Deciphering the histiocytic code

Many clinicians cringe when they see the word histiocytic on a diagnostic report. The nomenclature of histiocytic diseases can be difficult to understand, leading to confusion in regards to diagnostic and therapeutic options. To further compound the confusion, it can be easy to misdiagnose these diseases with only routine histopathology. This article is designed to provide a better understanding of the histiocytic diseases, as well as to provide information regarding the diagnosis and clinical presentation of these diseases and available treatment options.

Origin of histiocytes

In order to understand the classification of the histiocytic disorders, a brief review of immunology is needed. Traditionally the term histiocyte has been used to refer only to differentiated cells of the monocyte/macrophage line. However, the current classification scheme includes two cell lines: Langerhans/dendritic cells and the monocyte/ macrophage series. It is believed that these two cell lines arise from a common stem cell in the bone marrow since these cells share certain surface markers, respond to the same growth factors and can produce the same biologically active molecules. However, during the maturation process, the morphology and the function of these two lines become different (Cline 1994).

Macrophages develop from a stem cell known as the colony-forming unit granulocyte-macrophage (CFU-GM). Promonocytes mature into monocytes in the bone marrow, which then are released into the blood stream and enter the tissues to complete the maturation process. These cells are phagocytic, and they protect the body from micro-organisms as well as other organic and inorganic particles through the process of phagocytosis. Langerhans cells develop from a bone marrow stem cell, but the maturation process begins in the epidermis and is completed in T cell-rich areas. When fully mature, these are considered to be Langerhans or dendritic cells. These cells are not poorly phagocytic but function in the immune system as antigen presenting cells (Cline 1994).

Diagnosis of histiocytic diseases

With only routine H&E stains it can be difficult to make an accurate diagnosis of a histiocytic disease. Diseases that have been confused with the histiocytic disorders based on morphologic appearance include lymphomatoid pulmonary granulomatosis, large cell anaplastic carcinoma of the lung and granulomatous inflammatory conditions. There are also diseases that were initially classified to be of histiocytic linage but have since been found to arise from different stem cells (i.e. malignant fibrous histiocytoma). In addition, the term histiocytic has been applied to diseases in which the cells are morphologically similar to histiocytes but are of a different cell linage (i.e. histiocytic lymphoma).

The advent of immunohistochemical markers for histiocytes has led to a more accurate diagnosis and classification of the histiocytic diseases. In most cases, a panel of markers provides more information than only a single marker. Markers that can be used to identify histiocytic cells on formalin-fixed tissue include lysozyme and CD18. Fresh frozen tissue is considered superior to formalin-fixed tissue since it is possible to identify several additional markers (ie.CD1, MHC II). Depending on the differential diagnoses, markers for non-histiocytic cells such as CD3 (T-cells), CD79a (B cells) cytokeratin (carcinomas), immunoglobulin light chains (plasma cells) and toluidine blue (mast cells) are often included in the panel. A pathologist can recommend appropriate stains based on the differentials. Keep in mind that negative markers do not necessarily rule out a specific disease, since more undifferentiated cells may lose these markers.

Classification of histiocytic disorders

Most of the histiocytic disorders can be placed into one of four categories: reactive macrophage histiocytoses, malignant macrophage histiocytoses, reactive Langerhans cell (dendritic) histiocytoses and malignant Langerhans cell (dendritic) histiocytosis. In dogs, the majority of histiocytic diseases have been found to be of Langerhans cell origin, given that they express CD1 on the surface of the cells. The current classification scheme includes both reactive and malignant disease entities (Table 1).

Table 1 Histiocytic disorder classifications

Reactive disorders of histiocytic origin

• Cutaneous histiocytoma

This tumor type is typically classified as a reactive disorder of Langerhans cells, although also has been classified as a malignant disease. They are most commonly seen in dogs younger than 3 years old but can be seen in dogs of any age. The most common location is the head or pinnae (Photos 1 and 2). These tumors are considered solitary, but there are reports of dogs with multiple histiocytomas (Shar Peis) as well as migratory (metastatic) disease to lymph nodes (www.histiocytosis.ucdavis.edu). The diagnosis of multiple histiocytomas can be misdiagnosed as cutaneous histiocytosis because of the similar clinical presentation. It is speculated that these tumors are due to dysregulation of the immune system. In the majority of cases, there is no treatment required since they will spontaneously regress within three months, although dogs with multiple tumors can have delayed regression. Regression of migratory disease has been reported, which supports the diagnosis of histiocytomas being a reactive disorder.

Photo 1: Cutaneous histiocytoma in a dog.

• Cutaneous histiocytosis (CH) and systemic histiocytosis (SH)

Both of these diseases are considered a reactive disorder of Langerhans cells. The histologic appearance of CH and SH is identical, which suggests they may be the same disease process (Moore 2000). Collies, Shetland Sheep dogs and Bernese Mountain dogs appear to be predisposed to CH, while SH is seen mainly in male Bernese Mountain dogs. Both entities have been seen in other dog breeds as well. In Bernese Mountain dogs, it is felt that there is a genetic abnormality that predisposes them to this disease. It has been postulated that CH and SH are caused by abnormal interactions between dendritic cells and T lymphocytes (Moore 2000).

Photo 2: Aspirate of a histiocytoma.

