Read-Only Case Details Reviewed: Oct 2010

JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2022

I-N01

SLIDE A

Signalment (JPC #2794788): German shepherd dog

HISTORY: This mass is from the neck.

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Focally expanding the dermis, elevating the overlying epidermis, and compressing adjacent adnexa is a 5x7 mm, unencapsulated, well-circumscribed neoplasm composed of basaloid polygonal cells arranged in islands, cords, and trabeculae that form a complex cyst wall, exhibit gradual keratinization (with characteristic keratohyalin granules), and line a large keratin filled cyst that is contiguous with the epidermis forming a large central pore. Neoplastic cells are supported by a moderate fibrovascular and myxomatous stroma. Neoplastic cells are polygonal, have distinct cell borders, moderate amounts of eosinophilic cytoplasm, round to oval nuclei, finely stippled chromatin, and one variably distinct nucleolus. Mitoses average 1 to 2 per 2.37 mm². Multifocally, neoplastic cells form variably-sized cysts lined by gradually keratinizing epithelium and are filled with lamellated keratin (horn cysts). Within the adjacent dermis there are low numbers of lymphocytes and plasma cells.

MORPHOLOGIC DIAGNOSIS: Haired skin: Infundibular keratinizing acanthoma, German shepherd dog, canine.

SYNONYMS: Intracutaneous cornifying epithelioma, keratoacanthoma

SLIDE B

Signalment (JPC #2657259): Adult mixed breed dog

HISTORY: Dermal mass

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the subcutis and elevating the superficial dermis and epidermis is a 10x20 mm, unencapsulated, well-circumscribed, multilobulated neoplasm composed of islands and broad cords of basaloid polygonal cells supported by a moderate fibrovascular stroma. Neoplastic cells undergo incomplete trichogenesis. Neoplastic cells form variably sized keratin filled cysts and exhibit both gradual keratinization, characterized by a normal transition from basal cells to squamous cells with keratohyalin granules and the formation of lamellated keratin, and abrupt keratinization, characterized by direct transition of basal to keratinized squamous cells that lack keratohyalin granules and have faded nuclei (ghost cells). Neoplastic cells have indistinct cell borders, small amounts of eosinophilic cytoplasm, round to oval nuclei, coarsely stippled chromatin, and indistinct nucleoli. Mitoses average 1 to 2 per 2.37 mm². Multifocally, fewer cells occasionally contain small, red, intracytoplasmic trichohyaline granules. The dermis is diffusely mildly edematous characterized by increased clear space separating collagen bundles and multifocal ectatic lymphatics. There are few mast cells and plasma cells infiltrating the predominantly perivascular dermis.

MORPHOLOGIC DIAGNOSIS: Haired skin: Trichoepithelioma, breed not specified, canine.

SLIDE C

Signalment (JPC #4091294): 5-year-old MN Corgi

HISTORY: Mass removed from the right neck.

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis, elevating the overlying epidermis, compressing adjacent adnexa, and extending to the dorsal cut margin is an unencapsulated, well-circumscribed, densely cellular neoplasm composed of variably sized islands and lobules of polygonal cells separated by a fine fibrillar collagenous stroma. Neoplastic cells undergo incomplete recapitulation of the outer root sheath of the hair bulb, characterized by peripheral palisading of nuclei and peripheral abundant glassy cytoplasm (glycogen-rich) with more central neoplastic cells having abundant eosinophilic cytoplasm. Neoplastic cells palisade along a prominent eosinophilic basal lamina zone, have indistinct cell borders, abundant pale eosinophilic often vacuolated cytoplasm, irregularly round to oval vesiculate nuclei, and contain a single distinct nucleolus. Mitotic figures average 3-5 per 2.37 mm². Multifocally throughout the neoplasm, neoplastic cells at the center of islands contain deeper, more eosinophilic, fibrillar cytoplasm or occasionally are replaced by large areas of eosinophilic cellular and karyorrhectic debris (necrosis). Multifocally rare cells contain brown granular material (melanin).

MORPHOLOGIC DIAGNOSIS: Haired skin: Tricholemmoma, inferior (bulb) type, Pembroke Welsh corgi, canine.

SLIDE D

Signalment (21474-40): Dog

HISTORY: Dermal mass from the leg.

