Category: Case of the Month

History: A 69-year-old man presented with a slowly growing mass in the right knee. Twenty years prior he had trauma to the area and subsequently developed “arthritis” at the site. Physical exam demonstrated the mass but noted that the knee still had full range of motion without pain. MRI showed a 9.8 x 3.8 x 4.4 cm mass with a fat signal at the lateral knee that involved soft tissue and spared the bone. A previous biopsy had been called “lipoma”.

The excised specimen weighed 93 grams and was 10.0 x 5.0 x 3.5 cm. It was multi-nodular with a thin capsule. Villous projections of white-yellow adipose tissue were present consisting of white-yellow lobulated adipose tissue. A central portion showed a 2.0 x 1.8 cm region of calcification.“March 2015: A 69 year old man with a slowly growing knee mass”Continue reading

History: A 67-year-old woman presented with a 5 year history of non-tender swelling in the perineal area. There had been no drainage or infection. Physical examination showed a 3 x 2 cm, firm mass attached to the skin just below and lateral to the labia. It was superficial and did not involve underlying tissues.

The excised specimen consisted of a yellow-tan, ill-defined, 2.5 x 1.4 x 0.1 cm fibrous subcutaneous nodule (Fig. 1). The overlying epidermis showed elongated hyperplastic rete ridges (Fig. 2). The tumor was composed of sheets of eosinophilic cells with infiltrative borders (Fig. 3). Higher power views demonstrated large polygonal cells with eosinophilic granular cytoplasm, indistinct cell borders, and centrally-situated, small, hyperchromatic nuclei (Fig. 4). No spindling, atypia, pleomorphism, mitoses, nor necrosis were identified. The tumor cells were positive for S-100 (Fig. 5).

Diagnosis: Granular cell tumor, vulva

Li Lei, PGY2 and Donald R. Chase, M.D.
Department of Pathology and Human Anatomy,
Loma Linda University Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Granular cell tumor (GCT) was first described by Virchow and Weber in 1854, and was later characterized as granular cell myoblastoma by Abrikossoff in 1926. Other names, such as Abrikossoff’s tumor, and granular cell schwannoma, have also been used. After decades of debate regarding the histogenesis, most believe that GCT is of neurogenic origin, most likely Schwann cells. Others advocate that GCT is a degenerative change resulting in a cytoplasmic accumulation of lysosomes that occur primarily in Schwann cells as well as in a variety of other cell types. Despite the unresolved controversy on the histogenesis, the simple term “GCT” is currently used by most pathologists.

GCT accounts for 0.5 – 1.3% of all soft tissue tumors. It occurs in patients of all age groups, with a peak incidence in the third to sixth decades. Women are affected twice as often as men. GCT can occur anywhere in the body, but most commonly involves the tongue. It typically presents as a solitary, usually asymptomatic nodule, though pruritus, pain, and ulceration have occasionally been reported. GCT involving critical anatomic sites such as trachea and neurohypophysis can cause serious complications. Between 3 to 20% of patients have multiple tumors that appear synchronously or metachronously, making it a challenge in some cases to determine if the tumor is primary or metastatic.. Multiple GCTs may be part of LEOPARD syndrome which is associated with PTPN11 mutation. Rarely, familial cases have been reported, suggesting that GCT may be inheritable.

Approximately 5 – 16% of GCTs occur in the vulvar region. For reasons unknown, it is more common in African-Americans than Caucasians. Vulvar GCT generally involves the labium majus, though clitoris, mons pubis, perineum and perianal region may also be affected. The male counterparts, GCTs of scrotum and/or penis, are extremely rare with only 22 cases reported in the literature. Vulvar GCT is usually slow-growing, but may enlarge rapidly during pregnancy. Although most vulvar mesenchymal tumors express estrogen receptors and/or progesterone receptors, it is still unclear if vulvar GCTs do.

An MRI may help to diagnose the tumor pre-operatively. GCT usually shows a peripheral hyperintense rim encircling a central hypointense core. These features are most appreciated on T1-weighted images, and may become more prominent on T2-weighted images. There is also variable peripheral enhancement in post-contrast images.

Grossly, GCT is a stellate-shaped or circumscribed, nonencapsulated, subcutaneous mass. The cut surface is tan to yellow, firm and homogeneous. It is usually less than 3 cm, but may grow up to 12 cm.

