Penelitian

Association of Campylobacter pylori on the Gastric Mucosa with Antral Gastritis in Children
Brendan Drumm, M.B., Philip Sherman, M.D., Ernest Cutz, M.D., and Mohamed Karmali, M.D. N Engl J Med 1987; 316:1557-1561June 18, 1987 Abstract We investigated the presence of Campylobacter pylori colonization of the gastric mucosa and of histologic evidence of gastritis in a prospective study of 71 consecutive children undergoing upper gastrointestinal tract endoscopy and gastric biopsies because of gastrointestinal symptoms. Two tissue samples from the gastric antrum were obtained from 67 of the 71 children (mean age [SD], 11.43.8 years). One sample was evaluated for evidence of gastritis and stained with silver to detect organisms morphologically resembling campylobacter. The second sample was cultured for C. pylori, and a portion was used to perform a urease-screening test for the presence of C. pylori. Antral gastritis was diagnosed histologically in 18 of 67 patients. C. pylori was identified by both culture and silver staining on the antral mucosa in 7 of 10 patients with unexplained gastritis (primary gastritis) but in none of 8 patients with gastritis associated with an identifiable underlying cause (secondary gastritis). C. pylori was not identified in any of the 49 cases with normal histologic features. The urease-screening test was positive in only three of six patients with a positive culture for C. pylori. Duodenal ulcers were diagnosed by endoscopy in five patients. Each of the five had C. pylori on the antral mucosa, but organisms were not identified on the duodenal mucosa. We conclude that the presence of C. pylori on the antral mucosa is specifically associated with primary antral gastritis and may also be associated with primary duodenal ulceration. (N Engl J Med 1987; 316:155761.) Dr. Drumm is the recipient of the Anna Bradbury Springer Fellowship. Dr. Sherman is the recipient of a Career Scientist Award from the Ontario Ministry of Health Research Personnel Development Program. Presented at the March 1987 Annual Meeting of the American Society of Microbiology in Atlanta. We are indebted to Mrs. Mary Corey for performing the statistical analyses and to Ms. Margaret Roscoe for technical assistance. http://www.nejm.org/doi/full/10.1056/NEJM198706183162501

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Presentation of Case

Dr. Allison L. McDonough (Internal Medicine): A 51-year-old man with a history of gastric cancer was admitted to the hospital because of a new pulmonary lesion. The patient had been in good health until approximately 5 years before admission, when he had a decreased appetite and epigastric discomfort; evaluation at another facility revealed a hiatal hernia, gastroesophageal reflux, and a duodenal ulcer. Testing for Helicobacter pylori was positive. Omeprazole and metoclopramide were administered, and the hiatal hernia was surgically repaired. Pain, persistent gastroesophageal reflux, and weight loss developed approximately 2.5 years before admission. A primary care physician at this hospital prescribed combination therapy (lansoprazole, amoxicillin, and clarithromycin) for 2 weeks to treat the H. pylori infection; this therapy was repeated 3 months later because of noncompliance, but the symptoms persisted. At that time, the hematocrit was 38.8%, and the remainder of the complete blood count was normal. The phosphorus level was 1.3 mg per deciliter (0.4 mmol per liter; reference range, 2.6 to 4.5 mg per deciliter [0.8 to 1.5 mmol per liter]), the lipase level was 77 U per liter (reference range, 13 to 60), and the amylase level was 164 U per liter (reference range, 3 to 100). Electrolyte levels and the results of renal- and liver-function tests were normal. Ultrasonography of the abdomen was normal. Abdominal pain recurred intermittently, and 2 years before admission, upper gastrointestinal endoscopy revealed distal esophagitis; a nonbleeding linear ulceration, 10 mm in the greatest dimension, in the gastric antrum; marked edema in the prepyloric antrum; a nonbleeding, cratered ulcer, 12 mm in diameter, in the pyloric channel; and partial gastric-outlet obstruction. Pathological examination of biopsy specimens from the pylorus revealed poorly differentiated adenocarcinoma with signet-ring cells. Thiazine staining of biopsy specimens was negative for H. pylori. Computed tomography (CT) of the abdomen showed thickening of the wall of the antrum, without evidence of local invasion or intraabdominal metastases. A subtotal gastrectomy was performed. Pathological examination revealed a poorly differentiated signet-ringcell adenocarcinoma of the pylorus, 4.0 cm in the greatest dimension, leading to a diagnosis of stage II cancer (T2,N1,MX), with 2 of 12 lymph nodes positive for tumor and perineural invasion, with no vascular or lymphatic invasion. The tumor had invaded the subserosa but did not involve the serosal surface. The proximal, distal, and radial margins were free of tumor. Reactive gastropathy with mild chronic inflammation and intestinal metaplasia was present. Thiazine staining for H. pylori was negative. The hematocrit was 37.7%, the white-cell count was 12,000 per cubic millimeter, with 12% eosinophils (normal range, 0 to 8%), and the remainder of the complete blood count was normal. The phosphorus level was 2.2 mg per deciliter (0.7 mmol per liter), and the calcium level was 8.8 mg per deciliter (2.2 mmol per liter). The results of renal- and liver-function tests were normal. The patient was referred for an oncology evaluation but did not keep the appointments. Eleven months before admission, the patient came to the emergency department of this hospital because of a 3-month history of back and chest pain, as well as bilateral sharp, pleuritic,

