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.

History: A 69-year-old man was hospitalized for 10 days with complaints of easy fatigability. He was found to have dry skin with hyperpigmentation over the lower legs and some cracking of the skin of the lower abdomen. Lab studies showed a sodium level of 129 mEq and a potassium level of 4.5 mEq. The work up discovered chronic active hepatitis, arteriosclerotic heart disease, chronic renal disease, and early COPD. He had a femoral arteriogram to evaluate lower extremity vascular insufficiency, but died 2 months later of apparent cardiac arrest.

At autopsy, both adrenal glands were enlarged to 5 cm and appeared completely replaced by tumor. Each weighed 30 grams. There was no infiltration of surrounding tissue. Metastases were not seen.

Microscopically, the adrenal glands were necrotic and focally hemorrhagic (Fig. 1). Higher magnification revealed multiple organisms, including intracellular organisms within macrophages (Figs. 2, 3), some of which were adjacent to the areas of necrosis (Fig. 4).

Diagnosis: Adrenal Histoplasmosis

Dennis Aaron Reinke, M.D. 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: Histoplasmosis is caused by the fungus Histoplasma capsulatum. It can be seen in many countries including the United States where it usually occurs in the eastern and central regions. It is transmitted by spore inhalation which can result in a pulmonary infection. It can disseminate to other organs via the blood to affect the spleen, liver, lymph nodes, bone marrow and adrenal glands.

There are a number of causes of adrenal insufficiency which can be categorized as either primary or secondary. Primary causes to consider include infectious, autoimmune, bilateral adrenal hemorrhage (resulting from sepsis, etc.), drug-induced, certain genetic disorders, adrenal infiltration (resulting from metastases, amyloidosis, etc.), or bilateral adrenalectomy. Secondary causes would include isolated adrenocorticotropic hormone deficiency, prior chronic glucocorticoid excess (which may be due to Cushing’s syndrome or steroid therapy), hypothalamic-pituitary region tumors, or pituitary apoplexy.

The clinical presentation of adrenal histoplasmosis may include weight loss, chronic fatigue, fever and anorexia. Primary adrenal insufficiency/Addison’s disease may also manifest in 5-71% of cases, and it is the most frequent cause of fatality. In these cases symptoms may include malaise, fever, nausea, vomiting and orthostatic hypotension. Lab values may show eosinophilia, hyponatremia and hyperkalemia. Imaging studies can reveal symmetrical adrenal enlargement with areas of hemorrhage and necrosis. These findings would suggest a differential diagnosis of aspergillosis, tuberculosis, or other infections, but a definitive diagnosis of adrenal histoplasmosis is not made by imaging studies.

In immunocompromised individuals, the fungus develops in phagocytic cells and macrophages. In patients that are immunocompetent, granulomas may develop that appear similar to noncaseous tuberculosis.

Microscopically, intracellular Histoplasma can be seen on H&E-staining. However, in necrotic and epithelioid cell granulomatous lesions, special stains (i.e. GMS) may be necessary.

Yeast in these tissue sections are around 3 µm in diameter, may be grouped, and have a single bud connected by a narrow base. These organisms have a firm cell wall, and during fixation the protoplasm withdraws from this firm wall. This leaves a resulting clear space that presents the false effect of an unstained capsule in these organisms.

The differential may include Leishmania, Toxoplasma, Blastomyces and Cryptococcus. Leishmania may look very similar on low power, but higher magnification can show the kinetoplast of these organisms. Toxoplasma is generally smaller and not identified within macrophages. Blastomyces have two or more nuclei, while Histoplasma has a single nucleus. Cryptococcus can be differentiated from Histoplasma, as the former’s walls should stain with carmine dyes.

Suggested Reading:

Arlt W, Allolio B. Adrenal insufficiency. The Lancet. 2003;361(9372):1881-1893.

Binford, CH, Dooley, J. Histoplasmosis. In: Binford, CH, ed., Conner, DH, ed. Pathology of Tropical and Extraordinary Diseases. Volume 2. Washington, D.C.: Armed Forces Institute of Pathology; 1976:578-580.

Larbcharoensub N, Boonsakan P, Aroonroch R, et al. Adrenal histoplasmosis: a case series and review of the literature. Southeast Asian J Trop Med Public Health. 2011;42(4):920-5.

Vyas S, Kalra N, Das PJ, et al. Adrenal histoplasmosis: An unusual cause of adrenomegaly. Indian J Nephrol. 2011;21(4):283-5.