Microscopically, GCT displays either nodular or infiltrative growth pattern(s). It is composed of sheets, nests, or cords of large polygonal cells, which are characterized by indistinct cytoplasmic borders, abundant eosinophilic granular cytoplasm, and centrally-located small oval nuclei with hyperchromasia. Within the fine or coarsely granular cytoplasm, larger eosinophilic globules surrounded by clear halos are sometimes seen.

Benign GCTs may be slightly spindled, however prominent spindling is a clue of more aggressive behavior. Fibrosis or desmoplasia is variable. An important but nonspecific feature of these tumors is pseudoepitheliomatous hyperplasia of overlying squamous epithelium. This can be mistaken for well-differentiated squamous cell carcinoma if the tumor is only superficially sampled.

The cytoplasmic granules of tumor cells may contain large amounts of hydrolytic enzymes, which are positive for Luxol fast blue and Periodic Acid-Schiff (PAS) with diastase resistance. The cells show diffuse strong nuclear and cytoplasmic S-100 positivity, though some malignant GCTs may lose S-100 expression. Other ancillary positive markers include neuron specific enolase, myelin basic protein, laminin, calretinin, vimentin, osteopontin, inhibin-alpha, HLA-DR, protein gene product 9.5, CD68, carcinoembryonic antigen (CEA), and CD57 (Leu-7). The tumor cells are negative for cytokeratin, desmin, chromogranin, HMB-45, and glial fibrillary acidic protein (GFAP).

Ultrastructurally, the tumor cells are surrounded by replicated basal lamia suggestive of repeated cycles of cellular injury and repair. This is another feature supporting the degenerative theory of histiogenesis. The cytoplasmic granules are composed of membrane-bound, autophagic, vacuoles containing myelin figures and fragmented rough endoplasmic reticulum and mitochondria, consistent with phagolysosomes. There are also small interstitial cells with angulated bodies resulting in a Gaucher cell-like appearance.

Approximately 98% of the GCTs are benign. However, malignant transformation can develop as soon as 5 months after an initial benign diagnosis. Features suggestive of malignancy include large size (>4 cm), rapid growth, necrosis, spindling of tumor cells, vesicular nuclei with prominent nucleoli, high Ki67 labeling index (>10%), > 2 mitoses/10 high power fields at 200X magnification, high nuclear to cytoplasmic ratio, and pleomorphism. Note that mild to moderate nuclear atypia is not indicative of malignancy. Occasionally, granular cells may be found in in the wall or lumen of supporting blood vessels, but this phenomenon does not portend aggressive behavior. Malignant GCTs are usually very aggressive with local recurrence rates up to 70% and 3-year survival rates of less than 50%. They often metastasize to regional lymph nodes, lungs, liver, and bones. Since metastases may occur more than 10 years after treatment, long-term follow-up is necessary.

The differential diagnosis includes:

• Reactive histiocytic proliferation that occurs as nodular collections of histiocytes in response to a variety of stimuli such as trauma or foreign materials. The histiocytes typically have reniform vesicular nuclei, and are arranged to circumscribe the necrotic debris. A detailed clinical history also helps in making the correct diagnosis.

• Genital rhabdomyoma usually grows as a polypoid mass in younger patients. Tumor cells are characterized by strap-like or epithelioid morphology, cytoplasmic cross striations, large cigar-shaped nuclei, and immunoreactivity for muscle markers such as desmin.

• Genital leiomyoma usually shows myxoid change and an epithelioid phenotype. The tumor cells are positive for desmin and smooth muscle actin, and negative for S-100.

• Hibernoma also shows granular eosinophilic cells and strong S-100 positivity. The more unique features are multivacuolated cytoplasm with multiple small lipid droplets, which can be demonstrated by lipid stain such as Oil Red O. Moreover, vulvar hibernoma is exceedingly rare with only one case reported in the literature.

• Squamous cell carcinoma rarely has granular cells. In younger patients it is usually related to human papilloma virus (HPV) infection, and is positive for p16.

• Alveolar soft part sarcoma can be confused with malignant GCT on H&E. It is most commonly seen in patients 15 to 35 years of age but rarely involves the vulva. PAS staining with diastase reveals cytoplasmic glycogen and rhomboid or rod-shaped crystals. Most of cases show nuclear immunoreactivity for transcription factor E3 (TFE3).