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the subcutis is a 10x15 mm, well-circumscribed, unencapsulated, multilobulated neoplasm composed of basaloid polygonal cells lining variably sized cysts separated by a collagenous stroma. Neoplastic cells are intensely basophilic, often pile up to 30 cells deep, have indistinct cell borders, scant amounts of eosinophilic to amphophilic granular cytoplasm, round to oval nuclei, finely stippled chromatin, and indistinct nucleoli. Mitotic figures average 1-2 per 2.37 mm². Neoplastic cells exhibit abrupt keratinization characterized by direct transition of basal to keratinized squamous cells which lack keratohyalin granules and have faded nuclei (ghost cells). Cysts are multifocally ruptured; ruptured cysts are surrounded by fibroblasts; small caliber blood vessels; foci of brown, granular, intracellular and extracellular pigment (melanin); and many scattered plasma cells, melanin laden macrophages, moderate numbers of multinucleated giant cells (foreign body type), and fewer lymphocytes and neutrophils.

MORPHOLOGIC DIAGNOSIS: Haired skin: Pilomatricoma, breed unspecified, canine.

SYNONYMS: Pilomatrixoma; necrotizing and calcifying epithelioma of Malherbe

SLIDE E

Signalment (JPC #4088229): Yorkshire terrier

HISTORY: Mass from left caudal thorax

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis and subcutis, compressing adjacent adnexal structures and subjacent panniculus carnosus, and elevating the overlying epidermis, compressing and compacting surrounding collagen (pseudocapsule), is a well-demarcated, moderately cellular neoplasm composed of polygonal cells arranged in islands and radiating cords, supported and separated by a moderate fibrovascular stroma that variably contains lightly basophilic material (mucin). Neoplastic cells have indistinct cell borders, abundant pale, eosinophilic, often glassy cytoplasm, and round to oval to irregular, vesiculate nuclei that contains one often distinct nucleolus and rarely contain a round, eosinophilic, nuclear cytoplasmic invagination. Mitotic figures average <1 per 2.37 mm². Within islands of neoplastic cells are multifocal small lamellations of brightly eosinophilic keratin (trichilemmal-type keratinization); neoplastic cells lack both keratohyaline and trichohyaline granules. Occasionally, neoplastic cells contain intracytoplasmic brown granular material (melanin).

MORPHOLOGIC DIAGNOSIS: Haired skin: Tricholemmoma, isthmic type, Yorkshire terrier, canine.

GENERAL DISCUSSION:

Hair follicle (pilar) neoplasms attempt to recapitulate specific segments of the hair follicle (infundibulum, isthmus, and inferior segment); these tumors include the infundibular keratinizing acanthoma (IKA), trichoepithelioma, tricholemmoma (isthmic type), tricholemmoma (inferior (bulb) type), trichofolliculoma (I-N02), trichoblastoma (basal cell tumor) (I-N03), and pilomatricoma
Most follicular tumors are benign and excision is usually curative

Malignant trichoepitheliomas and pilomatricomas (called matrical carcinomas) exist

Follicular tumors are common in dogs, less so in cats, and rare in other species

PATHOGENESIS:

Specific cause for all is unknown
IKA
1. Arise from the infundibular portion of the hair follicle
Trichoepithelioma
1. Arise from primitive hair germ that exhibits rudimentary differentiation towards all three segments of the follicle (infundibulum, isthmus, inferior segment)
Tricholemmoma: Tumor of the outer root sheath (ORS), also called external root sheath
1. Isthmic tricholemmoma: differentiate into isthmic section of ORS
2. Inferior tricholemmoma: differentiate into inferior segment of ORS;
Pilomatricoma: Arise from the hair matrix of the hair bulb and shows matrical differentiation (towards hair cortex)

TYPICAL CLINICAL FINDINGS:

