. 14 Beitr. Path. Bd. 158
210 .
W. V. Bogomoletz,
J. Martinez Penuela V. and J. P. Velilla
attacks of asthma and involvement of the small intestine with diffuse eosinophilic infiltration suggest that this patient fits well into Class 1 of Ureles and Group 1 of O'Neill, i.e. a diffuse eosinophilic enteritis with peripheral blood eosinophilia. A post mortem not having been performed, there is no information as to the possibility of eosinophilic infiltration in other parts of the gastro-intestinal tract or in other organs. However, the presence of some eosinophilia in the bone marrow may be a pointer to a more systemic infiltration by eosinophils. In our Case No.2 there were some unusual features worthy of more comments. Penicillin allergy and Raynaud's phenomenon (elicited and confirmed clinically) were in favour of an allergic background. The presentation appeared to be that of gastric peptic ulceration. Macroscopically, the two ulcers were somewhat atypical. The widespread and transmural eosinophilic infiltration seen in both ulcers raised an important differential diagnosis: - two lesions of eosinophilic gastritis with secondary ulceration, or - two chronic ulcers related to peptic ulceration, with the added features of eosinophilic infiltration. In their often quoted paper on the subject, Ureles et al. (1961) described a regional form of circumscribed eosinophilic infiltration involving one part only of the gastro-intestinal tract: twelve such cases were described in the stomach and frequent ulceration was recorded. Furthermore Higgins et al. (1966) described a case (Case NO.4 in their series) which was fairly similar to our Case NO.2: a 41-year old man had a partial gastrectomy following a 6 months history of chronic peptic ulceration of the stomach and after an unsuccessful response to medical treatment. Study of the specimen revealed an acute on chronic benign ulcer with widespread eosinophilic infiltration throughout the stomach wall: regionallymphnodes also showed eosinophilic infiltration of the sinuses. On the other hand, Moyson and Goldstein (1956) reported a series of 257 gastrectomy specimens for benign chronic peptic ulceration of the stomach and showed marked eosinophilic infiltration in 70 cases. These authors pointed out that the lymphnodes examined were free of eosinophils and they related the presence of the eosinophilic infiltration in the gastric wall to an active phase of the disease. No mention was made of the concept of eosinophilic gastroenteritis. Nevertheless, we believe that our Case No.2 shows two lesions of genuine eosinophilic gastritis, and, together with our Case No. I, makes a contribution to the literature on eosinophilic infiltration of the gastrointestinal tract.
Eosinophilic Gastroenteritis .
2I I
Zusammenfassung Es wird iiber 2 FaIle eines eosinophil en Infiltrates im Bereiche des Gastrointestinaltraktes berichtet. In einem Fall war eine periphere Bluteosinophilie vorhanden. Klinischpathologische Zusammenhange werden diskutiert.
References Greenberger, N., and Gryboski, J. D.: Allergic Disorders of the Intestine and Eosinophilic Gastroenteritis, Gastrointestinal Disease, Ed. M. H. Sleisenger and J. S. Fordtran, p. 1066. Saunders, Philadelphia (1973) Higgins, G. A., Lamm, E. R., and Yutzy, C. V.: Eosinophilic Gastroenteritis. Arch. Surg. 92,476-482 (1966) Manko, M. A., Cooper, J. H., and Myers, R. N.: Disseminated Hypereosinophilic Disease. Amer. J. Gastroent. 57, 318-325 (1972) Morson, B. c., and Dawson, 1. M. P.: Gastritis. Gastro-intestinal Pathology, p. IOI. Blackwell, Oxford (1972) Moyson, F., et Goldstein, M.: L'infiltration a polynucleaires eosinophiles des ulceres gastriques. Acta Gastro-Ent. Belg., 19,730-734 (1956) O'Neill, T.: Eosinophilic granuloma of the gastro-intestinal tract. Brit. J. Surg. 57, 704708 (197 0) Ureles, A. 1., Alschibaja, T., Lodico, D., and Stabins, S. J.: Idiopathic Eosinophilic Infiltration of the Gastrointestinal Tract, Diffuse and Circumscribed. Amer. J. Med. 30, 899-909 (19 61 ) Dr. W. V. Bogomoletz, Dept. of Histopathology, Queen Mary's Hospital, Roehampton, London SW 15 5 PN, U.K.