• Melanoma may mimic malignant GCT if it is not pigmented. Both show strong nuclear and cytoplasmic S-100 staining. The diagnosis of melanoma can be confirmed by HMB-45 and Melan-A positivity as well as identification of melanosomes and premelanosomes on electron microscopy.

Treatment depends on the biologic behavior and growth pattern of the tumor. Benign GCTs with well-defined pushing borders are usually cured by simple local excision. Those with infiltrative borders need wide local excision to minimize the risk of recurrence. Some of them still recur even with negative surgical margins, and this may be the first sign of potential aggressive behavior. Malignant GCT warrants more aggressive intervention including radical local surgery with or without regional lymph node dissection. The role of radiation is controversial, however it seems that a dose of 60 Gy or higher may be necessary to be effective. The tumor does not respond to chemotherapy.

Suggested Reading:

Goldblum J, Folpe A, Weiss S. Enzinger & Weiss’ Soft Tissue Tumors, 6th ed: Philadelphia, Elsevier Inc, 2014; 43-44, 838-845.

Rosai J. Rosai and Ackerman’s Surgical Pathology, 10th ed: Philadelphia, Elsevier Inc, 2011; 2181-2182.

Abdullgaffar B, Keloth TR, Raman LG, Mahmood S, Almulla A, Almarzouqi M, Al-Hasani S. Unusual benign polypoid and papular neoplasms and tumor-like lesions of the vulva. Ann Diagn Pathol. 2014; 18(2):63-70.

Tawfiq N, Sabri S, Saiss K, Bouchbika Z, Benchekroun N, Jouhadi H, Sahraoui S, Benider A. Granular cell tumor: report of a complicated vulvar localization of pulmonary metastases. Cancer Radiother. 2013; 17(7):671-674.

Ramos PC1, Kapp DS, Longacre TA, Teng NN. Malignant granular cell tumor of the vulva in a 17-year-old: Case report and literature review. Int J Gynecol Cancer. 2000; 10(5):429-434.

Fanburg-Smith JC, Meis-Kindblom JM, Fante R, Kindblom LG. Malignant granular cell tumor of soft-tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol 1998; 22:779-94.

History: A 13 year-old boy presented with a left posterior maxillary nodule which had developed over a two year period.

The excised 2 x 2 x 1.5 cm oval, lobular nodule had a dark-red to pink-gray cut surface. Microscopically, it consisted of polygonal cells with eccentric nuclei and clear or mucin-containing cytoplasm that were admixed with nests of cells with eosinophilic cytoplasm, intercellular bridges and basal cells (Figs. 1 and 2). Pools of extracellular mucin were also seen. The cells failed to show mitotic figures and had only minimal nuclear atypia (Fig. 3). The nodule involved maxillary bone (Fig. 4).

Diagnosis: Central/intraosseous Mucoepidermoid Carcinoma of Maxilla

Tae Hun Kim, MSIV and Donald R. Chase, M.D.
Department of Pathology and Human Anatomy,
Loma Linda University Medical Center,
Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor. It occurs in both minor and major salivary glands with a predominance in the latter, especially the parotid gland. MEC can rarely occur in sites that are normally devoid of salivary gland tissue, e.g. the mandible and maxilla. The term central or intraosseous MEC is utilized for these cases.

Central MEC is a rare tumor with an estimated incidence rate of 2-4% of all MEC. Like traditional MEC, central MEC affects females more than men. It is more common in the molar regions of the mandible than the maxilla. The clinical presentation varies from asymptomatic individuals with an incidental nodule on radiologic evaluation to symptomatic individuals with swelling, pain, facial asymmetry, or trismus. Radiology usually demonstrates a well-circumscribed unilocular/multilocular radiolucent nodule with evidence of bony destruction.

The exact origin of central MEC is unknown. Some authors proposed that it originates from ectopic salivary gland tissue, while others thought that it develops from existing odontogenic cysts. The latter theory is favored because metaplastic cells have been seen in odontogenic lesions. Half of central MEC are associated with cyst(s) or unerupted tooth, and other neoplasms have been shown the develop from odontogenic cysts.

Histologically, central MEC is similar to that of low-grade MEC. It consists of mucous, epidermoid, and basal cells invading in nests and solid sheets. Pleomorphism is absent or minimal.

Immunohistochemically, central MEC are positive for keratin (CK7 and CK14) and mucin markers (MUC1, MUC2, MUC4, MUC5AC, and MUC5B). Central MEC can also demonstrate the MAML2 gene rearrangement.