IKA
1. Common tumor of dogs, seen in middle-aged to older (4-10 yrs of age)
2. Found along the dorsal neck, back, and tail
3. Commonly reported in Norwegian Elkhounds, Keeshonds, German shepherd dogs and Terriers
4. Spontaneous regression does not occur
Trichoepithelioma
1. Common in dogs (especially setter dogs), uncommon in cats (most common in Persian cats); usually in dogs and cats middle-aged to older (5-11 yrs of age); also reported in horses and cattle, and rodents
2. Multiple tumors most frequently in Basset Hounds
3. Can occur anywhere on the body, with a slight preference for the back in dogs and tail in cats
4. May be malignant; regional and pulmonary metastasis is possible
Tricholemmoma
1. Very rare tumor; isthmic tricholemmoma only recognized in dogs; inferior tricholemmoma recognized in dogs and cats middle-aged to older (5-11 yrs of age)
2. Most often on the head and neck
3. Afghan Hounds may be predisposed
Pilomatricoma
1. Uncommon in dogs, rare in cats (usually 5-10 years of age)
2. Poodles, Kerry blue terriers, Bedlington terriers, Schnauzers, Old English Sheepdogs, Wheaton terriers; breeds with continuously growing hair coat and anagen predominance seem to be more affected
3. Rare reports of malignancy

TYPICAL GROSS FINDINGS:

IKA
1. Partially alopecic, variably sized nodule with cystic neoplasm central pore, and often with a hard keratin plug
2. Usually solitary but can be multiple
3. Horny growth (cutaneous horn) projecting from surface of the tumor possible
Trichoepithelioma
1. Superficial to deep dermal or subcutaneous; superficial tumors often dome-shaped
2. Alopecic, firm, white-to-gray, multilobulated mass
3. Often become ulcerated
Tricholemmoma
1. Alopecic, firm, circumscribed, dome-shaped mass
2. Inferior tricholemmomas can be large (2-7 cm), isthmic tricholemmomas are smaller (<2 cm)
Pilomatricoma
1. Solitary, firm, often alopecic and sometimes ulcerated 1-10 cm diameter nodules most commonly on the proximal legs and dorsal trunk over the rump and shoulders
2. May be cystic; may be pigmented
3. Often internally mineralized (osseous metaplasia frequently present)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

All follicular neoplasms can rupture internally, inciting a marked granulomatous or pyogranulomatous reaction in surrounding dermis
1. Especially common in IKA and pilomatricoma
IKA
1. Well-demarcated cup-shaped dermal mass with central cyst filled with lamellar, concentric keratin
2. Trabecular, anastomosing cords and projections of epithelium extend from cyst wall to form small, secondary horn cysts (complex cyst wall)
3. Cyst wall consists of glassy stratified squamous epithelium with gradual keratinization and keratohyalin granules
4. Mucinous stroma is present, imparting a pale blue background
5. Sebaceous or hair differentiation not present; can have (occasionally marked) osseous or cartilaginous metaplasia
6. Focal rupture is common
Trichoepithelioma
1. Histologic appearance varies depending on amount of differentiation
2. Can be superficial or deep dermal to subcutaneous
3. Well-circumscribed, non-infiltrative, unencapsulated tumor, consisting of epithelial islands and cysts that show differentiation toward all 3 of the follicular segments:
  - Gradual keratinization with keratohyalin granules (infundibulum),
  - Abrupt keratinization (trichilemmal keratinization without granular layer) may be present (isthmus)
  - Trichohyalin granules (inner root sheath (IRS), inferior portion)
  - Small epithelial cells with hyperchromic nuclei and little cytoplasm (hair bulb)
  - Epithelium with squamous or matrical differentiation (shadow or ghost cells with central clear area, remnants of nucleus, and eosinophilic cytoplasm) typical of matrical differentiation
4. Incomplete or abortive trichogenesis may be visible
5. Matrical and ghost cells may be melanized
6. Cysts lined by either squamous epithelium and/or follicle-like basal cell nest; where basaloid cells are usually palisaded; may be surrounded by a thick, eosinophilic, hyalinized basement membrane
7. Malignant trichoepitheliomas have increased mitotic activity, cystic degeneration, necrosis, invasion of the subcutis +/- desmoplasia, possible lymphovascular invasion
Tricholemmoma
1. Well-demarcated, unencapsulated tumors; neither keratohyalin or trichohyalin granules
2. Isthmic tricholemmoma: Small, eosinophilic keratinocytes that form anastomosing cords and trabeculae radiating outwards; may have foci of trichilemmal keratinization; palisading is not present; +/- keratinaceous cysts or pseudocysts, mucinous stroma, melanization
3. Inferior tricholemmoma: Lobular groupings with small cells arranged in islands, nests, and delicate trabeculae; peripheral cells form prominent palisades and clear cytoplasm due to glycogen storage (ORS differentiation); central cells more eosinophilic; thick, eosinophilic, glassy basement membrane present (similar to vitreous sheath of the normal follicle); +/- foci of trichilemmal keratinization, mucinous matrix
Pilomatricoma
1. Multiple large, thick-walled cysts lined by basal cells (resembling matrical cells of the anagen bulb), undergoing abrupt keratinization, and partially filled with ghost cells
  - Ghost cells often undergo dystrophic mineralization; may progress to osseous metaplasia
2. Trichohyalin granules (IRS differentiation), usually present
3. Cells frequently exhibit high mitotic activity, but usually considered benign with rare exceptions (see below)
4. May be abundant melanin; amyloid may be found in center of lobules
5. Malignant pilomatricomas (matrical carcinomas) have the following features: Invasive (especially lymphatic invasion) and poorly circumscribed, increased basal: ghost cell ratio, anaplasia, erratic or rapid growth, increased mitotic index with atypical mitoses, and metastasis, ulceration and necrosis are common, desmoplastic stroma is present
  - Cutaneous pilomatrical carcinosarcoma reported in one dog had 2 malignant cell populations: sarcomatous and pilomatrical
  - Melanocytic matricoma reported in one dog, similar to pilomatricoma with the additional feature of neoplastic melanocyte proliferation

