AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2019

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 5 x 7 mm, unencapsulated, well-circumscribed, cystic neoplasm composed of basaloid polygonal cells arranged in islands, cords, and trabeculae that form a complex cyst wall, exhibit gradual keratinization, 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 generally 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 ten HPFs. 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 10 x 20 mm, unencapsulated, well-circumscribed, multiloculated neoplasm composed of islands, nests, and broad cords of basaloid polygonal cells supported by a moderate fibrovascular stroma. Neoplastic cells undergo incomplete trichogenesis. Islands and nests of 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 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 HPF. 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 nests of polygonal cells separated by a fine fibrillar collagenous stroma. Neoplastic cells undergo incomplete recapitulation of the external root sheath of the hair bulb. Neoplastic cells often 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 HPF. Multifocally throughout the neoplasm, neoplastic cells at the center of islands and nests 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 10 X 15 mm, well-circumscribed, unencapsulated, multilobulated neoplasm composed of basaloid polygonal cells lining variably sized cystic structures 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 HPF. 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 contain fibroblasts; small caliber blood vessels; foci of brown, granular, intracellular and extracellular pigment (melanin); and many scattered plasma cells, melanomacrophages, 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 focally associated with and elevating the overlying epidermis is a partially encapsulated, 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 contain one often distinct nucleolus and rarely contain a round, eosinophilic, nuclear cytoplasmic invagination. Mitotic figures average <1 per 10 HPF. Within the islands of neoplastic cells are multifocal small lamellations of brightly eosinophilic keratin; neoplastic cells lack both keratohyaline and trichohyaline granules (tricholemmal-type keratinization). Occasionally, neoplastic cells contain intracytoplasmic brown granular material (melanin).

 

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

 

GENERAL DISCUSSION:

·       Follicular tumors attempt to recapitulate specific segments of the hair follicle; these tumors include trichoblastoma, infundibular keratinizing acanthoma (IKA), trichoepithelioma, tricholemmoma, and pilomatricoma

·       Tricholemmomas have 2 distinct types: Inferior (bulb) type (only recognized in dogs) and isthmic type

·       Most follicular tumors are benign and excision is usually curative; however, malignant varieties of trichoepitheliomas and pilomatricomas (known as a matrical carcinoma) exist

·       Follicular tumors are rare in domestic species other than dogs and cats

 

PATHOGENESIS:

·       Specific cause for all is unknown

·       IKA: Arise from the infundibular portion of the hair follicle

·       Trichoepithelioma: Arise from the primitive hair germ that exhibits rudimentary differentiation towards all three segments of the follicle (infundibulum, isthmus, inferior segment)

·       Tricholemmoma, 2 types:

·       Inferior (bulb) type: Arise from the inferior segment of the external root sheath

·       Isthmic type: Arise from the isthmic segment of the external root sheath

·       Pilomatricoma: Arise from the primitive hair matrix cells; only shows matrical differentiation

·       One study found increased β-catenin expression in canine follicular tumors with matrical differentiation, suggesting a potential mutation in the CTNBB1 gene may have a role in these tumors

 

TYPICAL CLINICAL FINDINGS:

·       IKA

·       Cystic tumor commonly occurring in dogs (usually less than 5 years of age)

·       Affect more than one location

·       Commonly reported in Norwegian Elkhounds, Keeshonds, German shepherd dogs and Terriers

·       Tumors of this description arising in the subungual region are called keratoacanthomas

·       Trichoepithelioma

·       Common in dogs (especially setter dogs), uncommon in cats (most commonly in Persian cats); usually in dogs and cats older than 5 years of age; also reported in horses and cattle

·       May be malignant; regional and pulmonary metastasis is possible

·       Tricholemmoma

·       Rare, nonrecurring pilar tumors in dogs; rare in cats

·       Dogs 5 to 13 years of age, no breed/sex predilection

·       Inferior type only recognized in dogs

·       Pilomatricoma

·       Uncommon in dogs and rare in cats (usually between 2-7 years of age)

·       Rare reports of malignancy

·       Poodles, Kerry blue terriers, Bedlington terriers, Schnauzers, Old English Sheepdogs, Wheaton terriers

 

TYPICAL GROSS FINDINGS:

·       IKA

·       Usually solitary; cystic, firm, partially alopecic, dermal or subcutaneous; central pore

·       Predilection for the dorsum and trunk and also on the neck and tail

·       Trichoepithelioma

·       Very firm, white, multilobulated, encapsulated tumor that may infrequently be mineralized