Accepted criteria for the diagnosis of central MEC includes:
• Presence of intact cortical plates
• Radiologic evidence of bony destruction
• Exclusion of another primary tumor
• Histopathological confirmation
• Detectable intracellular mucin

Brookstone and Huvos proposed a staging system for central MEC:
• Stage I – Intact cortical bone without clinical bony expansion
• Stage II – Intact cortical bone with clinical bony expansion
• Stage III – Cortical bone perforation, breakdown of overlying periosteum, or nodal spread

The differential diagnosis includes:
• Glandular odontogenic cysts – Locally aggressive developmental cyst that occurs mostly in the mandible with an anterior predilection; cyst lined by stratified squamous epithelium, cuboidal, or columnar ciliated cells. Small microcysts and clusters of mucous cells can also be present. Because of its histologic similarity with central MEC, invasive growth, negative immunohistochemical staining of Maspin (expressed in MEC), and genetic abnormality are helpful in distinguishing these entities.
• Keratocystic odontogenic tumor – Parakeratinized stratified squamous epithelium with uniform thickness. No mucous cells are present.
• Adenosquamous carcinoma – Central MEC does not have anaplastic nuclear features or squamous cell carcinoma in-situ.
• Metastatic lesions to mandible/maxilla – Presence of primary tumor elsewhere in body

Central MEC may be treated by either conservative or aggressive surgical resection. Recurrence rates are up to 40% and 13% for conservative and aggressive resections, respectively. Less than 10% of central MEC cases present with metastatic disease.

Suggested Reading:

Brookstone MS, Huvos AG. Central salivary gland tumors of the maxilla and mandible: a clinicopathologic study of 11 cases with an analysis of the literature. J Oral Maxillofac Surg. 1992; 50:229-36.

Moghadam SA, Moghadam FA. Intraosseous mucoepidermoid carcinoma: Report of Two Cases. J Dent. 2014; 15(2): 86-90.

Rosai J. Rosai and Ackerman’s Surgical Pathology, 10th ed. Edinburgh, Mosby, 2011; 831-832.

Spoorthi BR, Rao RS, Rajashekaraiah PB, Patil S, Venktesaiah SS, Purushothama P. Predominantly cystic central mucoepidermoid carcinoma developing from a previously diagnosed dentigerous cyst: case report and review of the literature. Clin Pract. 2013 Jun 20;3(2)e19.

Wenig B. Atlas of Head and Neck Pathology, 2nd ed: Philadelphia, Saunders/Elsevier, 2008; 615-622.

History: A 3 year old girl presented with a solitary, painless, rapidly growing shoulder mass. On physical exam it was mobile, non-tender and irregular. The overlying skin did not show any changes. Neither the patient nor her family had any pertinent past medical history. The excised specimen was 5.5 x 5.0 x 3.0 cm, tan-yellow, poorly circumscribed and predominantly comprised of fibrofatty tissue.

Microscopically the nodule involved the subcutis (Fig. 1) and consisted of an admixture of mature adipose tissue, intersecting trabeculae of fibrous tissue with mature spindle-shaped cells and collagen bundles (Figs. 2, 3). It also showed loosely textured “organoid” areas of myxoid matrix with densely packed round to spindle shaped cells (Figs. 2–4). Neither muscular elements nor cellular atypia were seen.

Diagnosis: Fibrous Hamartoma of Infancy

Maral Rahvar, M.D; Donald R Chase, M.D
Department of Pathology and Human Anatomy,
Loma Linda University Medical Center,
Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Fibrous hamartoma of infancy (FHI) is an uncommon benign fibroproliferative tumor of mesenchymal origin. The entity was first described by Dr. Reye in 1956 as “subdermal fibromatous tumor of infancy”. The current term, FHI, was proposed in 1965 by Dr. Enzinger who described 30 cases from the files of the Armed Forces Institute of Pathology (AFIP). The newer term is currently preferred because of its emphasis on organoid microscopic appearance, and frequent occurrence in childhood and infancy.

FHI is most common in the first two years of life and often presents as a rapid growing mass in the subcutis or reticular dermis. Although it is usually freely movable, it may be fixed to subcutaneous fascia. Boys are affected two to three more times than girls. It does not spontaneously regress.