The clinical presentation can be variable and often has a waxing and waning course. With SH, clinical signs can include weight loss, anorexia and respiratory signs, depending on the organ systems involved. Clinical signs of both diseases include multiple, erythematous rapidly growing dermal or cutaneous plaques that are found anywhere on the body (Photo 3). Involvement of the nasal planum and mucosa can be seen. CH can also involve lymph nodes. In SH, other organ systems (lung, liver, spleen, bone marrow) are involved, as are cutaneous and mucosal lesions. CH does not always require treatment; but for SH and progressive cases of CH, immunomodulatory drugs such as prednisone, azathioprine, chlorambucil, cyclosporine and leflunomide have shown to be beneficial. Response to treatment is variable, with SH being more aggressive and less responsive to treatment.

Photo 3: Multiple, erythematous plaques are often seen in CH and SH.

• Hemophagocytic syndrome

Described in both dogs and cats, this syndrome is considered a reactive process. The diagnosis is based on the finding of histologically normal histiocytes, which are phagocytosing myeloid and erythroid precursors. This syndrome is secondary to other causes such as infectious, neoplastic or metabolic diseases.

Malignant diseases of histiocyticorigin (histiocytic sarcoma complex)

• Malignant histiocytosis (MH) and Diffuse histiocytic sarcoma (DHS)

MH was originally recognized in Bernese Mountain dogs, but it has been reported in other breeds including Flat Coated Retrievers, Golden Retrievers, Labradors and Rottweilers. There may be a male predisposition for MH. Given the strong breed association, it is thought that there is a genetic determinant of this disease. Research is being done to identify the specific genetic abnormality(ies), since this may identify dogs at risk, as well as provide a therapeutic target.

Photo 4: Bone marrow aspirate with malignant histiocytic cells present.

The hallmark of this disease is systemic proliferation and organ infiltration of large atypical cells of histiocytic origin. These cells can be multinucleated and display phagocytosis of erythrocytes and leukocytes. The distribution of these cells includes the lung, bone marrow (Photo 4), lymph nodes, liver, spleen and central nervous system (Photos 5 and 6). Clinical signs include lethargy, anorexia, fever, weight loss as well as respiratory and neurologic signs. Anemia, thrombocytopenia, pancytopenia and hypercalcemia also can be seen.

Photo 5: Diffuse histiocytic sarcoma with pulmonary mass.

DHS is similar to MH but is used to designate a localized histiocytic sarcoma that spread to distant sites. As with CH and SH, DHS and MH can appear clinically similar and can be difficult to distinguish as separate entities. The distinction may not be clinically significant as the staging, treatment and prognosis for both diseases is similar.

Photo 6: Aspirate of pulmonary mass.

Staging of a dog suspected of having MH or DHS includes a CBC, chemistry profile, thoracic radiographs (three views), abdominal ultrasound, aspirate of any affected organ and a bone marrow aspirate. The prognosis for dogs with MH or DHS is considered guarded. In the past, treatment has been unrewarding; however, many of these dogs were treated with lymphoma-type protocols. Most recently, oncologists have reported responses with lomustine (CCNU), doxorubicin, cyclophosphamide, Doxil and prednisone.

Photo 7: Localized histiocytic sarcoma.

Histiocytic sarcoma

This disease is also called localized histiocytic sarcoma (LHS). The breed disposition is similar to that seen with DHS. The most common location for these tumors is the subcutis, but they have been seen in other locations, such as the spleen. Many of these tumors occur on the limbs and are often periarticular (Photos 7 and 8). Periarticular tumors have been misdiagnosed as synovial cell sarcoma. They are locally invasive and can metastasize. The metastatic rate has been reported as high as 50 percent (Moore 2002, Fidel 2006). When LHS spreads beyond the local lymph nodes, it is considered DHS.

Staging for this disease would be similar to DHS. If these tumors are localized, aggressive treatment should be considered. For local control, surgery and/or radiation therapy would be recommended. In one study, dogs that had complete local control with surgery had no evidence of metastasis or local recurrence for an unspecified period (Moore 2002). Amputation is recommended for periarticular tumors. There are few published reports regarding the efficacy of radiation therapy for these tumors, but one study demonstrated that these tumors are responsive to radiation therapy even when treating gross disease (Fidel, 2006). The type of radiation protocol would vary depending on the clinical picture as well as the goal of treatment. Chemotherapy also plays a role in the treatment of these tumors and is recommended for non-resectable or metastatic tumors as well as an adjuvant therapy to surgery and/or radiation therapy. As with MH and DHS, there are no large published reports regarding the efficacy of chemotherapy, but responses have been documented using lomustine (CCNU), doxorubicin, cyclophosphamide, Doxil and prednisone.

Photo 8: Aspirate of tarsal lesion.

Non-histiocytic diseases

• Malignant fibrous histiocytoma

This tumor is thought to be of mesenchymal, rather than histiocytic, origin; but this has not been proven with immunohistochemical stains or molecular methods. It has been suggested that malignant fibrous histiocytoma may arise from a more primitive precursor that has the ability to differentiate either into mesenchymal cells or histiocytes (Kerlin 1996). Most pathologists classify this tumor as a soft tissue sarcoma. There is also a giant cell variant of this tumor that is called giant cell tumor of the soft parts.

Dr. Cronin earned her DVM degree from Cornell University in 1990. She completed an internship at the Animal Medical Center in New York and a medical oncology residency at North Carolina State University. She is a diplomate of the American College of Veterinary Internal Medicine in oncology. After completing her residency, she was lecturer at the University of Pennsylvania Veterinary Teaching Hospital and a medical oncologist at Angell Memorial Animal Hospital in Boston. In 2001, she co-founded the New England Veterinary Oncology Group in Waltham, Mass.