Histiocytic Sarcoma and Malignant Histiocytosis.

Histiocytic Sarcoma and Malignant Histiocytosis. The histiocytic sarcoma (HS) complex encompasses a number of distinctive clinical entities which will be described below. Some definitions are in order, and reflect the preferred nomenclature of the writing group of the Histiocyte Society. Histiocytic neoplasia which originates at a single site is called histiocytic sarcoma. This form of histiocytic sarcoma, which is often encountered on the extremities, has the best prognosis if treated early by surgical excision or by amputation of a limb. When spread to distant sites beyond the local lymph node occurs, the disease is then termed disseminated histiocytic sarcoma; this is more likely to occur unnoticed when primary lesions occur in cryptic sites (eg spleen, lung, and bone marrow). This latter form of HS is most like malignant histiocytosis (MH). MH is an aggressive, histiocytic neoplasm which arises in multiple sites simultaneously. Most lesions previously defined as MH are probably more correctly termed disseminated HS. The occurrence of true MH is difficult to establish because the lesions often occur in cryptic sites, and the existence of histiocytic neoplasia is only recognized after clinical signs have appeared and disease progression is advanced. HS and MH are capable of widespread metastasis, hence in time the 2 syndromes merge clinically and it is not always possible to differentiate true multicentric origin (MH) from widespread metastasis of disseminated HS. Also, it is never possible to know exactly how long the disease process has been operative. Hence, the perception is that both disseminated HS and MH follow a rapid clinical progression despite therapeutic intervention. This is certainly true once clinical signs are apparent, but the subclinical period is of unknown duration.

The HS complex of diseases is best recognized in the Bernese Mountain Dog in which a familial association is apparent. Other breeds are predisposed to HS complex diseases and include Rottweilers, Golden Retrievers, and Flat-coated Retrievers. Although HS complex is not limited to just these breeds and can occur sporadically in any breed. Primary lesions of HS occur in spleen, lymph node, lung, bone marrow, skin and subcutis especially of extremities. Secondary sites are widespread, but consistently include liver and lung (with splenic primary), and hilar lymph node (with lung primary). Clinical signs include anorexia, weight loss, and lethargy. Other signs depend on the organs involved and are a consequence of destructive mass formation. Accordingly, pulmonary symptoms such as cough and dyspnea have been seen. CNS involvement (primary or secondary) can lead to seizures, incoordination and paralysis. Regenerative and non-regenerative anemia have been consistently documented in hemophagocytic HS. Lameness is often observed in periarticular HS.

Treatment of HS complex.

Localized HS affecting skin and subcutis have been cured by early surgical excision. In the case of periarticular HS which occurs in the subsynovial tissues of the extremities, amputation of the affected limb is enforced by the inoperable nature of the primary lesion which ensnares structures vital to limb function. Disseminated HS (including MH) is not readily treated surgically, since even in the splenic form, early metastasis to the liver has often occurred. Response to chemotherapy has been at best brief, and the disease progresses rapidly (weeks to months) to death or euthanasia.

Morphological Features of HS.

Gross appearance. Lesions of HS are typically destructive mass lesions with a uniform, smooth cut surface and are white/cream to tan in color. Lesions have a soft consistency and may contain discolored areas (typically yellow) which indicate area of necrosis, which can be extensive. Lesions can be solitary or multiple within an organ (especially spleen). Periarticular HS has a distinctive appearance: it occurs as multiple tan nodules located in the subsynovium. These lesions may encircle the affected joint. Hemophagocytic HS does not initially form mass lesions in the primary sites (spleen and bone marrow). Typically, diffuse splenomegaly is observed; the cut surface is dark red and the consistency is firm. The liver is usually bile stained (jaundice) and disruption of the lobular pattern due to metastasis is observed - marked liver involvement can occur before destructive masses are noticeable.

Histiocytic Sarcoma(HS) in Spleen

Histiocytic sarcoma in spleen. Multiple masses occur throughout the spleen.

HS in Spleen

Histiocytic sarcoma in spleen. Diffuse splenomegaly in hemophagocytic HS.

HS in hilar lymph node

Histiocytic sarcoma in hilar lymph node. Primary lesion in this case was in the caudal lung lobe.

HS in thoracic vertebral body

Histiocytic sarcoma in thoracic vertebral body; lesion invaded the epidural space and caused spinal cord compression.

HS Cervical vertebral body with bony lysis

Histiocytic sarcoma in cervical vertebral body with bony lysis; this lesion also invaded the epidural space and caused cord compression.

Periarticular HS, stifle

Periarticular histiocytic sarcoma, stifle. The lesion is characteristically multinodular and encircles the joint.

Microscopic appearance. The histological appearance of HS lesions is consistent regardless of location. Lesions are composed of sheets of large, pleomorphic, mononuclear cells and multi-nucleated giant cells which show marked cytologic atypia and numerous bizarre mitotic figures. Phagocytosis of red cells, leukocytes and tumor cells occurs, but is not prevalent in most forms of HS. However, in hemophagocytic HS this behavior is amplified. Neoplastic histiocytes manifest marked erythrophagocytosis and the infiltrates obliterate the splenic red pulp and invade red pulp sinuses. Foci of extramedullary hemopoiesis (EMH) occur within and adjacent to the tumor infiltrates in the splenic red pulp. In some instances, the neoplastic infiltrates can be deceptively cytologically bland. Simultaneous involvement of bone marrow is frequent, and erythrophagia is observed here as well. Invasion of red pulp sinuses portends invasion of the hepatic sinusoids. In the early stages, liver metastases can easily be overlooked, because histiocytic infiltrates creep along sinusoids and do not form discrete masses until later. Neoplastic histiocytes in hemophagocytic HS express a distinctive surface antigen profile much like that expressed by macrophages in splenic red pulp and bone marrow (see below).

Histiocytic sarcoma (HS)

Multinucleated giant cells and large mononuclear cells obliterate a pulmonary hilar LN. Infiltration of neutrophils among histiocytes is frequently observed in HS.

Hemophagocytic HS splenic red pulp

Large mononuclear cells with variable hyperchromatic and pleomorphic nuclei have obliterated the red pulp cords and invaded the sinuses. These cells have foamy cytoplasm and some contain hemosiderin and phagocytosed red cells.

Hemophagocytic HS splenic red pulp

Extensive areas of EMH are interspersed between neoplastic histiocytes in the splenic red pulp.

Hemophagocytic HS BM

Cytological preparation showing expansion of histiocytes in bone marrow. Cytologically these cells mostly appear mature (in contrast to the frequent atypia seen in the spleen)- they have foamy cytoplasm and some contain phagocytosed red cells.

Hemophagocytic HS BM

CD11d immunostain of cytological preparation.Histiocytes in bone marrow (and spleen - not shown) express abundant CD11d and scant CD1 ( not shown). This phenotype is typical of macrophages in bone marrow and splenic red pulp. In contrast, DC typically express abundant CD11c and CD1.

Immunophenotypic Studies

MH and HS lesions express leukocyte surface molecules characteristic of DC (CD1, CD11c and MHC II). Diffuse expression of E cadherin, Thy-1 and CD4 has not been observed in HS or MH in skin or other sites; this together with cytomorphology assists in the distinction of MH and HS from histiocytoma and reactive histiocytosis (such as cutaneous and systemic histiocytosis). In histiocytoma, the phenotype is quite similar to that of HS except for the expression of E-cadherin which occurs in histiocytoma especially in the cellular infiltrate immediately adjacent to the epidermis. In reactive histiocytosis, infiltration and proliferation of activated interstitial (dermal) DC which consistently express CD4 and Thy-1 occurs.

In hemophagocytic HS, histiocytes express CD11d instead of CD11c, and MHC II. Expression of CD1 molecules is uniformly low or occasionally moderate but with a patchy distribution. This phenotype is consistent with macrophage differentiation rather than DC differentiation in which abundant expression of CD1 and CD11c is expected.

The exact sublineage of DC involved in HS has not been determined in most instances. The most likely candidates include interdigitating DC in lymphoid tissues and perivascular interstitial DC in other involved tissues.

Immunophenotyping and careful morphological assessment should also avoid confusion of HS and MH with the large cell form of cutaneous T cell lymphoma, and poorly differentiated mast cell tumors.