The most common location is anterior or posterior shoulder fold, but FHI has also been reported in the upper arm, thigh, shoulder, back and forearm. It mainly presents as a solitary lesion but can be multiple.

Grossly, FHI is poorly circumscribed, firm, grey-white with intermixed irregular small islands of yellow fat. The proportion of adipose to fibrous tissue varies from case to case. In lesions where fat occupies a large portion of tumor, the specimen may resemble a fibrolipoma. The tumor is usually about 4 cm in greatest diameter, but masses as large as 15 cm have been reported.

Histologically, FHI is recognized by the presence of three components forming an organoid pattern:

(1) intersecting trabeculae of fibrous tissue composed of spindle-shaped cells separated by collagen bundles,
(2) loosely textured areas consisting of immature round or stellate cells in a matrix of Alcian blue-positive hyaluronidase sensitive material, and a
(3) varying amount of mature fat.

Although the diagnosis is usually based on H&E examination, immunohistochemical stains may be helpful. Positive stains may include smooth muscle and muscle-specific actin reactivity in the trabecular component, and CD34 is occasionally expressed in the spindle cells.

Local excision is the preferred treatment and recurrences are unusual. Although the etiology of this tumor is still unknown, some cases have shown cytogenetic abnormalities including complex (6;12,8)(q25;q24.3;q13), reciprocal translocation of t(2;3)(q31;q21) and rearrangement of chromosome 1, 2, 5 and 17.

Suggested Reading:

Reye RDK. Considerations of certain subdermal ‘‘fibrous tumors’’ of infancy. J Pathol 1956; 72: 149–154.

Enzinger FM, Fibrous Hamartoma of Infancy. Cancer. 18, 241–8 (1965).

Ritchie EL, Gonzalez-Crussi F, Zaontz MR Fibrous hamartoma of infancy masquerading as a rhabdomyosarcoma of the spermatic cord. J. Urol. 140(4), 800–1 (1988).

Groisman G, Lichtig C Fibrous hamartoma of infancy: an immunohistochemical and ultrastructural study. Hum. Pathol. 22(9), 914–8 (1991).

Dickey GE, Sotelo-Avila C. Fibrous hamartoma of infancy: current review. Paediatr Dev Pathol 1999; 2: 236–243.

Fetsch JF, Miettinen M, Laskin WB, Michal M, Enzinger FM. A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis. Am. J. Surg. Pathol. 24(11), 1491–500 (2000).

Imaji R, Goto T, Takahashi Y, Akiyama T, Yamadori I A case of recurrent and synchronous fibrous hamartoma of infancy. Pediatr. Surg. Int. 21(2), 119–20 (2005).

Yoon TY, Kim JW Fibrous hamartoma of infancy manifesting as multiple nodules with hypertrichosis. J. Dermatol. 33(6), 427–9 (2006).

Enzinger FM, Weiss SW. Soft Tissue Tumor; 6th edition. Mosby; 2013, 9: 257-283.

History: A 60-year-old woman presented with a urinary tract infection. Past medical history was positive for recently-diagnosed lymphoma status post chemotherapy. Cystoscopy showed a small polypoid mass in the trigone of the bladder.

The excised specimen was 0.4 cm, tan-yellow and had urothelial denudation (Fig. 1). It involved the lamina propria, and to consisted of sheets of foamy histiocytes admixed with lymphocytes and plasma cells (Fig. 2). There were numerous small basophilic targetoid inclusions, most of which were within histiocytes, but some were extracellular (Figs 3a, 3b).

Diagnosis: Malakoplakia of Bladder

Li Lei M.D., PGY1 and Donald R. Chase, M. D.
Department of Pathology and Human Anatomy,
Loma Linda University Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California

Discussion: Malakoplakia, or malacoplakia (MP) was first described by Michaelis and Gutmann in 1902. It was named for its gross features notably “soft” (“malako” in Greek) and plaque-like (“plakia” in Greek). Though it may be mistaken for a neoplasm clinically, the entity is actually an abnormal chronic granulomatous inflammatory process in response to infection.

Malakoplakia typically involves the genitourinary tract, particularly the bladder, followed by the gastrointestinal tract. Other sites that have rarely been reported include female genital tract, skin, tonsils, middle ears, larynx, lungs, brain, eyes, bone, thyroid, adrenal glands, retroperitoneum, liver, gallbladder, pancreas, and lymph node.