subscapular pain that had occurred occasionally. He had had early satiety since his abdominal surgery. A chest radiograph showed a nodule, 4 mm in diameter, with the density of metal that was overlying the fifth posterior rib; the nodule was thought to represent a foreign body outside the chest cavity. The radiograph was otherwise normal. The hematocrit was 40.2%. The remainder of the complete blood count and measurements of electrolytes and renal function were normal. One month later, the patient was seen by pulmonary and gastroenterology specialists. He reported that his weight had increased after his partial gastrectomy but that he had lost weight in recent months. The subscapular pain had resolved spontaneously, and he had no respiratory symptoms, fever, or chills. Physical examination showed that he was a thin, anxious man with mild temporal wasting. The weight was 58.1 kg, and the oxygen saturation was 97% while the patient was breathing ambient air. The abdominal scar was well healed, and there was moderate clubbing of the fingers; the remainder of the examination was normal. CT of the chest revealed multiple, small centrilobular nodules and small cysts, each less than 3 mm in diameter. The patient was advised to have a follow-up CT scan 3 months later. A follow-up CT scan obtained 5.5 months later (4.5 months before admission) revealed persistent centrilobular ground-glass nodules and scattered, small parenchymal cysts in the lungs, with no evidence of metastatic disease in the abdomen or pelvis. The patient had pain in the abdominal wall at the site of the surgical scar, early satiety, nausea, fatigue, and weight loss. He appeared thin and chronically ill, with a weight of 56.7 kg. There was clubbing of all digits, and a small, tender, firm nodule consistent with a keloid was palpated in the surgical scar. The hematocrit was 40.1%, and the white-cell count 7700 per cubic millimeter, with 9% eosinophils. The remainder of the complete blood count was normal. Measurements of serum electrolytes and liver-function tests were normal. The urea nitrogen level was 21 mg per deciliter (7.5 mmol per liter), the creatinine level 1.0 mg per deciliter (88.4 mol per liter), and the lipase level 163 U per liter. Upper gastrointestinal endoscopy revealed mild reactive gastropathy and a nodule, 1 cm in diameter, in the gastric body; biopsy specimens of the nodule and of gastric and small-intestine mucosa at the anastomosis site showed both acute and chronic inflammation. Two weeks before admission, a CT scan of the abdomen and pelvis was unchanged, but CT of the chest showed a new nodule, 4.5 mm in diameter, in the lower lobe of the left lung, with a rim of ground-glass opacification. The small ground-glass nodules and cysts were unchanged as compared with those on the previous scans. He was admitted to this hospital. The patient did not have cough, hemoptysis, bone pain, or headaches, and his weight had been stable for the previous 4 months. His medications included metoclopramide, omeprazole, and cyclobenzaprine; he had no allergies. He had been born in Brazil and had immigrated to the United States more than 20 years earlier. He visited Brazil approximately annually, and 7 years earlier, he had lived in Japan for 1 year. He was married to a woman of JapaneseBrazilian ancestry and had lived with his wife and children until 4 months before admission, when his family returned to Brazil after he left his job in a factory because of poor health. He ate cooked, but not raw, shellfish. His father had died at 39 years of age from gastric cancer, and his mother had died at 65 years of age from bronchitis. His children and siblings were healthy. He had smoked cigarettes for 25 years but had stopped 3 months before admission.

