Vol. 334 No. 13 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 849 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL Weekly Clinicopathological Exercises FOUNDED BY RICHARD C . CABOT ROBERT E. SCULLY, M.D., Editor EUGENE J. MARK, M.D., Associate Editor WILLIAM F. MCNEELY, M.D., Associate Editor SALLY H. EBELING, Assistant Editor CASE 10-1996 PRESENTATION OF CASE A 36-year-old man was admitted to the hospital because of pain in the right lower quadrant of the abdomen and the lumbar region. There was a two-year history of intermittent pain in the right lower quadrant and right lumbar region, with “soreness” of the right testis, which occurred frequently during urination and less often on defecation. Twentysix months before admission an evaluation elsewhere led to a diagnosis of prostatitis, but antibiotic therapy was ineffective. Five months before admission the patient came to this hospital. He reported that his brother had hemochromatosis. The physical examination was normal except for tenderness in the right lower quadrant. The iron-binding capacity was almost totally saturated, and the ferritin level was 747 mg per liter. Microscopical examination of a needle-biopsy specimen of the liver showed moderate periportal parenchymal deposition of iron without ﬁbrosis, inﬂammation, or other abnormalities. A chemical analysis revealed 13,378 mg of iron per gram of liver tissue (normal value, 530). Arrangements were made for phlebotomies. A small-bowel follow-through study (Fig. 1) was performed three months before admission. The jejunum and ileum appeared normal with the exception of the ﬁnal 4 cm, which lacked the contours of normal mucosa. The distal portion of the terminal ileum was separated from adjacent bowel loops. Contrast material ﬂowed through that region into the cecum, but the cecum appeared incompletely distended. The appendix was not seen. Ten weeks before admission a colonoscopic examination, performed 10 to 15 cm into the terminal ileum, revealed a granular appearance of the distal 2 or 3 cm of the terminal ileum, with a few small, white submu- Figure 1. Film from the Small-Bowel Follow-through Examination. The small bowel is normal. The cecum is separated from the terminal ileum, and the medial wall of the cecal pole is incompletely distended. cosal nodules within the 5-cm portion proximal to the terminal ileum. The cecum was erythematous, with edema, superﬁcial erosions, and thick, blunted interhaustral folds about the base of the cecum around the appendix. The remainder of the colon appeared normal. Microscopical examination of biopsy specimens of the small bowel disclosed edema and focal eosinophilic inﬁltration. Examination of a cecal-biopsy specimen from the appendiceal area showed marked acute and chronic inﬂammation consistent with ulceration and granulation tissue, without granulomas. An ultrasonographic examination of the abdomen (Fig. 2) showed an enlarged hypoechoic appendix (1.2 cm in diameter). Two focal hyperechogenic areas with posterior shadowing within the appendix were interpreted as appendicoliths. The liver, common hepatic duct, gallbladder, pancreas, kidneys, and spleen appeared normal. A computed tomographic (CT) scan of the abdomen and pelvis (Fig. 3), obtained after the oral administration of contrast material, disclosed a tubular soft-tissue structure that extended medially from the cecum behind the terminal ileum. The structure was surrounded by inﬂammatory changes in the mesentery. No lymphadenopathy was seen, and the remainder of the examination was normal. The patient was admitted to the hospital. The patient did not smoke and consumed little alco- The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on March 24, 2012. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. 850 THE NEW ENGLAND JOURNAL OF MEDICINE March 28, 1996 limeter, and the platelet count was 192,000 per cubic millimeter. The mean corpuscular volume was 96 mm 3. The prothrombin and partial-thromboplastin times were normal, as were the urea nitrogen, creatinine, and electrolyte concentrations. An electrocardiogram showed a sinus bradycardia at a rate of 58 and was within normal limits. A radiograph of the chest was normal. A diagnostic procedure was performed. Figure 2. Compression Ultrasonogram Showing a Noncompressible Appendix in Cross-Section. The appendix is 1.2 cm in diameter. Echogenic foci with posterior acoustic shadowing consistent with appendicoliths are present in the lumen (arrows). Figure 3. CT Scan Showing a Thickened Appendix (Arrows) Extending Medially from the Cecum, with Streaking in the Surrounding Mesenteric Fat Consistent with Inﬂammation. hol. His bowel functions were normal. His