JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2025

I-N27B

SLIDE A

Signalment (JPC# 3044519): Hooded crossbred rat, rodent

HISTORY: Unspecified

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Infiltrating the subcutis, separating, surrounding, and replacing skeletal muscle, and extending to cut margins is an unencapsulated, infiltrative, densely cellular neoplasm composed of round to spindle cells arranged in broad sheets on a moderate preexisting fibrovascular stroma. Neoplastic cells have variably distinct cell borders, a moderate to abundant amount of eosinophilic, finely granular to microvacuolated cytoplasm, and a round, oval, or reniform nucleus with finely stippled chromatin and one distinct nucleolus. There are 3 mitotic figures per 2.37 mm². There is moderate anisocytosis and anisokaryosis. Multifocally, there are moderate numbers of neoplastic multinucleated giant cells up to 100 µm in diameter with up to 30 nuclei. There is scattered single cell necrosis as well as large areas of coagulative necrosis characterized by retention of cellular architecture and loss of differential staining admixed with foci of lytic necrosis characterized by eosinophilic cellular and karyorrhectic debris admixed with numerous cholesterol clefts. Multifocally there are hemosiderin-laden macrophages and hematoidin crystals. Multifocally, moderate numbers of myofibers are shrunken and angular with deeply eosinophilic sarcoplasm (atrophy), less commonly swollen with vacuolated sarcoplasm and loss of cross striations (degeneration), or rarely shrunken or fragmented with pyknotic nuclei (necrosis).

MORPHOLOGIC DIAGNOSIS: Haired skin: Cutaneous histiocytic sarcoma, Hooded crossbred rat, rodent.

SLIDE B

Signalment (JPC# 1918993): Cat, breed and age unspecified

HISTORY: Tissue from a multilobulated mass in the lumbar region

HISTOPATHOLOGIC DESCRIPTION: Haired skin and subcutis: Infiltrating the subcutis and deep dermis, elevating the epidermis, and extending to cut margins is an unencapsulated, densely cellular, multilobulated neoplasm composed of spindle cells arranged in long, interlacing streams and bundles on a moderate fibrovascular stroma with lobules are separated by broad bands of mature collagen. Neoplastic cells have indistinct borders and a moderate amount of eosinophilic, fibrillar cytoplasm. Nuclei are elongate with finely stippled chromatin and have 1-2 variably distinct nucleoli. There is mild anisocytosis and anisokaryosis. Admixed with spindle cells are moderate numbers of more round, pleomorphic, multinucleated giant cells up to 100 um in diameter with up to 20 nuclei and often prominent nucleoli. There are 3 mitotic figures per 2.37mm². Neoplastic cells surround a large, focally extensive area of drop-out, lytic necrosis, and artifactual separation. There are multifocal, variably sized, up to 2mm diameter, areas of lytic necrosis characterized by loss of architecture with replacement by eosinophilic and cellular debris as well as hemorrhage, fibrin, and edema. At the periphery of the neoplasm there are many perivascular aggregates of lymphocytes with fewer plasma cells. The surrounding connective tissue and dermis are loosely arranged and expanded by clear space, and lymphatics are mildly ectatic (edema).

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Undifferentiated pleomorphic sarcoma (previously known as malignant fibrous histiocytoma), breed not specified, feline

SYNONYMS: Malignant fibrous histiocytoma, malignant giant cell tumor of soft parts, extraskeletal giant cell tumors, dermatofibrosarcomas, anaplastic sarcoma with giant cells

GENERAL:

• Histiocytic sarcoma (HS) complex includes several subtypes of histiocytic sarcoma, dendritic cell leukemia, and feline progressive histiocytosis (FPH) (also see H-N03)
  • Histiocytic sarcoma subtypes: Hemophagocytic HS, articular/periarticular/synovial HS, central nervous system HS
  • HS occurs in dogs, rarely in cats, and can be localized or disseminated (disseminated HS was previously known as malignant histiocytosis); these two forms are histologically and immunophenotypically identical; rapid and highly aggressive course
    • Disseminated histiocytic sarcoma (malignant histiocytosis): May represent metastasis of primary lesion or multicentric neoplastic transformation of histiocytes
      • Multicentric (primary neoplasm) in skin, spleen, lung, bone marrow, meninges, lymph nodes, and synovium; +/- dissemination to liver, lymph nodes, lungs, brain (meninges), synovial tissues of limbs, rarely affects skin
  • Major cutaneous types of HS complex (2): Localized histiocytic sarcoma (LHS) and feline progressive histiocytosis (FPH)
    • Localized histiocytic sarcoma
      • Rapidly growing, malignant, dermal or subcuticular neoplasm, associated with soft tissues of the extremities; often periarticular
      • Locally invasive to the joint capsule, tendons, and muscles of the region
    • Feline progressive histiocytosis
      • Most common histiocytic disease in cats, albeit rare, originating in the skin
      • Despite the name, behaves as a low-grade histiocytic sarcoma
      • May develop invasive, expansile masses in kidneys, spleen, lymph nodes, lungs, and/or liver

