JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-N05

 

Slide A: Signalment (JPC #2237659): A 6½-year-old Bernese mountain dog

 

HISTORY: Unknown 

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Effacing approximately 95% of the pulmonary architecture and abutting the moderately thickened pleura is a poorly demarcated, infiltrative, densely cellular neoplasm composed of round to spindle cells (histiocytes) arranged haphazardly in short streams and variably sized sheets separating the pre-existing pulmonary fibrovascular stroma. Neoplastic cells have variably distinct cell borders; moderate to abundant eosinophilic, granular, often microvacuolated to foamy cytoplasm; and irregularly round to reniform nuclei with finely stippled chromatin and 1-3 variably distinct nucleoli. Anisocytosis and anisokaryosis are marked. Mitotic rate is regionally variable with up to 5 per high power field (0.237mm²) and with occasional bizarre mitotic figures present. There are numerous multinucleated neoplastic cells with up to 25 nuclei that occasionally exhibit nuclear molding. There are multifocal scattered phagocytosis of leukocytes and rarely erythrocytes by neoplastic cells; mixed areas of lytic and coagulative necrosis; multifocal invasion of vessels by neoplastic cells; rare single cell necrosis; and few ectatic lymphatics (edema).  Multifocally the pleura is lined by reactive mesothelium and expanded up to 500 µm by fibrous connective tissue (fibrosis) and fewer inflammatory cells. 

 

MORPHOLOGIC DIAGNOSIS: Lung: Histiocytic sarcoma, Bernese mountain dog, canine.

 

CONDITION: Disseminated histiocytic sarcoma

 

Slide B: Signalment: 13-year-old, female, domestic long hair, feline

 

HISTORY: The cat had a 5-day history of increased respiration, with 3-4 days of rapid shallow breathing and 2 weeks of weight loss. The owners had noticed a recent change in the cat's vocalization. Thoracic radiographs revealed a diffuse bronchointerstitial pattern throughout the lungs. There was no response to treatment with bronchodilators or glucocorticoids.

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Approximately 80% of alveoli and alveolar ducts are completely filled with densely packed, round to spindle cells arranged in dense, cohesive sheets and indistinct streams. The infiltrating cells have a histiocytic appearance characterized by variably distinct cell borders, a moderate amount of lightly eosinophilic to pale basophilic cytoplasm that is sometimes lightly vacuolated, and a round to oval to reniform, often eccentrically placed nuclei with variably condensed, smooth chromatin and typically indistinct nucleoli. Mitotic figures are rare, <1 per 2.37mm². Some alveoli also contain individual or small central clusters of alveolar macrophages with abundant, highly vacuolated, foamy cytoplasm and small, condensed nuclei. Many alveoli are segmentally lined by prominent, cuboidal epithelial cells (type II pneumocyte hyperplasia). There is frequently smooth muscle within alveolar septa that is thickened in many areas (smooth muscle hyperplasia). Peribronchiolar and peribronchial BALT is prominent, and clusters of densely packed lymphocytes with lesser numbers of plasma cells are also scattered throughout the section. The majority of lesser affected alveoli contain abundant eosinophilic proteinaceous fluid (edema). Occasionally normal alveolar architecture is replaced by thin interlacing bands of collagenous tissue (interstitial fibrosis), with moderate numbers of lymphocytes and plasma cells and multifocal areas of mild hemorrhage. Alveolar septa are occasionally lost resulting in enlarged, confluent air spaces (emphysema).