father was reported to have inﬂammatory bowel disease. The temperature was 37.4C, the pulse was 100, and the respirations were 16. The blood pressure was 145/75 mm Hg. The physical examination was normal except for mild tenderness in the right lower quadrant of the abdomen, without guarding or rebound tenderness. The bowel sounds were normal, as were the genitalia. The urine was normal. The hematocrit was 39.6 percent, the white-cell count was 5000 per cubic mil- DIFFERENTIAL DIAGNOSIS DR. LESLIE W. OTTINGER*: This otherwise healthy 36-year-old man had experienced pain in the right lower quadrant for two years. The sparse additional history includes intermittent pain in the right testis, a diagnosis of hemochromatosis documented by several tests, apparently normal bowel function throughout the illness, and a family history of hemochromatosis and inﬂammatory bowel disease. There is no information about the nature of the pain at its onset, its frequency, its radiation, or whether anything provoked or relieved it, and except for the pain, there is no mention of intestinal symptoms, even at the onset of the illness. May we review the radiologic studies? DR. MICHELLE M. MCNICHOLAS: The small-bowel follow-through examination (Fig. 1), which was performed three months before admission, shows the separation of the distal terminal ileum from the cecum, which did not distend completely. A compression spot view shows normal-appearing mucosa in the terminal ileum with incomplete ﬁlling of the cecum, which is separated from the terminal ileum. These ﬁndings are suggestive of a mass between the cecum and the terminal ileum, probably related to the appendix, which was not ﬁlled on this examination. The CT scan obtained just before admission (Fig. 3) shows a slight thickening of the posterior wall of the cecum, a normal-appearing terminal ileum, and a tubular soft-tissue density extending medially from the cecum, corresponding to an enlarged appendix. There is stranding in the periappendiceal fat. These ﬁndings are consistent with appendicitis. The compression ultrasonogram of the right lower quadrant (Fig. 2) conﬁrms the enlargement of the appendix, which appears as a tubular structure. It was 1.2 cm in diameter and noncompressible — features that are characteristic of appendicitis. Two echogenic foci within the lumen show posterior acoustic shadowing suggestive of appendicoliths. Appendicoliths were not visible on the plain ﬁlm but appeared as areas of slightly increased density on the CT scan. The radiologic ﬁndings suggested appendicitis, probably with appendicoliths and surrounding inﬂammation. DR. OTTINGER: The basic question in this case is whether the patient had an inﬂammatory or inﬁltrative *Visiting surgeon, Massachusetts General Hospital; associate professor of surgery, Harvard Medical School. The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on March 24, 2012. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. Vol. 334 No. 13 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL process involving primarily the terminal ileum and cecum, with obstruction and secondary changes in the appendix, or an appendiceal lesion, with secondary changes in the terminal ileum and tip of the cecum. The results of the upper gastrointestinal series and small-bowel follow-through study are consistent with either interpretation. The endoscopic ﬁndings suggest a primary process in the mucosa of the terminal ileum and the cecum, but the ﬁndings on the CT scan and ultrasonogram point to the appendix as the primary site of the disease. If the disease was a chronic process originating in the terminal ileum and cecum, it could have been an infection, such as yersiniosis, amebiasis, tuberculosis, or giardiasis, or even a typhoid infection. Although the relative absence of systemic and gastrointestinal symptoms is not consistent with any of those diagnoses, they merit brief consideration. Yersiniosis is the most likely infection in a patient with no history suggesting travel outside New England. Yersinia infections are caused by either the enterocolitica strain or the pseudotuberculosis strain. They are usually transmitted by a fecal–oral route and less often by contaminated food or water. The possibility of yersinia infection in this patient is particularly interesting. Yersinia strains are unable to absorb iron directly, not having the protein necessary to conjugate it, and are thus dependent on other bacteria or a host as their source of iron.1 Patients who have an excess of iron or hemochromatosis are said to be subject to rampant yersinia infections. Yersiniosis usually presents with acute gastroenteritis. I have seen patients in whom the infection