Signalment:  

Male, 8-year-old, dog, Shar Pei (Canis familiaris)This dog was dysorectic for 15 days and showed poor condition and severe weight loss. Examination by clinician revealed a caudal abdominal mass, pain at palpation and corneal edema of the right eye. No micturitional troubles were reported. Prostatic abscesses were suspected. Urinary analysis revealed inflammatory cells and macrophages according to the clinician. The dog was euthanized for humane reasons.

Gross Description:  

Along with dramatic cachexia, the dog showed a severely enlarged (20 cm diameter), white, multilobulated and cystic prostate. Numerous white, firm, sometimes umbilicated masses were encountered in lungs, kidneys, spleen and tracheo-bronchial lymph nodes. Three ulcers were detected in proximal duodenum. Urinary bladder exhibited muscular hypertrophy.

Histopathologic Description:

Prostate: Multifocal and very infiltrative cell proliferations are effacing normal prostatic architecture. They are poorly encapsulated, highly cellular and contain discrete amount of connective tissue. Cells are round-to-oval with a 15-μm diameter, not jointed, contain variable amounts of eosinophilic cytoplasm sometimes microvacuolated, have a highly vesicular and irregular nucleus showing prominent nucleoli (Fig. 4-1). Multinucleated cells, mitoses and abnormal mitotic figures are very frequent. Phagocytosis (erythrophagocytosis) is sometimes observed. Some areas of liquefaction necrosis are noted. Multifocal and discrete infiltrations by lymphocytes, plasma cells and neutrophils are observed. Tumoral cells can be found in the lumen of the prostatic glands. Immunohistochemical phenotype is: Vimentin-positive, cytokeratin-negative, CD3-negative, CD79a-negative.

Morphologic Diagnosis:  

Prostate: Malignant histiocytosis, Shar Pei, dog Lung, kidney, duodenum, spleen (not submitted): Malignant histiocytosis, Shar Pei, dog

Lab Results:  

Urinary Analysis

Parameter	Value
Density	1.026
Blood	+++
pH	6
Bilirubin	+
Leukocytes	+
Macrophages	+++

Blood Analysis

Parameter	Value	Normal Value
Urea	0.64 g/L	0.2-0.6 g/L
Creat	13 mg/L	< 12 mg/L
PAL	76 UI/L	< 200 UI/L
ALAT	24 UI/L	< 80 UI/L
TP	47 g/L	55-80 g/L
Glucose	0.87 g/L	0.6-1.1 g/L
Na+	138 mmo1/L	140-150 mmo1/L
K+	4.4 mmo1/L	3.8-5.2 mmo1/L
HCO3-	22 mmo1/L	25 mmo1/L

Condition:  

Histiocytic sarcoma (malignant histiocytosis)

Contributor Comment:  

Histiocytic disorders have been reported in many species, mainly in humans, dogs and rats, rarely in cats.^1,2,3,4,6 They arise from the large family of antigen-presenting cells (APC) originated from the bone marrow. The different APC cell types along with their immunophenotypes are presented in Table 1.

Table1: Immunophenotypes of the different antigen-presenting cells²

Multipotent bone marrow stem cells
CD34+ CLA+	CD34+ CLA-		CD34+ IL-3R
Langerhans cells (epithelial dendritic cells)	Intersitial dendritic cells	Macrophages/ Histiocytes	Dendritic cells of lymphoid organs
CD1+ CD14+ CD11c+ MHCII Birbeck granules+	CD1+ CD14- CD11c+ MHCII+ Thy-1+	CD1- CD14+ MHCII+ CD11c- CD11b+	IL-3R MHCII+ CD45RA+ CD4+

Origin lineage of histiocytic disorders in dogs is the subject of many debates. In humans, they tend to arise from both macrophages/histiocytes and dendritic cells whereas in rats, they are of macrophagic origin. In dogs and cats, they are believed to be mostly of dendritic origin.² In dogs, the main histiocytic disorders are: cutaneous histiocytoma, cutaneous histiocytosis, systemic histiocytosis, histiocytic sarcoma (HS) and malignant histiocytosis (MH).⁴ Whereas cutaneous and systemic histiocytosis are non-neoplastic proliferations of activated dendritic cells, the others are classified as true neoplasms. There is a lot of confusion concerning the terms HS and MH. HS should be used when the lesion is solitary or has metastasized. MH defines a multicentric proliferation. Thus, a disseminated histiocytic sarcoma could be undistinguishable from a malignant histiocytosis. Bernese mountain dogs (BMD) show particular susceptibility to histiocytic disorders and neoplasms.⁶ Properties of these histiocytic disorders are summarized in Table 2. Concerning HS/MH, respiratory symptoms are the most frequent cause of consultations. Anemia can be observed as part of a regenerative hemolytic process or a nonregenerative anemia caused by bone marrow invasion and erythrophagocytosis. Hypercalcemia can be observed as a paraneoplastic syndrome. On histopathologic examination, there is proliferation of round-to-oval cells with abundant eosinophilic cytoplasm, nuclear atypia, numerous mitoses, multinucleation, phagocytosis and some infiltration by lymphocytes, plasma cells and neutrophils.⁴ On immunohistochemistry, along with markers of Table 1, cells are positive for lysozyme, vimentin, and negative for cytokeratin A.³ Differential diagnosis includes: anaplastic carcinoma or lymphoma, rhabdomyosarcoma, and lymphomatoid granulomatosis. This case showed original features. Indeed, MH has only been reported in two Shar Peis and prostate involvement was only reported once.² Furthermore, no infiltration of the liver was observed, both at gross and microscopic examination. This feature is uncommon as the liver is one of the three most frequently involved organs.²

Table2: Properties of histiocytic disorders in dogs

Diseases	Concerned breeds	Mean age	Cytonuclear atypias	Involved organs	Metastatic potential	Prognosis
Cutaneous histiocytoma	All, predisposition of Boxer, dachshund, cocker spaniel, Great Dane, Shetland	Mostly young dogs	Rare	Skin (mainly solitary lesion). Draining lymph nodes involvement is exceptional	None	Good
Cutaneous histiocytosis	All, predisposition of golden retriever and German shepherd	Mostly young dogs	Rare	Skin (multiple lesions), sometimes lymph nodes	Rare	Good
Systemic histiocytosis	BMD, golden retriever, Doberman pinscher, rottweiler	Adults Mean age is 7 for BMD	Moderate	Skin (multiple lesions), lymph nodes sometimes ocular tissues	Moderate	Guarded
Histiocytic sarcoma		Adults Mean age is 6 for BMD	Severe	Subcutaneous tissues or internal organs	Elevated to draining lymph nodes	Guarded
Malignant histiocytosis			Severe	Rapid multicentric dissemination (lungs, liver, spleen)	Elevated	Poor

JPC Diagnosis:  

Prostate gland: Histiocytic sarcoma

Conference Comment:  

On additional immunohistochemical testing, the neoplastic cells were positive for CD18 and CD45 and negative for muscle actin. The diagnosis of histiocytic sarcoma was based on characteristic histopathologic and immunohistochemical findings.

Canine malignant histiocytosis/histiocytic sarcoma was first reported in Bernese mountain dogs and has since been reported in various dog breeds, cats, and other species.⁴ Malignant histiocytosis implies multicentric origin of the neoplasm. In cases of widespread disease, it is unclear whether the neoplasm arose multicentrically or metastasized widely from a single primary site. Since conference participants were only aware of the neoplasm in the prostate, histiocytic sarcoma was considered the most appropriate diagnosis. Given the presence of widespread disease, disseminated histiocytic sarcoma is preferred. These tumors are composed of pleomorphic histiocyte-like cells that are often multinucleated or may contain phagocytized material. Two major patterns have been described: round cell predominant and spindle cell predominant.⁴ In the round cell variant, neoplastic cells often have abundant eosinophilic cytoplasm and round to reniform nuclei.^4,5 The spindle cell variant is often composed of plump spindle cells and these tumors often resemble other sarcomas.⁴ Organs most commonly affected include the liver, lung, kidney, spleen, lymph node, and bones. Almost any organ may be affected by this neoplasm.⁵ Canine histiocytic sarcomas are of dendritic antigen presenting cell origin and express CD18, CD1, CD11c, ICAM-1 and MHC II; CD45 expression is variable. For immunohistochemistry on formalin-fixed, paraffin-embedded tissues, CD18 positivity and negative findings for CD3 and CD79a combined with characteristic histomorphology is considered diagnostic.

A variety of other histiocytic proliferative diseases have been described in dogs. Histiocytomas generally occur in dogs four years of age or younger, are extremely common and have a predilection for the head and ears. These tumors are of Langerhans cell origin and express CD1, CD11c, MHC II, and E-cadhedrin.⁷ At the subgross level, these tumors often appear dome shaped with aggregates of lymphocytes and plasma cells at the periphery. There is often superficial dermal edema, and tumor cells infiltrate the epidermis in a fashion similar to Pautriers microabscesses of epitheliotropic lymphoma. Neoplastic cells form sheets and generally lack a discernable stroma. Neoplastic cells have oval to reniform nuclei with a moderate to abundant amount of eosinophilic cytoplasm and mitotic figures are frequent. There is little cellular atypia.⁵ Multiple, persistent and recurring histiocytomas have also been described. Such tumors may progress to a malignancy characterized by dissemination to various organs. This condition has been designated Langerhans cell histiocytosis. Cutaneous histiocytosis is a nonneoplastic, reactive condition characterized by nodules of histiocytic cells that express CD45, CD18, CD1, CD11c, MHC II and E-cadherin. Mature lymphocytes and neutrophils are often scattered amongst the histiocytic cells. The mitotic rate is variable. Systemic histiocytosis is generally similar to cutaneous histiocytosis but has a more extensive distribution. The immunohistochemical profile is the same. Sites most commonly affected include lymph nodes, eyelids, sclera, nasal cavities, lungs, spleen and bone marrow.

References:

1. Affolter VK, Moore PF: In: Proceedings for ESVD Workshop on immunodermatology 2000: from the laboratory to the clinic, advances in the diagnosis and pathogenesis of animal skin diseases, Saint-Paul de Vence, 2000
2. Affolter VK, Moore PF: Localized and disseminated histiocytic sarcoma of dendritic cell origin in the dog. Vet. Pathol 39,74-83, 2002
3. Azakami D, Bonkobara M, Washizu T, et al: Establishment and biological characterization of canine histiocytic sarcoma cell lines. J Vet Med Sci 68(12):1343- 1346, 2006
4. Gross TL, Ihrke P, Walder EJ, Affolter VK: Histiocytic tumors. In: Skin diseases of the dog and cat, 2nd edition, pp. 848-851, 2005
5. Hendrick MJ, Mahaffey EA, Moore FM, Vos JH, Walder EJ: Histological classification of mesenchymal tumors of skin and soft tissues of domestic animals. In: World Health Organization Histological Classification of Tumors of Domestic Animals, ed. Schulman FY, Second Series, vol. 2, pp. 29-31, 58-59. Armed Forces Institute of Pathology,Washington, DC, 1999
6. Moore PF., Rosin A.: Malignant histiocytosis of Bernese Mountain dogs. Vet Pathol 23:1-10, 1986
7. Moore PF: Canine histiocytosis. At: http://www. histiocytosis.ucdavis.edu/

Click the slide to view.

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4-1. Prostate gland, dog

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