 

MORPHOLOGIC DIAGNOSIS: Lung: Alveolar and bronchiolar histiocytosis, diffuse, severe, with smooth muscle hyperplasia, type II pneumocyte hyperplasia, and moderate lymphoplasmacytic and histiocytic inflammation

 

CONDITION: Pulmonary Langerhans cell histiocytosis

 

GENERAL DISCUSSION: 

• Histiocytes are all cells of dendritic cell (DC) or macrophage lineage that differentiate from CD34+ stem cell precursors (myeloid DCs)
  1. Iba1 (ionized calcium binding adaptor molecule 1) is a highly conserved marker for histiocyte cell lines (Zhang, Am J Clin Pathol, 2021)
  2. All histiocytic cells express CD18, part of the heterodimeric β-2 integrin adhesion molecule that is composed of 1 of 4 different CD11 (a-d) subunits and the CD18 subunit
  3. DCs
     • Part of the adaptive immune response, act as potent antigen-presenting cells; all express CD1a, CD11c and MHC class I and II; activated DCs express CD4
     • Types include:
       • Langerhans cells (LC) 
         1. Epithelial dendritic cells found within epithelia/epidermis of the skin and alimentary, respiratory, and reproductive tracts 
         2. Birbeck’s granules are found in LCs of mice, humans, pigs, cats, and many other species (but NOT dogs)
         3. LCs are the source of feline pulmonary Langerhans cell histiocytosis (LCH) 
         4. Express E-cadherin, CD207 (langerin), CCR6 
       • Interstitial DCs (iDCs)
         1. Found in perivascular locations in almost all tissues (not in the brain, but are within the meninges and choroid plexus) 
         2. iDCs are the source of histiocytic sarcomas (HS) in dogs and cats
            • NOTE: In other species, HS may have markers of LCs, iDC, and/or macrophages (see Comp Path)
         3. Markers:
            • Do not express E-cadherin
            • Dermal iDCs are specifically in the dermis and express Thy-1 (CD90)
            • CD204 (macrophage scavenger receptor 1) is expressed on macrophages and iDCs
       • Other types of DCs: Interdigitating (in T-cell domains in lymph node/spleen), follicular, circulating (veiled)
  4. Macrophages 
     • Source of hemophagocytic histiocytic sarcomas
     • Markers
       • In most tissues, macrophages express CD11b/CD18 
       • In hematopoietic sites, such as the splenic red pulp, bone marrow, and lymph node medullary sinuses, they express CD11d/CD18
       • Other macrophage markers include: Mac387 (calprotectin), CD163, and MHC class II
       • CD204 (macrophage scavenger receptor 1) is expressed on macrophages and iDCs
• Histiocytic disorders 
  1. Frequently diagnosed in dogs and occur less often in cats; histiocytic sarcomas are commonly reported in a variety of species
  2. In domestic animals, originate from iDCs or LCs
     • Only hemophagocytic histiocytic sarcomas in dogs have been demonstrated to originate from macrophages, in particular red pulp macrophages from the spleen
  3. Can be classified into 3 major categories:
     • Nonmalignant non-neoplastic: Canine LC histiocytosis, canine cutaneous reactive histiocytosis and systemic reactive histiocytosis (I-M10)
     • Nonmalignant neoplastic: Canine cutaneous histiocytoma (I-N22)
     • Malignant neoplastic: Localized histiocytic sarcoma (I-N27), disseminated histiocytic sarcoma (P-N05 [this one]), hemophagocytic histiocytic sarcoma
• Histiocytic sarcomas (HS) are aggressive neoplasms from interstitial DCs (Exception: Hemophagocytic histiocytic sarcoma is of macrophage origin)
  1. Neoplasms begin as localized lesions, which rapidly disseminate to many organs 
  2. Primary sites include spleen, lung, skin, brain (meninges), lymph node, bone marrow, and synovial tissues of limbs
  3. Secondary sites are widespread but consistently include liver and lungs (with splenic primary) and hilar lymph nodes (with lung primary)
  4. Histiocytic sarcoma (HS) complex includes several subtypes of histiocytic sarcoma, dendritic cell leukemia, and feline progressive histiocytosis (FPH)
  5. Historically, “malignant histiocytosis” referred to disseminated histiocytic neoplasia (with multiple organ involvement) and “histiocytic sarcoma” referred to a single, solid tumor; now “disseminated histiocytic sarcoma” is used 

 

PATHOGENESIS: 