PATHOGENESIS:

Localized histiocytic sarcoma

• Interstitial dendritic cell (iDC) origin, found in perivascular spaces of most organs; typically originate within subcutis and can extend into the dermis; express CD1a, MDCII, and CD11c/CD18, CD204, Iba1, CD45
  • Exception: hemophagocytic histiocytic sarcoma is macrophage origin; express CD1a (+/-), CD11d/CD18, CD204, Iba1
• CD4 and E-cadherin negative; in contrast to canine reactive histiocytosis
• Bernese Mountain dogs, Rottweilers, golden retrievers, and flat-coated retrievers are predisposed
• Generally middle-aged to older
• Bernese Mountain dogs and flat-coated retrievers have abnormalities in tumor suppressor gene loci (CDKN2A/B, RB1, and PTEN)
• Mice: HS are considered to be derived from macrophages (Janke, 2023)

Feline progressive histiocytosis

• Typically iDC origin
  • histiocytic cells of both HS and FPH are variably positive for iDC/macrophage and Langerhans cell markers (variably CD204 and/or E-cadherin positive)
• Seen more in middle aged to older cats
• Lesions become invasive and can metastasize to regional lymph nodes

TYPICAL CLINICAL FINDINGS:

Localized histiocytic sarcoma

• Depend on the organ involved; often anorexia, weight loss, and lethargy
• Solitary or multiple lesions
• Possible mild nonregenerative anemia and hypercalcemia
• Hemophagocytic form: Lacks skin lesions; marked, regenerative, hemolytic anemia and thrombocytopenia

Feline progressive histiocytosis

• Lesion size may wax and wane; poor long-term prognosis; no spontaneous regression, as seen in canine cutaneous histiocytomas

TYPICAL GROSS FINDINGS:

Localized histiocytic sarcoma

• Pale tan infiltrative masses with uniform smooth cut surface
• Dogs: Usually occurs on an extremity or in close proximity to a joint

Feline progressive histiocytosis

• Solitary or more commonly multiple firm, nonpruritic, nonpainful, alopecic and ulcerated papules, nodules, and plaques
• Commonly on the head, trunk, and lower extremities

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Localized histiocytic sarcoma

• Sheets of pleomorphic, anaplastic, round , plump histiocytic cells, and multinucleated histiocytic giant cells that effaces normal tissue architecture
• Marked cytologic atypia with high mitotic rate and numerous bizarre mitotic figures
• Abundant eosinophilic cytoplasm
• Large oval to indented or twisted vesicular nuclei
• +/- pleomorphic spindle-shaped cells
• +/- phagocytosis (more profound in hemophagocytic HS)
• Cytology: Large individual round/oval to spindle shaped cells with indistinct cell borders, abundant blue, granular, sometimes vacuolated cytoplasm +/- phagocytized erythrocytes and leukocytes, hemosiderin, or cellular debris; round/oval/bean-shaped nucleus; moderate to marked anisocytosis, anisokaryosis, and pleomorphism; multinucleate giant cells; moderately to highly exfoliative; definitive diagnosis can be made with marked atypia, but cannot be made if cells appear relatively bland (ddx other diseases of macrophage origin or granulomatous inflammation)

Feline progressive histiocytosis

• Diffuse dermal or subcuticular infiltrate of morphologically normal histiocytes; <50% of cases exhibit epitheliotropism (intraepidermal accumulations of histiocytic clusters)
• Unencapsulated, poorly demarcated masses, broader at the surface than at the base
• Mild to moderate anisocytosis and anisokaryosis; variable mitotic rate, but usually low; +/- multinucleated cells
• In late stages, may resemble HS (pleomorphism, multinucleated giant cells, etc.)
• Cytology: Mixed cell types with predominantly histiocytes, some of which are multinucleate; may resemble lymphoid or plasmacytoid cells; inflamed lesions may contain neutrophils and lymphocytes; definitive diagnosis cannot be made on cytology

