Systemic Reactive Histiocytosis
JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M10

Signalment (JPC #1902435):  1-year-old Bernese mountain dog

HISTORY: This dog presented with chronic anorexia, weight loss, stertorous respiration, conjunctivitis with prominent chemosis, and multiple cutaneous nodules throughout the body, but most prominent on nasal regions, eyelids, and scrotum.

HISTOPATHOLOGIC DESCRIPTION:  Haired skin, pinna: Expanding the deep dermis both dorsal and ventral to the auricular cartilage are multifocal to coalescing perivascular nodules composed predominantly of histiocytes and lymphocytes admixed with fewer plasma cells, neutrophils, and multinucleated giant cells. Inflammatory cells occasionally surround adnexae or extend into the superficial dermis. Angiocentric nodules are separated by dense bands of fibrous connective tissue and edema. Vessel walls are often infiltrated or obscured by previously described inflammatory cells, fibrin, and necrotic debris (fibrinonecrotizing vasculitis), and vascular lumina are multifocally occluded by eosinophilic fibrillar material with embedded cellular debris and inflammatory cells (fibrin thrombi). The overlying epidermis is multifocally acanthotic with prominent rete ridge formation. There is moderate epidermal orthokeratotic hyperkeratosis and rare intracorneal foci of necrotic debris, degenerate neutrophils, and occasional colonies of 2 um diameter cocci (intracorneal pustules).  Within the superficial dermis, there are few macrophages containing melanin as well as free melanin (pigmentary incontinence). 

MORPHOLOGIC DIAGNOSIS:  Haired skin, pinna: Atypical histiocytic proliferation, angiocentric, multifocal to coalescing, marked, with fibrinonecrotizing vasculitis, fibrin thrombi, fibrosis, epidermal hyperplasia, and hyperkeratosis, Bernese Mountain Dog, canine.  

CAUSE:  Unknown

CONDITION:  Reactive histiocytosis

GENERAL DISCUSSION:

• Histiocytes are tissue macrophages, whose functions are primarily phagocytosis and antigen presentation
• Canine histiocytic diseases have been classified into 3 major categories:
  • Nonmalignant non-neoplastic (cutaneous reactive histiocytosis, systemic reactive histiocytosis)
  • Nonmalignant neoplastic (cutaneous histiocytoma)
  • Malignant neoplastic (localized histiocytic sarcoma, disseminated histiocytic sarcoma, hemophagocytic histiocytic sarcoma)
• Systemic reactive histiocytosis (“SRH”, or systemic histiocytosis)
  • This rare condition affects many locations; the nose (planum and apex), scrotum, and eyelids are common cutaneous sites; widespread metastasis to the ocular and nasal mucus membranes, lung, liver, bone marrow, spleen, peripheral and visceral lymph nodes, kidneys, and testes have been described
    • Not all cases of SRH have skin lesions
  • Bernese mountain dogs, Rottweilers, Labrador and golden retrievers, and Irish wolfhounds are predisposed
  • The age range for SRH is 2 to 11 years and prognosis is guarded; average age is 4 years old

PATHOGENESIS:

• Unknown
• Reactive histiocytosis is likely caused by immune dysregulation of activated dermal interstitial dendritic cells in response to an unknown antigenic stimulus rather than a neoplastic proliferation; may result as a progression from the cutaneous form
• Systemic reactive histiocytosis is likely a progression of the cutaneous disease to involve internal organs, though cutaneous lesions are not always appreciated; no evidence of progression to malignant neoplasm
• Ulceration of skin lesions may be secondary to vascular lesions that cause infarction
• T cells may provide a proliferative and activating effect on interstitial DC through Granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-a)
  • This is in contrast to cutaneous histiocytoma, where they have a downregulating effect

TYPICAL CLINICAL FINDINGS:

• Long history of remission and relapse; can spontaneously resolve
• Anorexia, weight loss, lethargy, renal disease, conjunctivitis, chemosis, and stertorous respiration due to nodular or diffuse swelling of the mucous membranes of the nares
• Does not respond to immunomodulating therapy

TYPICAL GROSS FINDINGS:

• Up to 4 cm wide, well-circumscribed, cutaneous nodules that may be alopecic or ulcerated; most commonly affected areas are flanks, face, nose, neck, extremities (including foot pads), perineum, and scrotum
• Lymphadenomegaly
• Chemosis
• Note: Systemic lesions may only be detectable via histologic examination

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Angiocentric nodular to diffuse infiltrates (exudates) composed of sheets of histiocytes that lack atypia and are admixed with numerous lymphocytes (mostly CD8⁺ T lymphocytes), occasional plasma cells, individual neutrophils, and rare eosinophils and multinucleated giant cells
• Lesions begin in the mid-dermis and favor deep infiltration into the deep dermis and panniculus; tend to be “bottom heavy”; older lesions may extend superficially and have a periadnexal distribution
  • This is in contrast to histiocytomas in which histiocytes predominate at the epidermal-dermal junction with some deeper extension (“top heavy”)
• Intimately associated with blood vessels (lymphohistiocytic vasculitis), causing vascular degeneration, obstruction, and thrombosis
• Fibrosis is observed with chronicity
• Lesions in other organ systems present as angiocentric nodules
• Ischemic necrosis may be present due to vascular invasion