• A familial predisposition for HS has been identified in many breeds of dog
  1. Disseminated HS has a predilection for Bernese mountain dogs (inherited); also reported in Rottweilers and golden, Labrador and flat-coated retrievers
  2. Incidence is highest in middle aged to older male dogs
  3. Recent studies of HS in Bernese mountain dogs and flat-coated retrievers have suggested a role for abnormalities in tumor suppressor gene loci (CDKN2A/B, RB1, and PTEN)
• HS may arise in the lung and spread to thoracic lymph nodes, or may arise elsewhere (e.g., splenic origin) and secondarily involve lungs and other organs

 

TYPICAL CLINICAL FINDINGS: 

• Disseminated HS
  1. Young to middle-aged dogs (2–8 years); rapidly progressive with no known successful therapy, poor prognosis
  2. Vague signs that include anorexia, weight loss, and lethargy and reflect the wide range of organ systems affected
  3. Pulmonary: Respiratory distress (e.g., coughing, dyspnea)
  4. CNS: Seizures, incoordination, and paralysis
  5. Articular: Lameness
  6. Bloodwork
     • Mild, nonregenerative anemia
       • More severe regenerative anemia, thrombocytopenia, hypoalbuminemia, and hypocholesterolemia documented with hemophagocytic HS
     • Hypercalcemia of malignancy may rarely be observed
     • Neoplastic cells may rarely be encountered in peripheral blood
       • Extremely rare cases of dendritic cell leukemia reported
• Feline pulmonary LCH
  1. Aged cats (10-15 yrs old), may present with severe respiratory distress (tachypnea, dyspnea) that leads to progressive respiratory failure
  2. Thoracic radiographs: Bronchointerstitial pattern of miliary to nodular opacities throughout all lung lobes

 

TYPICAL GROSS FINDINGS:

• Disseminated HS
  1. Affected organs may be uniformly enlarged and/or contain multiple coalescing white-tan nodules
• Feline pulmonary LCH
  1. All lung lobes diffusely firm and effaced by ill-defined, coalescing nodular masses (2–5 mm maximum dimension)
  2. Tracheobronchial lymph nodes also enlarged and diffusely effaced
  3. May also affect pancreas, kidney, liver, or distant lymph nodes

 

TYPICAL LIGHT MICROSCOPE FINDINGS:

• Disseminated HS
  1. Tissue architecture effaced by sheets of pleomorphic, round to spindle-shaped or dendritic cells with indistinct borders and round or cleaved nuclei
  2. Often marked cellular atypia with anisokaryosis, numerous karyomegalic cells, and multinucleated neoplastic cells
  3. Phagocytosis of red cells, leukocytes, and tumor cells occurs in HS, but is not usually pervasive except in hemophagocytic HS
• Feline pulmonary LCH
  1. Histiocytic infiltrates within terminal and respiratory bronchioles that can obliterate airway walls and fill lumina
  2. Histiocytes have homogeneous or finely vacuolated eosinophilic cytoplasm, anisokaryosis, poikilokaryosis, and nuclear hyperchromasia 

 

ULTRASTRUCTURAL FINDINGS:

 