persisted in a low-grade form in the cecum and terminal ileum for a long time. Yersinia infection is therefore a possible diagnosis in this case. Inﬂammatory bowel disease and a tumor, particularly a lymphoma, involving the terminal ileum and cecum are additional considerations, but there is nothing to support these diagnoses. An appendiceal disease with secondary inﬂammation in the ileum and cecum is the alternative possibility. The patient had a two-year history of a disease without systemic or gastrointestinal manifestations, and there were no acute symptoms or signs suggesting acute appendicitis or an acute exacerbation of chronic appendicitis. Chronic obstruction of the appendix must also be considered. The patient was thought to have two appendicoliths. Appendicoliths almost always occur singly, and when they are associated with appendiceal disease, it is usually acute appendicitis. Could a tumor have involved the appendix? A mucinous cystadenoma or cystadenocarcinoma would be the most likely possibility in this case. Mucinous cystadenomas, often called “mucoceles” in the past, are sometimes associated with myxoglobulosis, a mucocele with multiple calciﬁed spheres in the appendiceal lumen. The ultrasonographic ﬁndings in this case are not consistent with the presence of calciﬁed spheres. A 851 mucinous tumor of the appendix may be complicated by local perforation or periappendiceal inﬂammation. However, mucoceles are usually characterized by a much larger accumulation of mucin within the appendiceal lumen. The imaging studies in this case suggest that the appendiceal enlargement was due to a thickening of the wall rather than an intraluminal accumulation of ﬂuid. Another possibility is chronic appendicitis, which is probably caused by recurrent appendicitis, but there is no evidence of recurrence in this case. Other chronic, low-grade processes involving the wall of the appendix, such as isolated diverticulitis and regional enteritis, should be considered, but there is also no evidence to support these diagnoses. In conclusion, the most logical diagnosis in this case is a disease with an indolent course that accounts for the periappendiceal inﬂammation, with impairment of lymphatic drainage of the testis, resulting in testicular pain. I favor the diagnosis of a mucinous tumor of the appendix, even though there are few data to support it. DR. FIONA M. GRAEME-COOK: Dr. Schapiro, what was your clinical impression when you saw this patient? DR. ROBERT H. SCHAPIRO: He was referred to me for a liver biopsy because of the history of hemochromatosis. He told me incidentally about the episodes of abdominal discomfort. The most striking aspect of the colonoscopic examination was the abrupt demarcation between the area of inﬂammation that surrounded the appendiceal oriﬁce for 2 or 3 cm and the rest of the cecum. On the basis of these observations, I suspected that the patient had Crohn’s disease of the base of the cecum and the appendix. CLINICAL DIAGNOSIS Crohn’s disease of the cecum and appendix. DR. LESLIE W. OTTINGER’S DIAGNOSIS Mucinous tumor of the appendix. PATHOLOGICAL DISCUSSION DR. METIN OZDEMIRLI: The diagnostic procedure was a laparotomy, which revealed a cecal mass involving the base of the appendix. A right ileocolectomy was performed. The resected specimen consisted of a 20cm-long segment of the ileum and a 17-cm-long segment of the right colon, with an attached appendix that was 5 cm long. The abnormal ﬁndings were conﬁned to the cecum surrounding the appendiceal oriﬁce and the appendix. The cecum had a thickened wall, and its mucosa was congested with petechiae (Fig. 4). The appendix had a diffusely hyperemic serosa with a ﬁbrinous exudate and was bent into a U shape by soft ﬁbrous adhesions. The diameter ranged from 0.6 cm at the tip to 2 cm at the base. The lumen was ﬁlled with soft hemorrhagic material, but no obstruction by a tumor, a foreign body, or parasites was seen. The wall was ﬁrm and The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on March 24, 2012. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. 