ADDITIONAL DIAGNOSTIC TESTS:

Cytology: Populations of basilar epithelial cells can predominate or alternatively keratinized nucleated to anucleate keratinocytes
IHC and special staining:
1. IKA: CD34 +
2. Trichoepithelioma (benign): CD34 +; CK8, CK15 +/-
3. Trichoepithelioma (malignant): p63 ++; AE1/AE3 +; CK(8,15,19,34) +/-
4. Isthmic tricholemmoma: CK15 +; CK19 +/-
5. Inferior tricholemmoma: CD34 +; CK15 +/-; CK19 +/-
  - Also periodic acid-Schiff (PAS) positive due to high glycogen content
6. Pilomatricoma: p63 ++; AE1/AE3 +/-

DIFFERENTIAL DIAGNOSIS:

IKA
1. Cutaneous inverted papilloma (I-V01): Papillary projections from cyst wall (rather than secondary horn cysts); hydropic degeneration; koilocytes, abnormal keratohyaline granules; inclusion bodies
2. Squamous cell carcinomas (I-N04A, I-N04B) SCCs less well demarcated, are invasive, and prominent cellular pleomorphism
3. Trichoepithelioma: Usually possess both squamous and matrical epithelial cells; ghost cells present
4. Tricholemmoma: Lower cellularity; fewer cysts; epithelial cells are eosinophilic; no granules
Trichoepithelioma
1. Panfollicular cyst: Simple smooth wall lined by stratified squamous epithelium
Tricholemmoma
1. Isthmic tricholemmoma: IKA: Possess a pore-forming opening, multiple secondary keratinaceous cysts, and abundant mucinous stroma; Benign pilomatricoma: Usually has larger, but fewer, cysts; Trabecular trichoblastomas: Prominent palisading of cells and multifocal spindling of cells
2. Inferior tricholemmoma: Granular trichoblastomas: Form cords rather than islands and have peripherally-placed nuclei; Clear-cell basal cell carcinoma: have larger tumor cell aggregates; more malignant features, and associated with the epidermis
Pilomatricoma: Trichoepitheliomas: smaller cysts lines with squamous epithelium with keratohyalin granules, mineralization is rare; Keratinizing basal cell carcinomas: Have broad connection to the epidermis and features of malignancy, Matrical cysts: Unilocular cyst

COMPARATIVE PATHOLOGY:

Dogs: IKA common and only found in dogs; trichoepitheliomas common; inferior tricholemmoma only found in dogs; pilomatricoma only found in dogs
Cats: Trichoepitheliomas uncommonly found
Horses: Trichoepitheliomas uncommonly found
Cattle: Trichoepitheliomas uncommonly found
Alpaca: Trichoepithelioma allegedly reported in, however JKP author believes it was a hybrid follicular cyst
Lab animal
1. Guinea pigs: Trichofolliculoma/trichoepithelioma (I-N02) are the most common tumor of the skin
2. Hamster: Hair follicle epitheliomas (e.g. trichoepithelioma) are exclusively induced by hamster polyomavirus (HaPyV)
NHP: Trichoepithelioma reported in a Barbary macaque
ZEW: Trichoepithelioma reported in a captive rock hyrax

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