Clinically MP of the bladder shows a female predilection (4:1) with peak incidence in the fifth decade. It tends to present with hematuria, fever, and weight loss and many times is associated with recurrent urinary tract infection. Urine culture usually grows Escherichia coli or other bacteria. Findings on standard imaging are nonspecific. Both MRI and PET scans are helpful in the diagnosis. Magnetic resonance imaging (MRI) demonstrates nodules that are low in signal on T1, T2, early and late post gadolinium images with intervening fibrous stroma. Positron emission tomography (PET) scans show intense accumulation of fluoro-deoxyglucose.

Grossly, MP presents as solitary or multiple, soft, yellowish nodules or plaques involving the mucosa and underlying stroma. Lesions in bladder are often less than 2 centimeters, and are usually located in the region of the trigone. Focal necrosis is occasionally seen.

Microscopically, MP involves the lamina propria with sheets of epithelioid histiocytes with abundant granular eosinophilic cytoplasm, also known as von Hansemann cells. Lymphocytes, plasma cells and neutrophils are interspersed between the histiocytes. The pathognomonic finding is Michaelis-Gutmann bodies, which are basophilic targetoid or homogeneous inclusions, 3-10 micrometers in diameter. They are located in the cytoplasm or extracellularly in the stroma. Michaelis-Gutmann bodies can be highlighted by PAS-diastase stain, von Kossa stain for calcium, and Prussian blue stain for iron. Gram stain may show intracellular bacteria. Immunohistochemically, von Hansemann cells are positive for CD68, and negative for cytokeratin, calretinin, and Melan-A.

Electron microscopy shows Michaelis-Gutmann bodies to be concentrically layered structures with a central electron-dense core and radially oriented hydroxyapatite crystals. Von Hansemann cells have numerous phagolysosomes containing intact or partially digested bacteria, and lamellated crystalline bodies representing the early stage of Michaelis-Gutmann bodies.

The aforementioned ultrastructural findings are probably the most solid evidence we have so far to support bactericidal defect of macrophages as the etiology of malakoplakia. It has been proposed that impaired acidification of phagolysosomes results in bacterial accumulation within macrophages, which triggers the deposition of calcium, iron and phosphate, and then the formation of Michaelis-Gutmann bodies.

The pathogens are typically Gram-negative coliform bacteria, with Escherichia coli being the most common. In fact, a broad spectrum of bacteria has been involved, including other Gram-negative rods such as Proteus vulgaris and Pseudomonas as well as some Gram-positive cocci such as Staphylococcus aureus and Enterococcus. In patients with acquired immune deficiency syndrome (AIDS), the most common culprit is Rhodococcus equi, a Gram-positive coccobacillus. Mycobacterium, Candida albicans, human papillomavirus (HPV) and Epstein-Barr virus (EBV) are also rarely implicated, which sheds some light on the pathogenesis and supports the idea that malakoplakia is not necessarily bacteria-related.

To further complicate our understanding of malakoplakia, both lepromatous leprosy and Whipple’s disease are caused by macrophage dysfunction and subsequent intracellular accumulations of bacteria, but Michaelis-Gutmann bodies are not seen in either of them. These observations suggest that macrophage dysfunction followed by bacterial accumulation is not enough for malakoplakia to develop. Further research may help identify the unrecognized factor(s).

Overall, MP is a histologic diagnosis characterized by Michaelis-Gutmann bodies. The differential diagnosis, however, includes:

• Chemotherapy cystitis:
Cyclophosphamide, commonly used in the treatment of lymphoma, is notorious for causing hemorrhagic cystitis. Cystoscopic findings are mucosal edema and punctate hemorrhage other than soft plaques as seen in malakoplakia. Histologic findings include mucosal ulceration, vascular congestion, hemorrhage, and hemosiderin deposition.

• Xanthogranulomatous cystitis:
The characteristic finding is lipid-laden macrophages (“xanthoma cells”) many times associated with multinucleated giant cells. Although it resembles MP, it lacks Michaelis-Gutmann bodies.

• Langerhans cell histiocytosis:
H&E staining reveals diffuse infiltrates of Langerhans cells, noted for their abundant foamy cytoplasm and indented bland nuclei. These cells are immunoreactive for CD1a and S-100. On electron microscopy, Birbeck granules are characteristic, but are absent in MP.