Department of Histopathology, Queen Mary's Hospital London (W. V. Bogomoletz) United Kingdom, Department of Pathological Anatomy (J. Martinez Penuel a V.) and Department of Internal Medicine (J. P. Velilla), Hospital of Navarra, Pamplona, Spain
Eosinophilic Infiltration of the Gastro-Intestinal Tract (Eosinophilic Gastroenteritis) Eosinophiles Infiltrat des Gastrointestinaltraktes (Eosinophile Gastroenteritis) W. V. BOGOMOLETZ, J. P. VELILLA
J. MARTINEZ PENUELA V. and
With 4 Figures· Received November 5, 1975 . Accepted in revised form March
I,
1976
Key words: Eosinophilic infiltration - Gastroenteritis - Diagnosis
Summary Two further cases of eosinophilic infiltration of the gastro-intestinal tract (eosinophilic gastroenteritis) are presented, involving the small intestine of a 73-year old male and the stomach of a 39-year old male. Peripheral blood eosinophilia was present in one case. Clinico-pathological correlations are discussed.
Eosinophilic infiltration of the gastro-intestinal tract (eosinophilic gastroenteritis) is a fairly uncommon condition with protean manifestations. It is characterized histologically by a diffuse eosinophilic infiltrate of a portion of the digestive tract in the absence of gastric and/or intestinal parasitic infestation, vasculitis or neoplasm. Cases are classified, from the pathological viewpoint, into two groups: "diffuse eosinophilic gastroenteritis" and "eosinophilic granulomatous polyp", according to the distribution of the infiltrate. The latter is either widespread with multiple lesions or circumscribed and solitary (Morson and Dawson, 1972). Other criteria used for classification, particularly from the clinical aspect, include eosinophilia in peripheral blood, allergic disorders, response to corticosteroids,
204 .
W. V. Bogomoletz,
J. Martinez Penuel a V. and J. P. Velilla
challenging with specific foods and recurrence (Greenberger and Gryboski, 1973; O'Neill, 1970). In recent years, further interest in eosinophilic infiltration of the gastro-intestinal tract has been sustained by several publications emphasizing its possible relationship with other more lethal disorders such as the "disseminated hypereosinophilic disease" (Manko et al., 197 2). Two further cases of eosinophilic infiltration of small intestine and stomach are reported here, both showing instructive and interesting features.
Report of two cases Case No.
I
A 73-year old male had several hospital admissions for investigations, since 1972, with a clinical diagnosis of probable collagen disease. His main symptoms had been: pyrexia (38 0 C.), aches and pains in the limbs, severe headache of the migraine type, dyspnoea and orthopnoea, palbebral oedema and attacks of bronchial asthma. Numerous laboratory tests had been carried out repeatedly and the most relevant findings were: raised sedimentation rate (from 60 to 80 mm), peripheral blood eosinophilia (5 to 16%) and slightly raised gamma-globulin. Other tests were all within normal limits. Parasites were not identified on repeated stool examination. There was no evidence of malabsorption. A bone marrow biopsy from the iliac crest taken in 1972 had been reported as markedly hypoplastic but showing a slight eosinophilia. A skin biopsy taken in 1974 showed no abnormality of the blood vessels. High doses of corticosteroids were given almost throughout the illness, improving the bronchial asthma and the headaches. In February and April 1974, this patient had two episodes of abdominal distension, treated by gastric aspiration. In June 1974, he was readmitted for a third episode of abdominal distension progressing into a clinical picture of small bowel obstruction, with radiological evidence of small bowel distension with levels. At laparotomy, the small bowel loops were dilated and contained abundant fluid. The distal 30 cms. of ileum were rigid and thickened with a dull serosa. Owing to the poor condition of the patient, no resection was carried out but a latero-Iateral ileo-colic anastomosis was performed and a biopsy was taken from the abnormal ileum. The post-operative course was stormy with suture dehiscence, massive diarrhoea and the patient finally going into shock, with death occurring after a fortnight. A post mortem was not obtained.
Eosinophilic Gastroenteritis .
205
Histological examination of the biopsy revealed the following features: this full-thickness piece of small intestine showed a diffuse infiltration by sheets of mature eosinophils of all the various layers from the mucosa, right through the muscularis propria and into the serosa (Fig. I). The muscle bundles of the muscularis propria were dissociated by this eosinophilic infiltrate (Fig. 2). Histiocytes, lymphocytes and scattered neutrophils were also present, admixed to the eosinophils. The villous pattern of the mucosa was within normal limits as far as villi height and crypts depth were concerned, but the villi appeared somewhat bloated by the excess of eosinophils. Some fatty infiltration was present in the submucosa. There was no evidence of granulomatous lesions, vasculitis or neoplasia. The histopathological diagnosis was that of diffuse eosinophilic enteritis.
Case
NO.2
A 39-year old male was admitted in June 1974 for surgery, with a 6 years history and fairly typical clinical features of chronic peptic ulceration of stomach. His symptoms had been well controlled by medical treatment in the form of alkalis but had worsened recently. At no time had there been any episode of bleeding from the gastro-intestinal tract. This patient was noted to be allergic to penicillin and had complained for many years of Raynaud's phenomenon. Clinical examination and laboratory tests did not reveal any other significant abnormality; in particular, there was no peripheral blood eosinophilia. Radiological investigations showed an ulcer on the lesser curve. A Billroth I gastrectomy was carried out. The post-operative course was uneventful. Macroscopically, the partial gastrectomy specimen showed two ulcers (1.5 cm and 0.5 cm in diameter respectively) with smooth edges, situated on either side of the lesser curve (Fig. 3). A few slightly enlarged lymphnodes were identified along the lesser and greater curves. Histology of the two gastric lesions showed identical features (Fig. 4): the mucosa, submucosa and superficial portion of the muscle wall were ulcerated and partly replaced by granulation tissue. This granulation tissue was heavily and diffusely infiltrated by large numbers of eosinophils. Sheets of eosinophils also extended widely through the full-thickness of the muscle wall, spreading into the serosa. In addition, the deep portion of the muscle wall showed features suggestive of a chronic peptic ulcer: fibrosis, neuromatous hyperplasia and endarteritis obliterans. The mucosal edges of these two ulcers consisted of pyloric mucosa modified by chronic inflammation with patches of intestinal metaplasia. Sections of body mucosa taken at random showed no significant abnormality and, in particular,
206 .
W. V. Bogomolerz, ]. Martinez Penuel a V. and]. P. Velilla
Fig. I. (Case No. J) Full thickness section of the small intestinal biopsy showing a diffuse and transmural infiltration by eosinophils. X 37.5.
Eosinophilic Gastroenteritis . 20 7
Fig. 2. (Case No.1) Bundles of smooth muscle fibres from the muscularis propria ot small intestine, markedly dissociated by the dense and diffuse eosinophilic infiltration . X 150.
208 .
W. V. Bogomoletz,
J. Martinez Penuela V.
and
J. P. Velilla
no eosinophil infiltration. The lymphnodes examined from lesser and greater curves showed reactive hyperplasia and contained large numbers of eosinophils. A histopathological diagnosis of two ulcerated lesions of eosinophilic gastritis was suggested, although the possibility of chronic peptic ulceration with superimposed eosinophil infiltration was also entertained (see discussion) .
Discussion A number of classifications of eosinophilic infiltration of the gastrointestinal tract have been proposed (Ureles et al., 1952; Higgins et al., 1966; O'Neill, 1970), but sometimes cases cannot be easily fitted into one or the other of the schemes proposed. Our Case No. I presented with a background of "collagen disease" and had extensive investigations, but no satisfactory clinical diagnosis was made during this patient's lifetime. A slight peripheral blood eosinophilia,
ulcers situated on either side of the lesser curve ("kissing ulcers"). Fig. 3. (Case No.2) Mucosal aspect of the partial gastrectomy specimen showing twO
Eosinophilic Gastroenteritis .
20 9
Fig. 4. (Case No.2) Full thickness section of one gastric ulcer showing diffuse eOSlllOphilic infiltration of all layers. X 37.5. 14 Beitr. Path. Bd. 158
210 .
W. V. Bogomoletz,
J. Martinez Penuela V. and J. P. Velilla
attacks of asthma and involvement of the small intestine with diffuse eosinophilic infiltration suggest that this patient fits well into Class 1 of Ureles and Group 1 of O'Neill, i.e. a diffuse eosinophilic enteritis with peripheral blood eosinophilia. A post mortem not having been performed, there is no information as to the possibility of eosinophilic infiltration in other parts of the gastro-intestinal tract or in other organs. However, the presence of some eosinophilia in the bone marrow may be a pointer to a more systemic infiltration by eosinophils. In our Case No.2 there were some unusual features worthy of more comments. Penicillin allergy and Raynaud's phenomenon (elicited and confirmed clinically) were in favour of an allergic background. The presentation appeared to be that of gastric peptic ulceration. Macroscopically, the two ulcers were somewhat atypical. The widespread and transmural eosinophilic infiltration seen in both ulcers raised an important differential diagnosis: - two lesions of eosinophilic gastritis with secondary ulceration, or - two chronic ulcers related to peptic ulceration, with the added features of eosinophilic infiltration. In their often quoted paper on the subject, Ureles et al. (1961) described a regional form of circumscribed eosinophilic infiltration involving one part only of the gastro-intestinal tract: twelve such cases were described in the stomach and frequent ulceration was recorded. Furthermore Higgins et al. (1966) described a case (Case NO.4 in their series) which was fairly similar to our Case NO.2: a 41-year old man had a partial gastrectomy following a 6 months history of chronic peptic ulceration of the stomach and after an unsuccessful response to medical treatment. Study of the specimen revealed an acute on chronic benign ulcer with widespread eosinophilic infiltration throughout the stomach wall: regionallymphnodes also showed eosinophilic infiltration of the sinuses. On the other hand, Moyson and Goldstein (1956) reported a series of 257 gastrectomy specimens for benign chronic peptic ulceration of the stomach and showed marked eosinophilic infiltration in 70 cases. These authors pointed out that the lymphnodes examined were free of eosinophils and they related the presence of the eosinophilic infiltration in the gastric wall to an active phase of the disease. No mention was made of the concept of eosinophilic gastroenteritis. Nevertheless, we believe that our Case No.2 shows two lesions of genuine eosinophilic gastritis, and, together with our Case No. I, makes a contribution to the literature on eosinophilic infiltration of the gastrointestinal tract.
Eosinophilic Gastroenteritis .
2I I
Zusammenfassung Es wird iiber 2 FaIle eines eosinophil en Infiltrates im Bereiche des Gastrointestinaltraktes berichtet. In einem Fall war eine periphere Bluteosinophilie vorhanden. Klinischpathologische Zusammenhange werden diskutiert.
References Greenberger, N., and Gryboski, J. D.: Allergic Disorders of the Intestine and Eosinophilic Gastroenteritis, Gastrointestinal Disease, Ed. M. H. Sleisenger and J. S. Fordtran, p. 1066. Saunders, Philadelphia (1973) Higgins, G. A., Lamm, E. R., and Yutzy, C. V.: Eosinophilic Gastroenteritis. Arch. Surg. 92,476-482 (1966) Manko, M. A., Cooper, J. H., and Myers, R. N.: Disseminated Hypereosinophilic Disease. Amer. J. Gastroent. 57, 318-325 (1972) Morson, B. c., and Dawson, 1. M. P.: Gastritis. Gastro-intestinal Pathology, p. IOI. Blackwell, Oxford (1972) Moyson, F., et Goldstein, M.: L'infiltration a polynucleaires eosinophiles des ulceres gastriques. Acta Gastro-Ent. Belg., 19,730-734 (1956) O'Neill, T.: Eosinophilic granuloma of the gastro-intestinal tract. Brit. J. Surg. 57, 704708 (197 0) Ureles, A. 1., Alschibaja, T., Lodico, D., and Stabins, S. J.: Idiopathic Eosinophilic Infiltration of the Gastrointestinal Tract, Diffuse and Circumscribed. Amer. J. Med. 30, 899-909 (19 61 ) Dr. W. V. Bogomoletz, Dept. of Histopathology, Queen Mary's Hospital, Roehampton, London SW 15 5 PN, U.K.