ADDITIONAL DIAGNOSTIC TESTS:

Localized histiocytic sarcoma

• Immunoreactivity: CD1, CD11c/CD18, vimentin, CD45, +/- CD163, CD204, Iba1, CD90 (cutaneous histiocytic sarcomas only)
• Negative immunoreactivity: CD4, E-cadherin

Feline progressive histiocytosis

• Immunoreactivity: CD1a, CD1c, CD11b/CD18, Iba-1, and MHC-II
• Negative immunoreactivity: E-cadherin, except for epitheliotropic cases
• +/- CD5 (50%)
• negative correlation between overall survival and Ki67 proliferation index

DIFFERENTIAL DIAGNOSIS:

Localized histiocytic sarcoma

• Cutaneous histiocytosis (I-M10)
• Disseminated histiocytic sarcoma (malignant histiocytosis)- cutaneous involvement rare
• Canine cutaneous histiocytoma (I-N22)
• Wide variety of sarcomas
• Idiopathic nodular dermatitis / panniculitis (I-M12, I-M17)
• Granulomatous dermatitis caused by infectious agents (fungi, bacteria, parasites)

Feline progressive histiocytosis

• Atypical large cell lymphoma
• Dermatitis (generalized inflammatory)

COMPARATIVE PATHOLOGY:

• Pigs: Congenital histiocytosis- very rare condition of neonatal piglets; multiple cutaneous papules, macules, and plaques that may be widely distributed; histologically dense infiltrate of spindle cells in short bundles or storiform arrangement in dermis and subcutis with variable numbers of histiocytoid cells; no epidermotropism; low mitotic rate
• Pet and aviary birds: Intestinal tract diffuse or nodular thickenings, extending from mucosa to serosa, effacing normal tissue architecture; ddx- intestinal lymphoma, mycobacteriosis; also seen in the liver as pleomorphic, infiltrative cells with abundant cytoplasm
• Mice: Especially common is some strains of laboratory mice (aged B6 and SJL); marked enlargement of spleen with nodular involvement of other tissues such as uterus, vagina, ovaries, liver, kidney, and lung; may appear elongated in HS arising in the uterine wall, which may be easily misdiagnosed as a malignant Schwannoma; tumors in the lymph node are interspersed within a dense population of well-differentiated lymphocytes, which may be easily misdiagnosed as diffuse histiocyte-associated large B-cell lymphoma; renal proximal tubules may contain hyaline droplets associated with histiocytic sarcomas elsewhere in the body
• Rats: Occur most often in Sprague Dawley rats, primarily in animals older than 12 months; cells vary from elongated, palisading fusiform cells (unknown cellular origin) to plump, pleomorphic histiocytic cells (monocyte or histiocyte origin)
• Hamsters: HS is one of the most common tumors in hamsters, along with lymphoma and hemangiosarcoma
• Rabbits: Histiocytic giant cell sarcoma; rare; primarily affects lungs; only a single case report in the skin; CD204 is a good marker of cells of histiocytic lineage in rabbits; anaplastic giant cell sarcoma more common and mostly affects the skin or subcutis (these cells are CD204 negative, +/- SMA and desmin positive)
• African pygmy hedgehog: disseminated HS in multiple organs has been reported (Sirivisoot et al, 2021).
• Sugar glider: Recent report of disseminated histiocytic sarcoma in urinary bladder, abdominal lymph nodes, liver, spleen, small intestine, uterus, and left ovary (Son, J Comp Path, 2021)
• Bengal tiger: Recent report of a large, subcutaneous HS that infiltrated the dermis, subcutis, and abdominal wall with metastasis to the spleen, adrenal glands, and lungs (Matthews, J Comp Path, 2021)
• Wildlife: Has been reported in Bactrian camel, slow Loris, Crowned lemur, and Gray mouse lemur
• Amphibians: Histiocytic sarcoma was recently reported as a common neoplasm in a population of Puerto Rican crested toads (21% of toads with neoplasms had HS); HS was either disseminated or confined to the dermis/subcutis in these toads (Imanse et al, 2024).

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