• Inflammatory pseudotumor:
The urine culture is characteristically negative. The mass is composed of spindled myofibroblasts and has a lymphoplasmacytic infiltrate. Immunostaining is positive for smooth muscle actin, desmin and anaplastic lymphoma kinase.

• Urothelial carcinoma:
Tumor cells show an infiltrative growth pattern, significant cytologic atypia, and immunoreactivities for cytokeratin 7 and 20. A prominent inflammatory background is not usually seen.

• Lymphoma:
Frank lymphoma is composed of predominantly CD20 positive, or rarely CD3 positive, tumor cells. However, early lymphoma may be mistaken for lymphocytic infiltrate in the background of malakoplakia.

Malakoplakia is most commonly seen in immunocompromised patients, such as those on immunosuppressive medications or chemotherapy, and patients with hematopoietic malignancies or diabetes mellitus. Radiation-induced local immunosuppression also poses a risk for malakoplakia, and these cases are easily confused with recurrent malignancies. Although MP by itself is non-neoplastic , it may be associated with various benign or malignant neoplasms, including lymphoma, adenomatous polyp, and carcinomas of the bladder, prostate, colon and endometrium. A case of renal malakoplakia followed by chronic myelomonocytic leukemia has recently been reported. Skinnider et al. reported a case of vaginal malakoplakia followed by diffuse large B-cell lymphoma localized to vagina. Retrospective review of the initial biopsy specimen with the aid of immunostaining showed that there had been malignant lymphocytes interspersed inconspicuously within the MP. A similar case of MP occurred in the bladder of a 63-year-old woman with a recurrent urinary tract infection. Eighteen months later she was found to have non-Hodgkin’s lymphoma localized to the bladder. Therefore, we believe that malakoplakia may serve as a potential red flag for future or concurrent disease processes.

Depending on the location and extent of disease, malakoplakia is treated by surgical excision and/or antibiotics that can reach high concentration in macrophages, such as ciprofloxacin, trimethoprim/sulphamethoxazol, and rifampicin. Cholinergic agonist bethanechol has been reported to improve lysosomal function by increasing intracellular cyclic guanosine monophosphate level, but the clinical effect is controversial. In patients on immunosuppressant therapy, adjustment of immunosuppressive medications may be necessary. With appropriate management, the prognosis of malakoplakia is usually excellent, though both spontaneous regression and fatal cases have been reported.

Suggested Reading:

Goldblum J, Folpe A, Weiss S. Enzinger & Weiss’ Soft Tissue Tumors, 6th ed: Philadelphia, Elsevier Inc, 2014; 374-6.

Rosai J. Rosai and Ackerman’s Surgical Pathology, 10th ed: Philadelphia, Elsevier Inc, 2011; 1251

Kradin RL1, Sheldon TA, Nielsen P, Selig M, Hunt J. Malacoplakia of the tongue complicating the site of irradiation for squamous cell carcinoma with review of the literature. Ann Diagn Pathol. 2012;16:214-8.

Batchelor JS1, Philp NH, Ramsden KL, Scott KW. Primary lymphoma of the bladder arising from an area of Malakoplakia. Br J Urol. 1991; 68:550-1.

Ngadiman S1, Hoda SA, Campbell WG, Gardner T, May M. Concurrent malakoplakia and primary squamous cell carcinoma arising in long-standing chronic cystitis. Br J Urol. 1994;74:801-2.

Abdou NI, NaPombejara C, Sagawa A, Ragland C, Stechschulte DJ, Nilsson U, Gousley W, Watanabe I, Lindsey NJ, Allen MS. Malakoplakia evidence of monocyte lysosome abnormality correctable by cholinergic agonist in vitro and in vivo. N Engl J Med. 1977;297:1413-9.

Biggar WD, Crawford L, Cardella C, Bear RA, Gladman D, Reynolds WJ. Malakoplakia and immunosuppressive therapy. Reversal of clinical and leukocyte abnormalities after withdrawal of prednisone and azathioprine. Am J Pathol. 1985;119:5-11.
Molnar JJ, Poliak A. Recurrent endometrial malakoplakia. Am J Clin Pathol. 1983;80:762-4.

Skinnider BF, Clement PB, MacPherson N, Gascoyne RD, Viswanatha DS. Primary non-Hodgkin’s lymphoma and malakoplakia of the vagina: a case report. Hum Pathol. 1999;30:871-4.