ADDITIONAL DIAGNOSTICS

• Gross presentation, histopathology, and IHC is usually sufficient to diagnose most histiocytic diseases; rarely additional frozen sections will be required 
• Disseminated HS
  1. Cytology: 
     • Individual round cells or spindle to pleomorphic cells with abundant amount of lightly to moderately basophilic cytoplasm +/- vacuolation, with oval to reniform nuclei containing lacy chromatin and prominent nucleoli; large, multinucleate cells present. 
     • Cytologically difficult to differentiate from granulomatous inflammation, large cell anaplastic carcinoma, large cell T-cell lymphoma, and plasmacytoma extramedullary myeloma
  2. Immunohistochemistry
     • Interstitial DC origin (except hemophagocytic HS which originates in splenic red pulp macrophages), therefore:
       • Positive reactivity: CD204 (macrophage scavenger receptor 1), CD1a, CD11c/CD18, MHC class II (frozen section)
         1. Thy-1 (CD90) (dermal iDCs)
         2. Positive also to Iba1 (works on formalin-fixed or decalcified sections) (Cora, Toxicol Pathol. 2020)
       • Negative reactivity: CD11d, E-cadherin
         1. CD4 negative, because not derived from activated iDCs
     • A recent report suggests histiocytic cells of both HS and feline progressive histiocytosis 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)
     • May have increased NF-kB expression (also seen in other canine tumors, including lymphomas, hemangiosarcomas, and mast cell tumors) demonstrated by increased p65 and p100/p52 (Schlein, Vet Pathol 2023)
• Feline pulmonary LCH
  1. Immunohistochemistry:
     • Langerhans cells (LC) origin, therefore:
       • Positive reactivity: CD18 and E-cadherin (E-cadherin expression most often markedly reduced in extra-pulmonary lesions
         1. Positive also to Iba1 (works on formalin-fixed or decalcified sections) (Cora, Toxicol Pathol. 2020)
       • Negative reactivity: CD4, CD11d, CD90 (Thy-1)
         1. CD204 (macrophage scavenger receptor 1): Positive in some species (see above, Comp Path)

 

DIFFERENTIAL DIAGNOSIS:

• Disseminated HS
  1. Malignant fibrous histiocytoma (MFH) (I-N27)
     • Neoplastic cells have features of fibroblasts and histiocytes
     • Some regard this an all-inclusive diagnosis of pleomorphic forms of other soft tissue sarcomas (leiomyosarcoma, rhabdomyosarcoma, and liposarcoma); others consider MFH part of a continuum 
     • The term “MFH” has fallen out of favor; those neoplasms that cannot be further classified as specific soft tissue tumors (such as HS) are simply termed pleomorphic undifferentiated sarcoma
  2. Lymphomatoid granulomatosis
     • Usually only in lungs and lymph nodes; angiocentric/angioinvasive infiltrates of pleomorphic mononuclear cells; small T-cell and large, atypical B-cells (resemble centroblasts and immunoblasts) admixed with histiocytes
     • Multinucleated giant cells not a prominent feature; lysozyme negative
     • Solitary to multinodular white or tan masses at the base of the caudodorsal lung lobes
     • IHC studies most consistent with TCRBCL
  3. Anaplastic or giant cell carcinoma
     • Similar lung lesions; stains positive for cytokeratin
• Feline pulmonary LCH
  1. Histiocytic sarcoma: Neoplastic cells have features of fibroblasts and histiocytes
  2. Feline progressive histiocytosis (FPH, most common histiocytic disease in cats)
     • Indolent form of localized histiocytic sarcoma, originates in skin of cats; female > male; middle aged to older cats
     • Solitary or multiple nonpruritic firm papules, nodules, and plaques with a predilection for feet, legs and face
     • Invasive, expansile masses in lymph nodes, lungs, kidneys, spleen, liver may develop
     • Diffuse dermal infiltrate of morphologically normal histiocytes
     • Occasional epitheliotropism characterized by intraepidermal accumulations of cluster(s) of histiocytes
     • Positive for CD1a, CD1c, CD18 (feline specific), MHC class II; E-cadherin negative; interstitial DC origin
• Histiocytic proliferative disorders:
  1. Canine cutaneous histiocytoma (CCH) (I-N22): 
     • Seen in dogs only; a benign neoplasm of epidermal Langerhans cell origin; spontaneous regression
     • Expresses: Vimentin, CD1a, CD11a/CD18, CD11c/CD18, CD44, CD45, and MHC class II; +/- E-cadherin, lysozyme, CD11d/CD18, CD54
     • Located primarily in the dermis; “top heavy”
     • Base of the tumor may have infiltrates of CD8+ cytotoxic T lymphocytes; sign of host-mediated spontaneous tumor regression
  2. Cutaneous Langerhans cell histiocytosis (LCH):
     • Dogs only; typically presents as multiple cutaneous lesions; occasional lymph node and systemic metastasis (worse prognosis)
     • Histologically resembles CCH; similar immunohistochemical features; lesions may be larger and extend into the subcutis and muscle; Shar Pei dog may be overrepresented
     • Similar condition described in humans; a recent study suggests that over-production of GM-CSF by T-cells could be a pathogenic factor in human LCH (GM-CSF is drives differentiation of monocyte-derived inflammatory dendritic cells)
  3. Reactive histiocytosis (I-M10): 
     • Dogs only; angiocentric, angio-invasive proliferation of activated interstitial dendritic cells (admixed with CD8+ T-cells); positive for CD1a, CD11c/CD18, MCH class II, CD4 (marker of activated DCs), Thy-1 (CD90, marker for dermal DCs); negative for E-cadherin
     • Cutaneous reactive histiocytosis: 
       • More common; young collies, Shetland sheepdogs
       • Often multiple dermal/subcutaneous nodules
     • Systemic reactive histiocytosis: 
       • Young, middle aged, male Bernese mountain dogs
       • Often in the skin, eyelids/sclera and draining lymph nodes
       • Histopathology similar to cutaneous form, but not limited to the skin; widespread metastasis is possible; guarded prognosis
     • Both systemic and cutaneous histiocytosis are inflammatory diseases with underlying immune dysregulation; waxing/waning course, lesions may disappear and reappear in other locations, occasional spontaneous resolution
     • Cutaneous lesions are “bottom heavy”; dermal interstitial DC and T cells infiltrate blood vessel walls in the mid-dermis, leading to lymphohistiocytic vasculitis; may cause vascular compromise and infarction
  4. Histiocytic sarcoma (H-N03): 
     • Neoplasm of interstitial dendritic cells positive for CD1a, MHC class II, and CD11c/CD18, but NOT CD4:
     • Local histiocytic sarcoma: 
       • Rapidly growing dermal/subcutaneous nodules, often near joint (periarticular/articular HS)
         1. Most commonly occurring tumor within the joints of dogs
         2. A recent study found a significant association between previous joint disease/trauma and periarticular HS
            • Stifle, elbow most commonly affected joints; Rottweilers overrepresented
       • Composed of bundles and whorls of spindle cells, sheets of large round cells; multinucleated giant cells; often contain abundant vacuoles; mitoses are usually frequent and sometimes bizarre
       • CD18 membrane staining of cells with appropriate morphology is considered diagnostic
       • Joint location has a more favorable outcome than HS at other sites; poorer prognosis than other joint tumors
     • Disseminated histiocytic sarcoma (formerly malignant histiocytosis): 
       • Fatal familial disease of older Bernese mountain dogs
       • Primary neoplasm in spleen, lung, bone marrow; +/- dissemination to liver, lymph nodes, brain (meninges), synovial tissues of limbs; cutaneous involvement is rare
       • Pleomorphic/anaplastic histiocytes; numerous multinucleated giant cells
       • Widespread metastasis and rapid clinical progression with extremely poor prognosis
       • Majority of infiltrating T cells in histiocytic sarcomas of soft tissue origin in flat-coated retrievers are FoxP3+, suggesting the presence of regulatory T cells
  5. Hemophagocytic histiocytic sarcoma: 
     • Neoplasm of splenic red pulp/bone marrow macrophages positive for CD11d (beta 2-integrin) and CD18; negative for CD11c
     • The only macrophage-derived entity; occurs primarily in dogs
     • Primary neoplasm of spleen, bone marrow; well-differentiated neoplastic cells
     • Massive erythrophagocytosis by neoplastic cells
     • Clinical pathology: Regenerative hemolytic anemia (no agglutination), leukopenia, and thrombocytopenia due to erythrophagocytosis; thrombocytopenia; mild hyperbilirubinemia, hypoalbuminemia and often hypocholesterolemia (resembles an immune-mediated hemolytic anemia but are Coombs test negative)
  6. Central nervous system histiocytic sarcoma
     • Rare
     • Usually originates in leptomeninges (may extend into brain); neoplastic cells may have a tendency to be more undifferentiated
     • Pembroke Welsh corgis may be overrepresented
     • Positive for: CD1a, CD11c/CD18, MHC class II, Iba1 (ionized calcium binding adaptor molecule 1), CD163 & CD204 (scavenger receptors on macrophages, but a small subset of interstitial DCs have them too)
  7. Dendritic cell leukemia
     • Rare (2 reports in dogs)
     • Atypical histiocytes in peripheral blood; diffuse infiltration of affected organs (bone marrow, spleen, lung, and liver) without mass formation
     • Interstitial DC lineage: Positive for CD1a, CD11c, MHC class II; Negative for CD11d