The vital signs were normal, and the physical examination was unchanged. An electrocardiogram was normal, and pulmonary-function tests showed a low diffusion capacity of the lung for carbon monoxide, after correction for alveolar volume. The complete blood count, serum electrolyte levels, liver function, and renal function were normal. A diagnostic procedure was performed.
First Differential Diagnosis

Dr. Edward T. Ryan: I was involved in the care of this patient and am aware of the diagnosis. I believe that this 51-year-old man originally from Brazil, with gastric cancer and a new pulmonary nodule, has sequelae of two common infectious diseases. Is this patient's gastric cancer a sequela of an infection? The World Heath Organization currently estimates that approximately one fifth of all cancer cases worldwide are due to chronic infections, including cases of liver cancer associated with hepatitis B, cervical cancer associated with the human papillomavirus, lymphoma associated with the human immunodeficiency virus and Kaposi's sarcoma, bladder cancer associated with schistosomiasis, cholangiocarcinoma associated with liver-fluke infection, and gastric cancer associated with H. pylori infection.1 Gastric adenocarcinoma has historically been the most common nonskin cancer and the most common cause of cancer-related deaths in humans, and a number of prospective and retrospective studies have clearly linked H. pylori colonization of the stomach to both distal gastric adenocarcinoma and gastric B-cell lymphoma.2-5
H. pylori Infection and Gastric Cancer

Five years before admission, the patient had received a diagnosis of H. pylori infection, based on symptoms of gastroesophageal reflux and peptic ulcer disease and evidence of H. pylori on examination of gastric tissue. H. pylori is a motile gram-negative bacillus that infects more than half the human population. Infection usually occurs in childhood and is associated with crowding, poor sanitation, and residence in resource-poor areas of the world, suggesting oral oral or fecaloral transmission. This patient was raised in Brazil, where both H. pylori infection and gastric cancer are relatively common. Persons with H. pylori infection have a risk of gastric cancer that is three to six times that of persons without such infection, as well as an attributable risk of 50 to 80% for gastric adenocarcinoma.2,4 The risk of gastric adenocarcinoma varies even among geographic areas in which H. pylori infection is highly prevalent, suggesting that additional factors lead to H. pyloriassociated gastric cancer. For instance, certain polymorphisms in genes coding for proinflammatory cytokines have been associated with gastric cancer, suggesting that differences in host inflammatory responses to H. pylori infection may affect the development of gastric carcinoma.6 This patient has a family history of gastric cancer and infection with H. pylori; both are risk factors for distal gastric adenocarcinoma. Persons of JapaneseBrazilian ancestry have a high risk of gastric cancer, which remains relatively high even after emigration; however, although the patient has lived in Japan, he is not of Japanese descent.7-9

Although the majority of H. pylori infections are asymptomatic, this patient had multiple complications. H. pylori strains that are positive for CagA, a toxin injected by the bacteria into eukaryotic cells, are most likely to cause illness in humans, including chronic gastritis, peptic ulcer disease, and gastric adenocarcinoma, all of which this patient had.10-12 Chronic gastritis caused by infection with H. pylori is associated with intestinal metaplasia and loss of production of gastric acid, and the strains of H. pylori that cause gastritis and gastric cancer have been associated with a protective effect against gastroesophageal reflux disease, Barrett's esophagus, and adenocarcinoma of the distal esophagus.13,14 The incidence of gastric cancer has decreased in resource-rich areas in recent decades, predominantly because of a decrease in the incidence of adenocarcinomas of the distal stomach, and concomitantly, there has been an increase in the incidence of adenocarcinomas of the proximal stomach and distal esophagus, cancers associated with gastroesophageal reflux disease.15 Therefore, paradoxically, an adverse effect of H. pylori infection may be replaced by an adverse effect of its eradication. Not surprisingly, our patient's symptoms of gastroesophageal reflux persisted after the H. pylori infection was treated. At the time of the diagnosis of gastric adenocarcinoma, no organisms were seen in the pathological specimens. This finding is not infrequent. In studies in Brazil, 15 to 45% of patients with gastric carcinoma had no evidence of active H. pylori infection on microscopical examination at the time of treatment of their gastric cancer.16,17
Pulmonary Nodules

