JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2022

I-N27

 

 

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, well demarcated, 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 fibrillar to microvacuolated cytoplasm, and a round, oval, or reniform nucleus with finely stippled chromatin and one distinct nucleolus. The mitotic count is regionally variable with up to 3 per 2.37mm². There is moderate anisocytosis and anisokaryosis. Multifocally, there are moderate numbers of neoplastic multinucleated giant cells up to 100µm 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 100um 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. Multifocally within the neoplasm there are 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 often 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 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)

Feline progressive histiocytosis

• Typically iDC origin
  1. A recent report suggests histiocytic cells of both HS and FPH are variably positive for iDC/macrophage and Langerhans cell markers (variably CD204 and/or E-cadherin positive), and their immunophenotype can change in different microenvironments (Hirabayashi, Vet Pathol, 2020)
• 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

 

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, anisokaryis, 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 (Coste, JVDI 2019)
• +/- CD5 (50%)
• A recent report suggests Ki67 as a promising prognostic marker; there is a negative correlation between overall survival and proliferation index (Coste, JVDI 2019)

 

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 distrubted; 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 previously reported at the ileocecocolic junction of an animal affected by Helicobacter spp. From a recent retrospective study, HS is one of the most common tumors in hamsters, along with lymphoma and hemangiosarcoma (Tuan, J Comp Path, 2018)
• 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 affect the skin or subcutis (these cells are CD204 negative, +/- SMA and desmin positive) (Bertram, Vet Pathol 2020)
• Four-toed hedgehogs: From recent report, tumor cells have variable features of histiocyte origin, including Langerhans cells, dendritic cells, and macrophages; very aggressive; 50% of cases died within 90 days of resection; local cutaneous HS tend to recur after resection (Son, J Comp Path, 2020)
• African pygmy hedgehog: Recent report of disseminated HS in multiple organs (Thompson, J Vet Diagn Inves, 2020)
• 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

 

REFERENCES:

1. Agnew D. Camelidae. In: Pathology of Wildlife and Zoo Animals. Eds. Terio KA, McAloose D, St. Leger J. San Diego, CA: Elsevier; 2018: 193.
2. Barthold SW, Griffey SM, Percy DH. Mouse. In: Pathology of Laboratory Rodents and Rabbits. 4^th Ed. Ames, IA: Wiley Blackwell; 2016: 103, 110-111, 167-168, 183.
3. Bertram CA, Garner MM, Reavill D, et al. Giant Cell Sarcomas in Domestic Rabbits (Oryctolagus cuniculus). 2020; 57(4):490-496.
4. Brannick EM, Newkirk KM, and Schaefer DMW. Neoplasia and Tumor biology. In: Pathologic Basis of Veterinary Disease. 7^th ed. Ed. Zachary JF. St. Louis, MO: Elsevier; 2022:383-384.
5. Camus MS, Kelly LS, and Barger AM. Immunocytochemistry. In: Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th ed. Eds. Valenciano AC and Cowell RL. St. Louis, MO: Elsevier; 2020:517.
6. Coste M, Prata D, Castiglioni V, et al. Feline progressive histiocytosis: a retrospective investigation of 26 cases and preliminary study of Ki67 as a prognostic marker. Jour of Vet Diag Inves. 2019; 31(6):801-808.
7. Delaney MA, Treuting PM, et al. Rodentia. In: Pathology of Wildlife and Zoo Animals. Eds. Terio KA, McAloose D, St. Leger J. San Diego, CA: Elsevier; 2018: 513.e2.
8. Fisher DJ. Cutaneous and Subcutaneous Lesions. In: Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th ed. Eds. Valenciano AC and Cowell RL. St. Louis, MO: Elsevier; 2020:90.
9. Jacocks K, Hoepp N, Denicola DB. Round cells. In: Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th ed. Eds. Valenciano AC and Cowell RL. St. Louis, MO: Elsevier; 2020:72. 
10. Hirabayashi M, Chambers JK, Sumi A, et al. Immunophenotyping of Nonneoplastic and Neoplastic Histiocytes in Cats and Characterization of a Novel Cell Line Derived From Feline Progressive Histiocytosis. Vet Pathol. 2020; 57(6):758-773.
11. McAloose D, Stalis IH. Prosimians. In: Pathology of Wildlife and Zoo Animals. Eds. Terio KA, McAloose D, St. Leger J. San Diego, CA: Elsevier; 2018: 334, 339.e8-339.e9.
12. Matthews M, Hilliard B, Pearson M, and Waggoner A. J Comp Path. 2021;188:32-36. 
13. Maudlin EA, Peters-Kennedy J.  Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th ed. Philadelphia, PA: Elsevier Saunders; 2016: 728-730. 
14. Meinkoth JH, Cowell RL, and Tyler RD. Cell Types and Criteria of Malignancy. In: Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th ed. Eds. Valenciano AC and Cowell RL. St. Louis, MO: Elsevier; 2020:28.
15. Moore PF. A review of histiocytic diseases of dogs and cats. Vet Pathol. 2014; 51(1):167-184.
16. Schmidt RE, Reavill DR, and Phalen DN. Pathology of Pet and Aviary Birds. 2^nd ed. Ames, IA: Wiley Blackwell; 2015:85, 121. 
17. Raskin RE and Conrado FO. Integumentary System. In: Canine and Feline Cytopathology. 4^th ed. Eds. Raskin RE, Meyer DJ, and Boes KM. St. Louis, MO; 2023:101.
18. Son NV, Chambers JK, Dung LT, et al. Histological and Immunohistochemical Features of Normal Histiocytes and Langerhans Cells, and Histiocytic Sarcomas in Four-Toed Hedgehogs (Atelerix albiventris). J Comp Path. 2020; 178:32-40.
19. Son NV, Chambers JK, Nam NH, et al. Pathological and Immunohistochemical Findings of Disseminated Histiocytic Sarcoma in a Sugar Glider (Petaurus breviceps). J Comp Path. 2021;187:83-88. 
20. Thompson LA, Morita A, Murakami S, et al. Wobbly hedgehog syndrome with disseminated histiocytic sarcoma and lateral ventricular meningioma in an African pygmy hedgehog. J Vet Diagn Invest. 2020; 32(6):953-956. 
21. Tuan YC, Wan RC, Kao JP, et al. Retrospective Pathological Studies of Splenic Lesions in Domestic Hamsters (Phodopus spp). J Comp Path. 2018;164:37-43. 
22. Valli VEO, Kiupel M, Bienzle D, Wood RD. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6^th ed. Philadelphia, PA: Elsevier Saunders; 2016: 250-254. 
23. Welle MM and Linder KE. The Integument. In: Pathologic Basis of Veterinary Disease. 7^th ed. Ed. Zachary JF. St. Louis, MO: Elsevier; 2022:1260. 

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