852 THE NEW ENGLAND JOURNAL OF MEDICINE had a maximal thickness of 0.5 cm; no diverticula were observed. Microscopical examination of the cecum revealed nonspeciﬁc chronic inﬂammatory changes. The appendix had a thickened wall with transmural lymphoid aggregates, hypertrophy of the muscularis, ﬁbrosis, and neural hyperplasia (Fig. 5). Crypt abscesses (Fig. 6), ﬁssures, and erosions were present in the mucosa. Numerous small, noncaseating, sarcoid-like granulomas were seen throughout the wall, particularly in the submucosa but also in the serosa (Fig. 7). There was acute serositis with ﬁbrin deposition and ﬁbrous adhesions. The serositis extended focally into the adjacent ileum. There were no acute or chronic inﬂammatory changes in multiple sections of the ileum and right colon. The regional lymph nodes were reactive and also contained sarcoid-like granulomas. Special stains for microorganisms were negative. A diagnosis of granulomatous appendicitis was made. Chronic granulomatous appendicitis can be either infectious or noninfectious. Mycobacterium tuberculosis, schistosoma, and yersinia species are among the wellknown infectious causes. Infection with actinomyces and campylobacter species, Histoplasma capsulatum, and some parasites may also result in granulomas. Most of these infections can be ruled out by special stains for micro- Figure 4. Close-up View of the Ileocecal Region of the Specimen. The cecal mucosa around the appendiceal oriﬁce is congested with petechiae. March 28, 1996 Figure 5. Cross Section of the Appendix (Hematoxylin and Eosin, 35). The wall is thickened, with transmural lymphoid aggregates and ﬁbrosis. organisms, cultures, serologic tests, and relevant clinical ﬁndings. Yersiniosis of the appendix may be indistinguishable from Crohn’s disease. In general, however, yersinia infections occur in younger persons and often present with mesenteric lymphadenitis. On histologic examination, the inﬂammation is conﬁned to the mucosa and submucosa, and granulomas characteristically exhibit central necrosis and contain microabscesses. Also, serologic tests obtained retrospectively may be positive for yersiniosis. Noninfectious forms of granulomatous appendicitis include those due to foreign material, obstruction, sarcoidosis, and Crohn’s disease, as well as the idiopathic form. Foreign material can easily be ruled out on the basis of microscopical ﬁndings under polarized light and the nature of the granulomatous reaction. In rare cases, obstruction due to tumors such as mucinous neoplasms can elicit a granulomatous reaction, but tumors should be recognizable on pathological examination. Sarcoidosis rarely involves the appendix but is always associated with the involvement of other organs at the time of diagnosis. Crohn’s disease can involve the appendix by extension from the terminal ileum or the cecum and present as acute or subacute appendicitis. About 25 percent of patients with ileal Crohn’s disease and 50 percent of those with colonic Crohn’s disease have appendiceal involvement. However, appendiceal involvement is rarely the ﬁrst manifestation of the disease. Approximately 100 cases of Crohn’s disease limited to the appendix have been reported in the English literature.2-7 These cases have usually been classiﬁed as primary Crohn’s disease of the appendix, because the histopathological features are often very similar to those of colonic Crohn’s disease. These features include a thickening of the wall, panmural chronic inﬂammation, mucosal ﬁssures, crypt abscesses, sarcoid-like The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on March 24, 2012. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. Vol. 334 No. 13 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL Figure 6. Crypt Abscess (Right) in the Appendiceal Mucosa (Hematoxylin and Eosin, 90). Figure 7. Noncaseating Sarcoid-like Granuloma (Right) in the Appendiceal Submucosa (Hematoxylin and Eosin, 150). granulomas in the wall and regional lymph nodes, and less commonly, neural hyperplasia and lymphangiectasia.2 In 1990 Ruiz et al.3 reported three cases of presumptive Crohn’s disease limited to the appendix and reviewed 85 cases in the literature. The average age of the patients was 24 years, and the ratio of male to female patients was 2:1. Eighty-ﬁve percent of the patients presented with pain in the right lower quadrant, 27 percent had a palpable mass, and 86 percent had radiologic evidence of disease. In another study, marked thickening of the appendiceal wall on radiologic studies strongly suggested the diagnosis of 853 Crohn’s disease of the appendix.4 In most cases, the preoperative diagnosis was acute appendicitis (in 68 percent of the cases) or appendiceal abscess (in 27 percent). A simple appendectomy was the surgical procedure performed in 64 percent of the cases. Postoperative complications, which were rare, included pelvic abscess, wound infection, ﬁstula formation, bowel obstruction, toxic megacolon, and hematoma. No postoperative deaths were reported. A follow-up study (average period, 2.5 years) revealed a recurrence rate of 16 percent. On the basis of the low rate of ﬁstula formation and recurrence, the evidence suggests that presumptive Crohn’s disease limited to the appendix comprises two disorders: unequivocal Crohn’s