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• W4254726079 abstract "Clinicopathologic ConferenceClinicopathologic Conference Fred Rosen, MD, Clinical Discussant William Cumming, MD, Radiologist Mohammed Akhtar, MD, Pathologist Harb A. Harfi, MD, FAAA Christian Ferentzi, MD Yehia Sbeiti, and MD John T. GodwinMD Fred Rosen Chief, Immunology Division, James L. Gamble, Professor of Medicine, Harvard Medical School, Boston, Massachusetts Search for more papers by this author , William Cumming Staff Radiologist, Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Search for more papers by this author , Mohammed Akhtar Pathologist, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Search for more papers by this author , Harb A. Harfi Staff, Allergist-Immunologist, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Search for more papers by this author , Christian Ferentzi Staff, Gastroenterologist, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Search for more papers by this author , Yehia Sbeiti Resident, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Search for more papers by this author , and John T. Godwin Chairman, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Search for more papers by this author Published Online:1 Apr 1984https://doi.org/10.5144/0256-4947.1984.185SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutCASE PRESENTATIONDr Sbeiti:This is the case of an 11-year-old Saudi boy (#181515) who was referred to King Faisal Specialist Hospital on 1 July 1982 because of a 1-year history of recurrent bloody diarrhea, intermittent crampy abdominal pain, and progressive pallor, weakness, and weight loss. Stools often contained mucus and fresh blood. About 6 months prior to onset of his illness, the patient had a bout of abdominal pain. Stool examination done at that time showed E. histolytica and he was treated with a course of Flagyl. There was no history of fever, excessive perspiration or flushing, arthritis, photophobia, constipation, oral thrush, recurrent pneumonia, pyoderma, or other skin rashes. Past medical history was noncontributory and family history was unremarkable. There was no consanguinity among the parents.On physical examination his blood pressure was 95/60 mmHg, pulse 110/min, respiratory rate 18/min, and temperature 36.8°C. His height was 134 cm, the average height of a 9-year-old boy, and weight was 20 kg, the average weight of a 5-year-old boy. The patient appeared apprehensive, pale, and cachectic but not in acute distress. The skin examination showed markedly diminished subcutaneous tissue but findings were otherwise normal. ENT examination was within normal limits. The chest examination showed prominent ribs but no deformities. The lungs were clear and resonant and the heart was regular and rhythmic. The abdomen was slightly distended and tender in the epigastric area. A firm tender mass 8 x 12 cm was palpable in the midline above the umbilicus. The mass was nonballotable and was not trans-illuminable. No other masses were palpable in the abdomen. Bowel sounds were normal. There was no hepatosplenomegaly. Rectal examination revealed several soft polypoid masses 1 x 1 cm each. There were no associated fissures, ulcers, or fistulas. There was no lymphadenopathy. The remainder of the physical findings were unremarkable.Laboratory investigation revealed the following: WBC was 8700, segmented 67%, bands 6%, lymphocytes 17%, and monocytes 10%. Platelet count was 642,000, hemoglobin 9.3gm/dl, hematocrit 28%, mean corpuscular volume 71.4 cu microns, mean corpuscular hemoglobin 23.5 pg, and mean corpuscular hemoglobin concentration was 33gm/dl. The erythrocyte sedimentation rate was 59 mm/1st hour (Westergren). Albumin was 2.9gm/dl and total serum protein 6.6 gm/dl. Febrile agglutinins were negative. Stool was positive for polymorphonuclear leukocytes (PMN) and occult blood and negative for ameba and Giardia. Cultures of colonic fluid, rectal biopsy and fine needle aspirate of the abdominal mass grew E. coli sensitive to trimethoprim-sulfamethoxazole. Immunoglobulins were IgG 1700, IgM 105, and IgA 170mg/dl, and IgE 53 U/ml. C3, C4, and CH50 were normal. T and B cell counts and T cell transformation were normal. The nitroblue tetra-zolium (NBT) test was slightly decreased. Skin tests with PPD, Candida, streptokinase-streptodornase, and mumps antigens were all nonreactive except for a 2-mm reaction to mumps. The dinitro-chlorobenzene (DNCB) skin test was positive.Radiologic studies including ultrasound and CT scan of the abdomen showed a retroperitoneal mass in the midabdomen, separate from the liver, extending to the anterior abdominal wall. The IVP showed normal kidneys and collecting system. A barium enema study showed multiple polyps throughout the length of the colon.Dr Camming:There is a soft-tissue mass lying in the upper part of the midabdomen with nothing very distinctive about it. Ultrasonography of this mass shows it to be solid, not cystic. It is separate from the liver, in the region of the pancreas, and relatively echo-free. In Saudi Arabia, the likeliest thing that looks like this is lymphoma arising in para-aortic lymph nodes. CT examination of the same area confirms this large mass (Figure 1). A barium examination showed an indentation of the gastric antrum and deformity of the duodenum typical of a pancreatic mass. At this point I was thinking of some unusual tumor of the pancreas, such as a carcinoma. An air-barium double contrast examination shows a large number of small polypoid lesions throughout the entire length of the colon (Figure 2).Figure 1. A CT scan of the abdomen shows a midline para-aortic mass.Download FigureFigure 2. An air-barium examination shows many small polyps throughout the colon.Download FigureThe differential diagnosis includes juvenile poly, posis, familial polyposis, Gardner’s syndrome, Peutz-Jeghers syndrome and ulcerative colitis with pseudopolyps. There were no apparent polyps in the stomach or small bowel. The patient is too young to manifest familial polyposis and he has no cutaneous or facial abnormalities that would indicate Peutz-Jeghers or Gardner’s syndromes. Ulcerative colitis is an extremely rare disease in this country.Relating this unusual polypoid disease of the colon to the abdominal mass is difficult. We have not seen lymphoma look like this in the bowel.Granulomatous colitis or tuberculosis could cause colonic disease and retroperitoneal lymphadeno-pathy. None of these possibilities seem likely and I suspect this is a disease we have not seen before.Dr Ferentzi:Tissue for routine and electron microscopy as well as culture was obtained by diathermic snare polypectomy of one of the polypoid lesions in the sigmoid colon. On colonoscopy there are multiple sessile polypoid lesions of varying sizes (Figure 3). The larger lesions have central ulcerations. The surrounding mucosa is normal with a normal submucosal pattern. The smaller polyps resemble those seen in juvenile polyps which could be expected in a child of this age, but the larger lesions look more like infiltrates composed of different tissues. Colonoscopy after 3 months of treatment shows a definite regression in tumor size (Figure 4). The polyps are now shiny, seemingly covered by normal mucosa and they appear more like fibrous nodules. The surrounding mucosa of the sigmoid colon still appears normal.Figure 3. Colonoscopy shows multiple sessile polypoid lesions.Download FigureFigure 4. Regression in tumor size after 3 months of treatment.Download FigureDr Sbeiti:As you have seen, the patient had multiple polypoid lesions which were seen throughout the entire large bowel. These lesions were partially eroded and partly fungating with normal mucosa intervening. A biopsy was taken from the colon and a fine needle aspiration of the abdominal mass was performed. Both samples showed the same lesion. The patient was treated medically and within a week his symptoms markedly abated. He started to gain weight and finally was discharged in a relatively good state of health.DIFFERENTIAL DIAGNOSISDr Rosen:One is dealing here with a boy who has a chronic illness that is characterized by predominantly bowel symptoms. Having ruled out inflammatory bowel disease because of its rarity here, we next focus on what this retroperitoneal mass could be. My first thought was that this is an 11-year-old and that this is an age of common recrudescence of neuroblastoma.Neuroblastoma is a tumor that secretes certain catecholamines that cause chronic diarrhea, and this is a possibility. But two things are wrong with it. First, the IVP is normal. The most common origin of neuroblastoma is the adrenal gland, which causes a displacement of the kidney and this has not happened. The second disturbing thing is that neuroblastoma most frequently metastasizes to the liver and we are told that this child has a normal-sized liver. Except in its terminal stages, I do not recall this tumor causing polyps in the gut. This could still be a neuroblastoma, but of the organ of Zuckerkandl which lies low in the retroperitoneum. This is a very uncommon tumor of childhood, but nonetheless occurs. Again I was bothered by the polyps in the colon and so I discarded that. Then my attention turned to what Dr Cumming has already mentioned—is this a lymphoma? Is this a lymphoma that is commonly seen in this part of the world—namely alpha-heavy chain disease? Now alpha-heavy chain disease is a tumor that is seen around the southern Mediterranean littoral and gives predominantly retroperitoneal and intestinal lymphomatous symptoms. It clearly is related to chronic infection, because if you free these people of infection before the tumor metastasizes, you can also rid them of the tumor. But this can be ruled out because the child had a normal IgA, about 170 mg/dl, which is perfectly respectable for an 11-year-old, and if he had Mediterranean lymphoma with alpha-heavy chain disease his IgA would be sky high.I started looking at the lab results which are very interesting to the extent that they are unin-formative. We see that this child has a perfectly normal white count and that there seems to be nothing wrong with his platelet count. He has a slight microcytic anemia but this would be expected for someone with a disease of this length who has been leaking blood into the gastrointestinal tract with all these erosions. His erythrocyte sedimentation rate (ESR) was slightly elevated. There are only two things that make the ESR go up: an elevated blood fibrinogen level or an elevated IgG level. This boy’s IgG level was elevated to 1700 mg/dl, accounting for the slightly elevated sedimentation rate. Well, what gives you a high IgG like this boy has? There are only three things that will do this: liver disease, which he does not have, a collagen-vascular disease, which he does not appear to have, or a chronic infection, which he appears to have. So I settled on the fact that this boy’s slightly elevated sedimentation rate and slightly elevated IgG were due to chronic infection.The next question is if this boy is immuno-deficient. I immediately discarded the idea that he had a primary specific immunodeficiency because his B-cell function was apparently normal. He was making all these immunoglobulins. His complement and T-cell transformation were normal. Then we find that his NBT test was slightly decreased. The NBT test was invented to diagnose chronic granulomatous disease. It uses a simple dye that is used by cytochemists to measure oxidative transport systems in leukocytes and since it turns out that these are defective in boys with chronic granulomatous disease, the reduction of this dye from a pale limpid yellow to a deep royal purple inside the leukocytes has been used to quantitate peroxide and oxygen radical generating systems inside leukocytes. Now this test was unfortunately perverted into a simple slide test in which you just smear some leukocytes on an ordinary slide and dump some NBT on it and see if it gets reduced—that is an absurd test because it is not measuring what is going on inside leukocytes, it is measuring the diapiresis in the cell membrane and is a relatively useless test.I did not know whether this slide test was done or whether a true quantitative NBT test was done. I chose the latter possibility because that does become informative. We know that something is wrong with, this boy’s leukocytes, and the next striking fact about this child is that he seems to have E. coli everywhere. So this combination of the possibility of a leukocyte defect in this child, together with the fact that he is riddled with E. coli, apparently chronically because of the raised IgG level, led me to take the next plunge, having discarded as Dr Cumming did all the common causes of intestinal polyposis in childhood. peutz-Jeghers syndrome, one of the congenital forms of polyposis of the gut, is accompanied by hypermelanization around the edges of the lips and fingers, but none of this is mentioned here. In all the congenital intestinal polyposis syndromes the mucosa is not eroded, but there is mucosal erosion here. There are eroded masses in the gut of this child, the tumor in the retroperitoneum, he is riddled with E. coli and is not handling the E. coli well. So, I leapt to the conclusion that this boy had malacoplakia.Malacoplakia is one of the rarest diseases in man and what is even more rare is that it usually does not appear in the gut or the retroperitoneum. I felt as if I were standing on the edge of a cliff as I convinced myself further and further that this was what this boy had. These lesions were first described in the bladder at the turn of this century in Germany and are characterized by accumulations of histiocytes and monocytes which become stuffed with PAS-positive bacterial debris which has been called Michaelis-Gutmann bodies after the original describers. I believe that the biopsy is going to reveal aberrant, eccentric granulomatous masses consisting of histiocytes, lymphocytes and mostly monocytes filled with debris, the Michaelis-Gutmann bodies that are diagnostic of this disease.Additionally, this child was given something which made him better. I thought it could not be an antitumor agent—they do not make you better, they make you sicker. So what could this be that this child was given? Literature reports in the past couple of years indicate that malacoplakia can be cured by cholinergic agonists. This was based on the observation that the degranulation of leukocytes is aided by cyclic GMP and antagonized by cyclic AMP. If you can raise the cyclic GMP level you can enhance neutrophil degranulation, and it was demonstrated that cholinergic agents such as carbachol increase the degranulation and ameliorate the disease.What is the acquired lesion in this disease? It must have something to do with the E. coli inside the leukocytes interfering with the metabolic pathway converting hypoxanthine to guanosine, guano-sine to guanosine triphosphate, and then to cyclic GMP.Clinical Diagnosis: Malacoplakia.PATHOLOGIC DISCUSSIONDr Akhtar:On colonic biopsy of the area of ulceration, an infiltrate is seen in the lamina propria (Figure 5).Figure 5. Photomicrograph featuring part of the colonic mucosal in which the lamina propria is full of large numbers of histiocytes with abundant eosinophilic granular cytoplasm. Within the cytoplasm of many of these histiocytes calcified spherical inclusion bodies (Michaelis-Gutmann bodies) are also present. In addition to histiocytes clusters of polymorphonuclear cells are also present (H&E stain × 100).Download FigureSlightly higher magnification reveals a mixture of lymphocytes and plasma cells and large sheets of cells with abundant eosinophilic cytoplasm. Higher magnification shows plasma cells, lymphocytes, some polymorphonuclear cells, and closely packed sheet-like arrangements of large eosinophilic cells, which are in reality histiocytes. Many of these contain granular material as well as the calcified laminated inclusion bodies termed Michaelis-Gutmann bodies. PAS stain shows the Michaelis-Gutmann bodies in greater detail (Figure 6). Some of the bodies tend to be laminated while others have a target-shaped appearance. The diagnosis here is malacoplakia, which is a Greek word meaning soft plaque.Figure 6. A higher magnification of an area in the colonic mucosa showing numerous histiocytes with Michaelis-Gutmann bodies (PAS stain × 150).Download FigureThe most common site of malacoplakia is the urinary tract, most notably the urinary bladder. The disease has now been described in several locations. The second most common site is the gastrointestinal tract. Other sites include testes, epididymis, skin, adrenal glands, brain, vagina, bone, lung, conjunctiva, endometrium, broad ligaments, lymph nodes, inguinal region, tonsils, and synovium.1,2 So far approximately 200 cases have been reported in the literature.Fine-needle aspiration biopsy is a very effective way of diagnosing this disease because it can demonstrate clearly the Michaelis-Gutmann bodies (Figure 7). In this case, fine needle aspiration was also helpful in delineating that many histiocytes contained large numbers of bacillary bodies (Figure 8). The history indicated that all cultures grew E. coli. It is reasonable to presume that large numbers of these bacteria seen within the cytoplasm of the cells are indeed E. coli. In another slide from the fine-needle aspiration biopsy there are bacteria not only within the cells but also within the interstitium, so there are intracellular as well as extracellular organisms.Figure 7. Photomicrograph of a smear from fine-needle aspiration biopsy. Michaelis-Gutmann bodies are clearly visible within the cytoplasm of the histiocytes (Diff-Quick stain × 300).Download FigureFigure 8. Photomicrograph of a histiocyte in the fine-needle aspiration biopsy smear featuring large numbers of intracytoplasmic bacilli (Diff-Quick stain × 400).Download FigureThe material from the fine-needle aspiration biopsy was additionally studied by electron microscopy and it showed a very characteristic appearance.3 The cytoplasm of the histiocytes is full of membrane-bound structures that we know as phagolysosomes, which are secondary lysosomes produced by the presence of the debris within the membranes (Figure 9). There is some controversy as to where this material really originates. It is derived most likely from a variety of sources including autophagocytosis, in which the cell phagocytoses its own cytoplasm. It may also come from outside the cell. In this disease the bacteria undergo some kind of breakdown, but not complete breakdown, resulting in a large number of cells full of phagolysosomes. The eosinophilic granular cytoplasm of the histiocytes seen in this disease in H & E sections is due to the presence of a large number of these phagolysosomes. Electron microscopy also demonstrates that the Michaelis-Gutmann body is a large phagolysosome that secondarily becomes calcified. On electron microscopy the classical full-fledged laminated Michaelis-Gutmann body has several layers of calcification rings with relatively clear spaces in between (Figure 9). Some of these cells, as expected, contain bacillary bodies seen by light microscopy.Figure 9. Electronmicrograph from an area in the lesion of malacoplakia. Several histiocytes containing large numbers of phagolysosomes within the cytoplasm are present (small arrows). One Michaelis-Gutmann body with concentric rings of calcification (large arrow) can be seen (uranyl acetate and lead citrate stain × 6000).Download FigureAfter the treatment was started, we were able to follow this patient with subsequent biopsies and it was interesting to observe the changes in these cells. The initial biopsy contained not only histiocytic cells, but also a large number of other inflammatory cells (Figure 5). The biopsy after 2 months of treatment shows all inflammatory cells to have disappeared, leaving only large numbers of histiocytic cells (Figure 10). In searching the literature a sequential study of malacoplakia could not be found. Following treatment, fine-needle aspiration biopsies revealed that bacillary bodies had disappeared, both at the light microscopy as well as electron microscopy level. However, in the last biopsy, which was obtained about 2 weeks ago, an occasional cell shows bacillae. As is known, this disease has some morphologic features in common with Whipple’s disease in that there are histiocytes containing large numbers of bacillae. In Whipple’s disease it has been shown that the appearance of bacillae precedes clinical exacerbation by a few weeks. One may ask whether a similar sequence of events takes place in malacoplakia. If that is indeed the case, it may be that this patient is developing and exacerbation of his disease.Figure 10. Photomicrograph of a repeat biopsy of colon. Large numbers of histiocytes are present but no polymorphonuclear cells can be seen (H & E stain × 100).Download FigurePathologic diagnosis: Malacoplakia of the colon and retroperitoneum.Dr Harfi:The patient was treated with the cholinergic agent bethanechol 10 mg 3 times a day and ascorbic acid, which is reported to enhance the production of cyclic GMP to help degranulation of the leukocytes. In addition, he was given Septra for the gram-negative bacillae. Another antibiotic which has been reported to be effective in these patients is rifampicin. The patient went home and gained about 8 kg in a period of 6 months. However, in the last 2 months he again complained of abdominal pain and backache, began to lose weight and was readmitted for evaluation. The mass had increased after the initial decrease and he had a low-grade fever. He was very pale but gave no history of rectal bleeding. He underwent laparotomy because the upper GI series showed a tract connecting the second part of the duodenum with the abdominal mass.At surgery an inflammatory mass was found to be adherent to the abdominal wall, the lower surface of the liver, and the transverse colon. In addition there was a large number of inflammatory lymph nodes, almost all of them mesenteric. Therefore, the surgery was terminated and the patient was started on rifampicin in hopes of halting the progress of the disease.In about 50% of patients with malacoplakia, as noted in the literature, the disease acts like a malignant lesion spreading to different organs and the patients eventually die. Experience at this institution with four patients has shown longevity not to exceed 3 years. All malacoplakia patients seem to suffer from some form of an underlying disease. Immunodeficiency has been considered in two patients and TB in three patients in the literature, but most of them have cancer of the GI tract. The four patients here have shown damage to the mucous membranes, either in the GI or urinary system.Dr Atiyeh:One of the patients we saw here 6 years ago was given bethanechol for 6 months and rifampicin for 1 month but neither worked. He was discharged from the hospital as a hopeless case. Should he have been given vitamin C for six months?Dr Harfi:It seems that medical treatment works in the very early stages of the disease but in advanced stages no medical treatment is effective.Unfortunately, we were unable to do the cyclic GMP study in our patient and we were unable to do the bacterial killing and phagocytic studies. There is a report that the monocytes seem to be defective in releasing the lysosomal enzymes; therefore, the bacteria persist intracellularly, and this is the reason for the progress of the disease and its resistance to medical therapy.Dr Cumming:We have a new entity to add to the list of differential diagnoses of colonic polyposis.ARTICLE REFERENCES:1. Joyeuse R, Lott JV, Michaelis M, et al.: Malakoplakia of the colon and rectum: report of a case and review of the literature . Surgery 81(2): 1891977. Google Scholar2. Nakabayashi H, Ito T, Izutsu Ket al.: Malakoplakia of the stomach. Report of a case and review of the literature . Arch Pathol Lab Med 102(3): 1361978. Google Scholar3. Akhtar M, Robinson CR, Ali MA, et al.: Malacoplakia of the colon and rectum: Report of two cases with review of the literature . KFSH Med J 2(3): 147, 1982. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 4, Issue 2April 1984 Metrics History Published online1 April 1984 InformationCopyright © 1984, Annals of Saudi MedicinePDF download" @default.
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