DIAGNOSTIC TESTS:

• The proliferating histiocytic cells of reactive histiocytosis consistently express CD18, CD1a, CD11c, MHCII, CD4 (marker of dendritic cell activation), and THY-1 (CD90) but lack expression of E-cadherin; they are immunophenotypically identified as activated dermal (interstitial) dendritic antigen presenting cells
  • Histiocytes within histiocytic sarcoma (iDC) and cutaneous histiocytoma (LC) inconsistently express Thy-1 (CD90), and do not express CD4, nor do epidermal dendritic antigen presenting cells (Langerhans cells)
• Culture to rule out granulomas due to an infectious agent
  • Do not culture for fungal elements until blastomycosis, histoplasmosis, and coccidioidomycosis are ruled out

DIFFERENTIAL DIAGNOSIS:

For microscopic findings:

• Cutaneous reactive histiocytosis: Limited to the skin and lymph nodes; nasal planum involvement may result in a “clown nose” appearance; multiple dermal nodules typically on the head/face, neck, extremities, scrotum, and trunk; young dogs; long, waxing and waning course; nodular to diffuse histiocytic inflammation; responds to immunomodulating therapy
  • Histologically, skin lesions of cutaneous and systemic reactive histiocytosis are identical
• Histiocytic sarcoma: Localized or disseminated; derived from interstitial dendritic cells; fatal, familial disease of middle aged to older Bernese mountain dogs and flat coated retrievers; mixture of pleomorphic, anaplastic, plump, round histiocytic cells and MNGC; marked atypia and bizarre mitotic figures; expression of CD4 is not observed
  • Localized histiocytic sarcoma (I-N27A): Rapidly growing malignant neoplasms in the skin, subcutis, soft tissue of extremities; periarticular and invade joint; gross masses are infiltrative, destructive, pale tan, and have a uniform smooth cut surface
  • Disseminated histiocytic sarcoma (old name: malignant histiocytosis): lesions primarily in the lung and liver, rarely the skin; prognosis is guarded and rapidly progressive; more profound and grossly detectable systemic lesions than in SRH
• Canine cutaneous histiocytoma (I-N22): Langerhans cell origin; common skin tumor of younger dogs that undergoes spontaneous immune-mediated regression; composed of neoplastic histiocytes with bland oval nuclei, abundant eosinophilic cytoplasm, high mitotic rate, and epitheliotropism; “top heavy”; positive for E-cadherin
• Idiopathic nodular dermatitis/panniculitis (I-M12): Benign nodular cutaneous disease of unknown etiology; periadnexal distribution of large, pale-staining histiocytes, lymphocytes, neutrophils, plasma cells, and rare eosinophils
• Lymphomatoid granulomatosis: Uncommon lymphoma; most common in the lung as large neoplastic nodules, but also seen in skin, kidney, and other non-lymphoid locations; characterized by a mixed infiltrate of lymphoid cells admixed with lymphohistiocytic cells; can form granulomas; prominent angiocentricity and angioinvasion
• Sterile granuloma/pyogranuloma syndrome (I-M17): cutaneous nodules with ulceration and draining tracts that are composed of periadnexal granulomas and/or pyogranulomas; absent infectious agents and foreign material
• Granulomatous dermatitis caused by infectious agents (fungi, bacteria, parasites)
• Cutaneous drug reactions causing a cutaneous granulomatous or pyogranulomatous response

COMPARATIVE PATHOLOGY:

• Cat: Limited reports of histiocytic disease; reactive histiocytosis not reported
  • Feline progressive histiocytosis: Begins as cutaneous nodules and plaques that may resemble canine cutaneous reactive histiocytosis; located on head, lower extremities, trunk; resembles a low-grade histiocytic sarcoma originating from cutaneous interstitial dendritic cells; may progress to organs (lung, kidney, spleen, liver); morphologically normal histiocytes of interstitial dendritic cell origin; spontaneous regression is not documented
  • Pulmonary Langerhans cell histiocytosis (PLCH): Progressive respiratory failure due to extensive obliteration of the pulmonary parenchyma/filling of airways by an infiltrate dominated by Langerhans cells; cutaneous forms of LCH are not documented cats

REFERENCES:

1. Gross TL, Ihrke PJ, Walder WJ, Affolter VK. Noninfectious nodular and diffuse granulomatous and pyogranulomatous diseases of the dermis. In: Skin Disease of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Publishing; 2005:323-327.
2. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Ltd. 2016:728-730.
3. Moore PF. A review of histiocytic diseases of dogs and cats. Vet Pathol. 2014;51:167-184
4. Valli VEO, Kiupel M, Bienzle D. Histiocytic proliferative diseases. In: Maxie MG Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Ltd. 2016:247-250.
   1. Welle MM, Linder KE. The Integument. In: Zachary FJ ed. Pathologic Basis of Veterinary Disease. 7^th St. Louis, MO: Elsevier; 2022:1248.

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