disease involving the appendix, which is rare, and idiopathic granulomatous appendicitis. Dudley and Dean5 addressed this differential diagnosis by studying the comparative clinical and histopathological features of 10 cases of idiopathic granulomatous appendicitis and 14 cases of Crohn’s disease involving the appendix. The histopathological features of the two disorders overlapped considerably. They were characterized by a similar degree of acute inﬂammatory change in the mucosa, transmural lymphoid aggregates, and ﬁbrosis. However, there were two notable differences. Fistulas were seen only in association with Crohn’s disease, and there were many more granulomas in the cases of idiopathic granulomatous appendicitis (mean number per case, 144) than in the cases of Crohn’s disease involving the appendix (mean number, 1). In addition, serosal and lymph-node granulomas were seen only in the cases of idiopathic granulomatous appendicitis. The diagnosis of idiopathic granulomatous appendicitis can be made only after careful exclusion of other forms of appendicitis. One should not make a diagnosis of Crohn’s disease unless one is certain, since it has grave implications. In the present case, the most probable diagnosis, based on a combination of clinical and histopathological ﬁndings, is idiopathic granulomatous appendicitis. DR. MICHAEL B. HODGES: Postoperatively, the patient had obstruction and remained in the hospital for one month. After he was sent home his condition improved, and he is now asymptomatic. DR. SCHAPIRO: Are these pathological ﬁndings compatible with an infection such as Yersinia enterocolitica? Was tissue from the surgical specimen cultured? A stool culture for yersinia was not performed preoperatively. DR. OZDEMIRLI: Unfortunately, no culture was performed. In most of the reported cases of yersiniosis, cultures were not done preoperatively, and the diagnosis was made retrospectively by serologic testing. DR. SCHAPIRO: I am still concerned that this patient may ultimately prove to have Crohn’s disease, particularly because of the family history. From a practical standpoint, I have decided not to treat him at the The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on March 24, 2012. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved. 854 THE NEW ENGLAND JOURNAL OF MEDICINE present time. There is ongoing controversy in the literature about whether any prophylactic medication can reduce the frequency of recurrent Crohn’s disease. The most recent reports suggest that the administration of 5-aminosalicylic acid preparations may be helpful. In the absence of a speciﬁc diagnosis of Crohn’s disease, however, I shall simply observe the patient and not be surprised if symptoms recur. He remains well nine months postoperatively. ANATOMICAL DIAGNOSES Idiopathic granulomatous appendicitis, probable. ? Crohn’s disease of the appendix. March 28, 1996 REFERENCES 1. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989;321:16-24. 2. Ariel I, Vinograd I, Hershlag A, et al. Crohn’s disease isolated to the appendix: truths and fallacies. Hum Pathol 1986;17:1116-21. 3. Ruiz V, Unger SW, Morgan J, Wallack MK. Crohn’s disease of the appendix. Surgery 1990;107:113-7. 4. Agha FP, Ghahremani GG, Panella JS, Kaufman MW. Appendicitis as the initial manifestation of Crohn’s disease: radiologic features and prognosis. AJR Am J Roentgenol 1987;149:515-8. 5. Dudley TH Jr, Dean PJ. Idiopathic granulomatous appendicitis, and Crohn’s disease of the appendix revisited. Hum Pathol 1993;24:595-601. 6. Yang SS, Gibson P, McCaughey RS, Arcari FA, Bernstein J. Primary Crohn’s disease of the appendix: report of 14 cases and review of the literature. Ann Surg 1979;189:334-9. 7. Timmcke AE. Granulomatous appendicitis: is it Crohn’s disease? Report of a case and review of the literature. Am J Gastroenterol 1986;81:2837. 1996, Massachusetts Medical Society. The Massachusetts General Hospital wishes to acknowledge the generous support of Glaxo, Inc., whose sponsorship makes possible the continued preparation of the Case Records. 35-MILLIMETER SLIDES FOR THE CASE RECORDS Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, of the pertinent x-ray ﬁlms, electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a standard 35-mm projector. These slides, which illustrate the current cases in the Journal, are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately 250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114 (Telephone [617] 726-4369). The New England Journal of Medicine Downloaded from nejm.org by LOKESH VUYYURU on March 24, 2012. For personal use only. No other uses without permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved.