Malakoplakia Outside the Urinary Tract
By Yousef, George M; Naghibi, Bibi
* Context.-Malakoplakia is a rare granulomatous disease that occurs commonly in the urinary tract. Histologically, it is defined by sheets of histiocytes (Hansemann cells) with accumulation of granular basophilic periodic acid-Schiff- positive, diastase- resistant inclusions and calcified Michaelis- Gutmann bodies, which are pathognomonic but not necessary for diagnosis. In addition to the urinary tract, malakoplakia has been reported in other organs, including the gastrointestinal tract, central nervous system, female genital tract, and the tongue.
Objectives.-To review the literature of reported sites of malakoplakia outside the urinary tract and their variable clinical presentations, and to discuss the main diagnostic features and differential diagnoses of malakoplakia. The pathogenesis and possible etiologic factors are also presented.
Data Sources.-Data for this work were collected from the published literature, textbooks, and the Internet.
Conclusions.-It is important to be aware of the existence of this entity in abnormal locations. In many situations, malignancy can be mimicked, especially when the lesion is ulcerated and is accompanied by lymph node involvement. Misinterpreting large, rapidly growing nodules of malakoplakia as tumor might lead to overstaging. Pathologists should be also aware of the possibility of malakoplakia coexisting with other lesions, such as tuberculosis and carcinoma, in the same specimen.
(Arch Pathol Lab Med. 2007;131:297-300)
Malakoplakia (from the Greek malacos, soft, and placos, plaques) is a rare granulomatous disease that occurs commonly in the urinary tract. It was first described by Michaelis and Gutmann in 1902.1 Grossly, malakoplakia can present as soft tan yellow plaques and nodules or even extensive bands.2 The lesion is usually solitary but can be multiple.
Histologically, malakoplakia is defined by sheets of ovoid histiocytes (called von Hansemann histiocytes or Hansemann cells) with accumulation of 5- to 15-mm granular basophilic periodic acid- Schiff-positive, diastase-resistant inclusions (Figure 1) and calcified Michaelis-Gutmann bodies1 (Figure 2), which are pathognomonic, although not necessary for diagnosis. By light microscopy, the Michaelis-Gutmann bodies often exhibit a targetoid appearance with a dense central core. The targetoid structure of these bodies results from the initial mineralization of the matrix cores and peripherally arranged, continuously accumulated phospholipids and microvesicles that represent incompletely digested debris.3 Michaelis-Gutmann bodies can be intracellular or extracellular and can be visualized by von Kossa stain for calcium or Prussian blue stain for iron (Figure 3).
Immunohistochemical studies show histiocytes, which are positive for CD68 antibodies, lysosomes, and α-chymotrypsin. Gram stain may demonstrate gram-negative bacteria. Ultrastructurally, there are curved membrane-bound phagolysosomes containing whorled and parallel lamellar phospholipids.4
ETIOLOGY AND PATHOGENESIS
The etiology of malakoplakia has not been fully elucidated, but because of similar morphologic features of the disease regardless of the site of involvement, it is highly possible that the pathogenesis may be the same in all organs. Three possible mechanisms have been suggested. The first postulates that microorganisms might play a role in the pathogenesis.5 Several organisms have been implicated, particularly Escherichia coli (found in more than two thirds of cases), Mycobacterium tuberculosis, Proteus, and Staphylococcus aureus. Specific bacteria are found in certain categories of patients, for example, coliform bacteria in patients with chemotherapy and Rhodococcus equi in patients with acquired immunodeficiency syndrome. An abnormal or altered immune response has been also implicated in the pathogenesis. Table 1 lists the most common conditions of immunosuppression or chronic prolonged illness that can be associated with malakoplakia. The third hypothesis is an abnormal macrophage response because of defective lysosomal function.4,6 It is suggested that macrophages in malakoplakia are capable of phagocytosis but unable to digest the bacteria.7 Partially digested bacteria accumulate in monocytes or macrophages and lead to the deposition of calcium and iron on residual bacterial glycolipid. The resulting basophilic structures, the Michaelis- Gutmann bodies, are considered pathognomonic for malakoplakia.7 The composition of Michaelis-Gutmann bodies has been shown to be 94.6% organic and 5.4% inorganic, with the inorganic components being calcium, phosphorus, and iron.6
The inability to digest microorganisms is related to low levels of intracellular cyclic guanosine monophosphate and diminished release of β-glucuronidase.8 Studies have suggested that a decreased intracellular cyclic guanosine monophosphate level may interfere with adequate microtubular function and lysosomal activity, leading to incomplete elimination of bacteria from macrophages and monocytes. It is probably an interaction between all previously mentioned factors that is responsible for the pathogenesis. Reports indicate functional and morphologic monocyte abnormalities in patients with malakoplakia,9 and there is a documented association between malakoplakia and immunosuppression as in patients with human immunodeficiency virus,10 tuberculosis,6 and cancer.2
Aside from the urinary tract where there is a female predominance (female-male ratio of 4:1), there does not seem to be any racial, gender, or age predilection for malakoplakia. The total number of patients with malakoplakia in the United States is fewer than 500, with most patients having genitourinary tract or gastrointestinal tract involvement. Malakoplakia tends to occur in an older age group, with an average age of 50 years at presentation. The age at diagnosis ranges from 6 weeks to 85 years.11 Pediatric cases are, however, very few.