In summary, this patient's gastric carcinoma is in all likelihood a complication of an infectious disease namely, infection with H. pylori. One year after his gastrectomy, he presented with symptoms of pleuritic chest pain and abnormalities on imaging studies of the chest. May we review the imaging studies? Dr. Suzanne L. Aquino: The chest radiograph obtained 11 months before admission was normal. CT of the thorax 10 months and 4.5 months before admission did not show evidence of metastatic cancer. High-resolution CT with the use of 1.25-mm slices, however, showed bilateral centrilobular nodules (Figure 1AFigure 1 CT of the Thorax.) and cysts; some cysts were clustered and showed perceptible walls (Figure 1B). The differential diagnosis of these lesions includes centrilobular emphysema with respiratory bronchiolitis caused by smoking, Langerhans'-cell histiocytosis, and less likely, a disseminated infectious process. The lesions are not typical of a neoplasm, sarcoidosis, Wegener's granulomatosis, tuberculosis, or fungal infection. The CT scan obtained 2 weeks before admission showed a new nodule in the left lower lobe (Figure 1C), which was solid in the center with surrounding ground-glass opacification suspicious for a metastatic lesion with surrounding hemorrhage or mucin. The clustered centrilobular cysts and ground-glass nodules were unchanged. Dr. Ryan: This patient had two types of pulmonary lesions, which were probably not related. Pulmonary nodules and cysts can have many causes, including cancer, infections, and noninfectious inflammatory conditions. Sarcoidosis and Wegener's granulomatosis are not likely,

given the findings on imaging. Langerhans'-cell histiocytosis occurs in smokers and could explain the small nodules. Infection with Mycobacterium tuberculosis or other mycobacteria, as well as invasive fungal infections such as cryptococcosis, histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis, could be considered. The small size and scattered nature of most of the lesions and the absence of characteristic symptoms or signs make most infections unlikely. This patient initially had pleuritic, subscapular pain, and laboratory evaluation showed a slightly elevated peripheral-blood eosinophil count on several occasions. Peripheral eosinophilia (defined as an eosinophil count of >400 per cubic millimeter) had actually been present for at least 3 years, and this patient traveled frequently to Brazil and had resided in Japan. Although these factors could prompt consideration of infection with lung parasites, such as in dirofilariasis and paragonimiasis, given this patient's history of gastric cancer and smoking, his caregivers were concerned that the new pulmonary nodule could be a manifestation of a malignant tumor in the lung either metastatic gastric cancer or a new primary lung cancer. Evaluation of tissue specimens was warranted, and the nodule was resected by means of video-assisted thoracoscopic surgery.
Clinical Diagnoses

Adenocarcinoma of the stomach, associated with H. pylori infection. Possible metastasis of the cancer to the lung.
First Pathological Discussion

Dr. Richard L. Kradin: Examination of the specimen from the wedge resection of the left lung (Figure 2AFigure 2 Lung-Biopsy Specimen (Hematoxylin and Eosin Stain).) revealed two tracts of necrotizing granulomatous inflammation with eosinophilic debris at their centers. There was centriacinar emphysema of the surrounding lung and pigmented macrophages, which are typically found in the lungs of smokers. Within the debris at the center of the granulomas, examination at a higher magnification showed a severely degenerated helminth with tegument composed of layers of smooth muscle and dead tegumental cells (Figure 2B). The morphologic characteristics were consistent with those of a trematode or fluke, but given the degree of degeneration, it was impossible to accurately measure the size. A second fluke was seen in an adjacent section. Ova with refractile cortexes (Figure 2C) were surrounded by granulomatous inflammation and foreign-body giant cells. Paragonimus is the most common fluke to infect the lung. It is a plump, oval fluke that on average is approximately 10 mm long and 5 mm wide, with both oral and ventral suckers. The body wall is composed of a tegument that includes two layers of smooth muscle and tegumental cells and is characteristically covered with spines, which were not seen in this case. The eggs are ovoid, varying in size among species from 80 to 120 m in length, and birefringent, with a double-layered cortex. The ova in this case were highly refractile, but they did not show strong birefringence under polarized light.

Schistosomiasis can also involve the lung, typically through translocation of ova into the pulmonary arterial system, but aberrant migration of adult schistosomes into the lung does occasionally occur. Adult schistosoma are typically longer and thinner than adult paragonimus, and their ova are larger. The cortical surfaces of the ova of Schistosoma mansoni or S. haematobium may exhibit prominent lateral or terminal spines, respectively, but these were not evident in the case under discussion. The degree of degeneration of both the parasites and ova in this case made it impossible to establish a specific morphologic diagnosis with certainty. In summary, the large lung nodule is due to infection with a trematode, which cannot be definitively identified but is most consistent with paragonimus. The small centrilobular nodules seen on CT most likely represent changes caused by smoking, with respiratory bronchiolitis, centriacinar emphysema, and peribronchiolar scarring.
Second Differential Diagnosis

Dr. Ryan: I first saw this patient after examination of the lung-biopsy specimen showed evidence of a worm. Helminths that infect humans include roundworms (nematodes), flatworms (tapeworms or cestodes), and flukes (trematodes). Flukes that infect humans include intravascular, hepatic, pulmonary, and intestinal flukes (Table 1Table 1 Common Trematode (Fluke) Infections in Humans.). Worldwide, the majority of the illness and death related to human infection with trematodes is due to schistosoma species; however, the vast majority of the approximately 20 million persons worldwide infected with lung flukes are infected with paragonimus species, usually Paragonimus westermani.
Paragonimiasis

The majority of paragonimus infections in humans are reported in East and Southeast Asia, including Japan, where this patient had lived. Most people become infected after eating raw or undercooked crabs or crayfish or the meat of infected paratenic hosts such as pigs or boars. Although this patient ate shellfish, he reported that he did not eat uncooked shellfish. After the ingestion of paragonimus, metacercariae penetrate the intestinal wall, cross the diaphragm, and migrate through the lungs, where they may cause pneumothorax, pleural effusions, and diffuse or nodular pulmonary infiltrates.16 Eventually, cystic structures from 1 to 5 cm in diameter form; these structures often contain two or three worms, are filled with thick bloody fluid, and typically have bronchopulmonary fistulas. During the acute phase of the disease, abdominal pain, pleurisy, cough, fever, eosinophilia, and urticaria may develop. Chronic pulmonary paragonimiasis is usually relatively asymptomatic, but patients may have cough, with brown or blood-tinged sputum. A presumptive diagnosis of pulmonary paragonimiasis is made on the basis of characteristic findings on imaging, persistent cough, and epidemiologic and geographic risk factors. This patient had resided in Japan and had a history of abdominal pain, pleurisy, and mild eosinophilia, but no cough; the radiologic findings are consistent with paragonimiasis, although the absence of a central cavity in the lung nodule makes paragonimiasis less likely. A specific diagnosis rests on

the identification of eggs in sputum, bronchial washings, gastric aspirates, or stool specimens or on the pathological identification of worms in resected tissue, as in this case. Serologic assays17 and antigen-detection assays18 are also available. Although the diagnosis of paragonimiasis is tempting in this case, a number of atypical features raise questions about this diagnosis. Where and when could this patient have acquired this infection? Although paragonimiasis is endemic in some areas of Latin America, to my knowledge, human acquisition has not been convincingly documented in Brazil. Although this patient could have acquired the infection in Japan, his last visit was 7 years earlier, and it is difficult to link the new pulmonary nodule with such a distant possible exposure to paragonimus. There have been rare case reports of paragonimiasis in the United States,19 usually after ingestion of undercooked crayfish.
Schistosomiasis