 

COMPARATIVE PATHOLOGY:

• Canine and feline
  1. Single case report of Langerhans cell histiocytosis affecting the pancreas of a cat (Rissi, J Vet Diagn Invest, 2020)
  2. 6 cases of canine CNS HS (4 brain, 1 spinal cord, 1 both); histiocytic morphology, including multinucleate neoplastic cells, effaced the neuroparenchyma and leptomeninges, immunolabeling positive for Iba1 and negative for E-cadherin, CD3, CD79, and MUM1, confirming histiocytic origin (Riker, J Vet Diagn Invest 2023)
• Lab animals
  1. Mice: 
     • Especially common in some strains of (aged B6 and SJL); arise from mononuclear phagocytic cells; present with splenic enlargement, with nodular involvement of other tissues: Liver, uterus, vagina, kidney, lung, LN, intestines, bone marrow, and ovaries; rarely only a single organ may be involved (without spleen)
     • Renal tubular epithelial cells often contain hyaline droplets (renal tubular hyaline bodies) from distant HS
     • May be difficult to differentiate from histiocyte-associated diffuse large B-cell lymphoma
     • Due to varying morphology, may be easy to confuse with hepatic hemangiosarcoma, uterine schwannoma, leiomyosarcoma, uterine stromal cell tumor, intramedullary osteosarcoma, and myeloid leukemia; therefore, IHC needed to differentiate (F4/80 (97%), IBA1 (100%), MAC2 (100%), CD163 (56%), CD68 (100%), and lysozyme (72%) (Janke, Vet Pathol 2023)
  2. Rats: Occur most often in Sprague Dawley rats, primarily >12 months old; cells vary from elongated, palisading fusiform cells (unknown cellular origin) to plump, pleomorphic histiocytic cells (monocyte or histiocyte origin) 
  3. Hamsters: HS is previously reported at the ileocecocolic junction of an animal affected by Helicobacter spp.
  4. 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)
• Avian species
  1. Occasionally reported in the liver or as diffuse or nodular +/-transmural thickenings within the intestine that efface normal tissue; must be differentiated from mycobacteriosis and intestinal lymphoma (Schmidt, 2015)
• ZEW: 
  1. 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)
  2. African pygmy hedgehog: Recent reports of disseminated HS in multiple organs (Thompson, J Vet Diagn Inves, 2020) and disseminated haemophagocytic histiocytic sarcoma that immunolabeled for CD204 (Sirivisoot, J Comp Pathol, 2021) 
  3. 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)
  4. 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)
  5. Reported in Bactrian camel, slow Loris, Crowned lemur, and Gray mouse lemur

 

Cell of origin	Disease(s)	Immunohistochemistry
		Positive	Negative
Langerhans cell	Canine cutaneous histiocytoma; Feline pulmonary LCH (1 report of feline pancreatic Langerhans cell histiocytosis (Riss, Jour Vet Diagn Invest 2019)	E-cadherin, CD1a, CD11a/CD11c/CD18, MHC II, Iba1	Thy-1, CD4, CD204
Interstitial dendritic cell	Canine reactive histiocytoses	Thy-1, CD4, CD1a, CD11c/CD18, MHC II, CD204, Iba1	E-cadherin
Interstitial dendritic cell	HS complex, FPH	CD1a, CD11c/CD18, MHC II, CD204, Iba1,	Thy-1, CD4,  E-cadherin
Macrophage (splenic red pulp)	Hemophagocytic HS (dogs and cats)	CD11d/CD18, CD204, MHCII, Iba1	CD1a, CD11c

 

 

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