Mortality in patients with malakoplakia is most often because of an underlying condition. Significant morbidity relates to the chronicity of the condition, which can resist local and systemic therapy. In cutaneous malakoplakia, draining sinuses, persistence of disfiguring skin lesions, and involvement of visceral organs constitute significant morbidity in patients with malakoplakia.
There are 2 therapeutic approaches to malakoplakia. Antibiotics that can penetrate cell membrane and concentrate in macrophages (eg, rifampicin, quinolone, trimethoprim- sulfamethoxazole) are associated with high cure rates. The second approach is to attempt to correct the lysosomal defect by a cholinergic agonist, bethanechol chloride. Antibiotic therapy in combination with surgery provides the best chance of cure. Malignant transformation of malakoplakia has not been reported.
CLINICAL PRESENTATIONS IN DIFFERENT ORGANS
The urinary tract is the most commonly involved site of malakoplakia. Wielenberg et al,12 in a review of 153 cases, found 89 cases (58%) that involved the urinary tract, out of which 63 (40%) occurred in the urinary bladder. Next to the bladder, common urinary sites are the kidneys, ureters, and renal pelvis.
The first description of malakoplakia outside the urinary tract was in 1958.13 There are now accumulating reports of malakoplakia occurring in a wide variety of organs other than the urinary tract, most commonly in the gastrointestinal system. Table 2 summarizes the published reports of malakoplakia outside the urinary tract. There are only very few cases of malakoplakia reported in the central nervous system. Most of these cases are in infants in a clinical setting of herpes viral infection.4,14 In adults, 3 cases were reported in patients with cerebral infarction.
Clinically, malakoplakia is difficult to diagnose because the clinical appearance varies from silent nodules to various manifestations according to the organ involved. In the respiratory system, it can mimic bronchogenic carcinoma or tuberculosis.15 Malakoplakia of the female genital tract usually presents by vaginal bleeding.16 Various appearances can also occur in the gastrointestinal tract, as discussed later.
The coexistence of malakoplakia with other lesions has been documented. A recent report demonstrated a case of malakoplakia associated with a small focus of adenocarcinoma in the prostate.17 Malakoplakia associated with tuberculosis has been also reported.6
MALAKOPLAKIA AND COLON CANCER
The gastrointestinal tract is the second most common site of involvement by malakoplakia after the urinary tract. The descending colon, sigmoid, and rectum are the most common sites of involvement. Other sites include the terminal ileum, stomach, appendix, and cecum. Presentation of malakoplakia of the gastrointestinal tract varies from being clinically silent to diarrhea, abdominal pain, hemorrhage, or obstruction.5 The typical endoscopic lesions have 3 patterns: (1) unifocal mucosal tan to yellow nodules or plaques (the most common), (2) multinodular or polypoidal lesions, and (3) large mass lesions.5
The association between malakoplakia and colon cancer is well documented in the literature. An early report found an association between malakoplakia of the gastrointestinal tract and colorectal carcinoma in more than 30% of patients examined.18 In most reported cases, however, it was an incidental finding confined to the area adj\acent to the carcinoma.19 Involvement of regional lymph nodes in the setting of malakoplakia associated with colorectal carcinoma has been reported.20 Local alteration in the gut flora was postulated as a mechanism for development of malakoplakia in colon cancer. These nodules might also represent a local response to the tumor.21 Other reports show an association of malakoplakia with adenomatous polyps. We have recently reported a case of malakoplakia of the soft tissues of the neck in a patient with colon cancer (unpublished data). Isolated gastric involvement of malakoplakia has been reported but is still questionable.5
Grossly, the major differential diagnoses include primary or metastatic malignancies, especially when the lesion is ulcerated or involving lymph nodes. The differential diagnosis of gastrointestinal tract involvement includes Crohn disease, military tuberculosis, and malignancy.5 Microscopically, malakoplakia of the gastrointestinal tract must be differentiated from Whipple disease, Chediak-Higashi syndrome, tuberculosis, sarcoidosis, other infectious or noninfectious granulomas, and histiocytic storage diseases.
In the kidney, it should be differentiated from xanthogranulomatous pyelonephritis and megalocytic interstitial nephritis.22 In certain locations, malakoplakia is to be differentiated from granular cell tumor (which is S100 positive).16 In the skin, malakoplakia must be differentiated from other skin diseases including fungal infections and other granulomatous inflammations that might resemble malakoplakia clinically and microscopically.23
Many of the case reports of malakoplakia demonstrate the protean nature of the presentation of this condition in which malignancy can be mimicked, especially when the lesion is ulcerated or is accompanied with lymph node involvement. Misinterpreting the large, rapidly growing nodules of malakoplakia as tumors might lead to unnecessary radical surgical intervention. Also, pathologists should be alert to the possibility of more than 1 pathology being present in the specimen (examples mentioned in this review are tuberculosis with malakoplakia or carcinoma with malakoplakia), because this may influence the therapeutic options available. Finally, in cases of malakoplakia associated with cancer, the pathologist has to be careful of the potential to overstage or understage tumors because of the presence of nodules of malakoplakia in the area of the tumor mass, which might have serious implications on the treatment decision.
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George M. Yousef, MD, PhD, FRCPC; Bibi Naghibi, MD, FRCPC
Accepted for publication August 10, 2006.
From the Discipline of Pathology, Eastern Health, St John’s, Newfoundland.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: George M. Yousef, MD, PhD, FRCPC, Eastern Health Discipline of Pathology, 300 Prince Philip Dr, St John’s, Newfoundland, Canada A1B 3V6 (e-mail: email@example.com).’
Copyright College of American Pathologists Feb 2007
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