Could the degenerated trematodes in the lung represent another type of fluke? Schistosomiasis due to S. mansoni is endemic in many areas of Brazil. Pairs of adult worms usually reside in the mesenteric veins; a local inflammatory response to the eggs permits passive transit of the eggs into the intestinal lumen (where they are shed in feces) and also into the liver (where they may cause inflammation, fibrosis, and cirrhosis). Eggs may passively enter the pulmonary circulation, usually by means of portal shunting caused by hepatic schistosomiasis, where they can lead to pulmonary inflammation, fibrosis, hypertension, and cor pulmonale. Rarely, pairs of adult schistosomal worms may migrate aberrantly into the pulmonary vasculature, and they have been identified within pulmonary nodules.20 The pathological evaluation shows the presence of lung flukes and eggs that could be due to paragonimiasis or schistosomiasis. The sequence of events, epidemiologic factors, and exposure history are most consistent with pulmonary schistosomiasis caused by a worm pair that entered the pulmonary circulation at about the time of the onset of the pleurisy. To distinguish between paragonimiasis and schistosomiasis, we recommended the analysis of stool specimens for ova and parasites and conducted serum antibody testing. The treatment for both infections involves the same drug, praziquantel; it has a favorable side-effect profile and is highly effective.21
Dr. Edward T. Ryan's Diagnosis

Infection with a lung fluke.

Second Pathological Discussion

Dr. Kradin: A serum sample from the patient was sent to the Centers for Disease Control and Prevention. An immunoblot for the paragonimus antibody was negative (this assay has a 96% sensitivity in egg-proven cases of P. westermani infection in Southeast Asians, with a 99% specificity). In contrast, S. mansoni antibodies were detected with both an enzyme-linked immunosorbent assay and an immunoblot assay, confirming the diagnosis of S. mansoni infection. No antibodies against S. haematobium were detected. No stool specimen was submitted for analysis.

Dr. Ryan: Dr. McDonough, can you tell us about the treatment and follow-up of this patient? Dr. McDonough: The patient was treated with a 2-day course of praziquantel. Follow-up CT scans of the chest showed no change in the diffuse ground-glass cystic lesions and no further large nodules. Unfortunately, 8 months after the lung biopsy, symptoms of pancreatic and biliary-duct obstruction developed; laparotomy showed extensive metastatic adenocarcinoma within the abdomen. Treatment with chemotherapy was initiated, and 10 months later, the patient has relatively asymptomatic, stable metastatic disease. He intends to return to Brazil to be with his family. A Physician: Both gastric cancer and infection with schistosoma are prevalent in Asia. Is there any link between gastric cancer and schistosomiasis? Dr. Ryan: There is no recognized association of schistosomiasis with gastric or intestinal cancer. This contrasts with S. haematobium infection, which is associated with an increased risk of squamous-cell carcinoma of the bladder.
Anatomical Diagnoses

Schistosoma mansoni infection with pulmonary involvement. Respiratory bronchiolitis, peribronchiolar scarring, and centrilobular emphysema. Adenocarcinoma of the distal stomach, after Helicobacter pylori infection. Chronic gastritis with intestinal metaplasia. No potential conflict of interest relevant to this article was reported.
Source Information

From the Division of Infectious Disease (E.T.R.) and the Departments of Radiology (S.L.A.) and Pathology (R.L.K.), Massachusetts General Hospital; and the Departments of Medicine (E.T.R.), Radiology (S.L.A.), and Pathology (R.L.K.), Harvard Medical School.
http://www.nejm.org/doi/full/10.1056/NEJMcpc079023 artikel review

Gastroscopic Biopsy in the Differential Diagnosis of Gastritis and Carcinoma

Edward B. Benedict, M.D. N Engl J Med 1951; 245:203-206August 9, 1951

SINCE the introduction of the Benedict flexible operating gastroscope in 1948,1 203 biopsies of the stomach have been taken by this means in the Massachusetts General Hospital Endoscopy Clinic. No accidents and no complications have resulted. As already reported,2 3 4 5 the advantages of this instrument are: biopsy of the stomach under direct vision, aspiration of gastric secretions and inflation and deflation of the stomach at will. It seems hardly necessary to point out the importance of gastroscopic biopsy in the differentiation of benign and malignant lesions of the stomach. In all other endoscopies biopsy is practiced routinely, and its advantages are . . . *From the Department of Surgery, Massachusetts General Hospital.
Source Information

BOSTON Assistant clinical professor of surgery, Harvard Medical School; Endoscopist, Massachusetts General Hospital. http://www.nejm.org/doi/full/10.1056/NEJM195108092450602