·       Predilection for the back, neck, thorax and tail in dogs; common in tail in cats

·       Can incite a strong inflammatory response from keratin release

·       Tricholemmoma

·       More common on the head and neck

·       Well-encapsulated, intradermal and subcutaneous, alopecic

·       Isthmic type tend to be smaller than inferior (bulb) type

·       Pilomatricoma

·       Macroscopically resembles a trichoepitheliomas but are more heavily mineralized, also consists of fewer and larger cysts than a trichoepithelioma

·       Almost always solitary; solid to cystic, alopecic, often ulcerated

·       Predilection for the neck but also found on the back, thorax, tail, and proximal legs

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·       IKA

·       Simple or multiloculated, often large cavity filled with lamellated keratin (no ghost cells) and lined by squamous epithelium that resembles normal follicular infundibulum exhibiting gradual keratinization from basaloid cells to large, pale eosinophilic squamous cells that multifocally contain keratohyaline granules

·       Cyst wall commonly contains secondary horn cysts (complex cyst wall) resembling keratin pearls

·       Mucinous stroma

·       No sebaceous/hair differentiation

·       Can have osseous or cartilaginous metaplasia

·       Focal rupture is common; free keratin in the dermis incites a granulomatous or pyogranulomatous reaction

·       Trichoepithelioma

·       Histologic appearance varies depending on amount of differentiation

·       Multiple islands and nests of basal cells with differentiation into the external and/or internal root sheath surrounded by a thickened basement membrane and a collagenous to mucinous stroma

·       The center of each island undergoes gradual and abrupt keratinization

·       Ghost cells may be highly melanized

·       Occasional papillary mesenchymal bodies may also be present

·       Cystic variant can occur and contains one or more large central cysts lined by epithelium undergoing trichogenic differentiation

·       Malignant trichoepitheliomas have the additional features of: increased mitotic activity, cystic degeneration, necrosis, invasion of the subcutis +/- desmoplasia, possible lymphovascular invasion

·       Tricholemmoma

·       Lobules surrounded by distinct basement membrane; centers of lobules often contain small foci of tricholemmal-type keratinization

·       May arise from different segments of the hair follicle:

·       Inferior tricholemmoma (inferior segment of the hair follicle): Tumor cells form nests separated by a fine collagenous stroma; tumor cells have abundant eosinophilic cytoplasm that is pale (clear cells) peripherally and more intensely eosinophilic towards the center of the nests; pallor of the outer most layer of cells is due to marked cytoplasmic glycogen storage

·       Isthmic tricholemmoma (isthmic type): Islands and radiating cords that may intersect or be associated with the epidermis; the tumor cells show central tricholemmal-type keratinization; granular layer is absent; can be heavily melanized

·       Pilomatricoma

·       One or more large, thick-walled cysts lined by multiple layers of basal cells undergoing abrupt keratinization and partially filled with “shadow” or “ghost cells” typical of matrical differentiation

·       Ghost cells are flattened, eosinophilic epithelial cells with a central empty halo in place of the lysed nucleus

·       May have small or large foci of dystrophic calcification and/or osseous metaplasia

·       Abundant melanin

·       Foci of necrosis is frequently observed; mitotic activity may be high

·       Rupture of cyst wall with subsequent pyogranulomatous inflammation and fibroplasia is very typical

·       Malignant pilomatricomas (matrical carcinomas) have the following features: lack differentiation, atypical histologic structure, anaplasia, erratic or rapid growth, increased mitotic index, infiltrative growth and metastasis, ulceration and necrosis is common, desmoplastic stroma;

·       Lymphatic invasion, typically at the periphery of the tumor, indicates malignancy

·       Recent report (Rissi, J Comp Path, 2019) of a cutaneous pilomatrical carcinosarcoma in a dog; similar to a variant of malignant pilomatricomas in humans

 

ADDITIONAL DIAGNOSTIC TESTS:

·       Isthmic tricholemmomas are PAS positive due to their high glycogen content

·       Bcl-2 immunohistochemistry may help to differentiate IKAs from trichepitheliomas; in one study, IKAs stained for Bcl-2 in the trabeculae only, and basaloid cells resembling matrical cells within a trichoepithelioma and malignant trichoepitheliomas expressed Bcl-2

·       Recent study (Kok, Vet Pathol, 2018) discussed the following IHC staining:

·       IKA: CD34 +

·       Trichoepithelioma (Benign): CD34 +; CK8,CK15 +/-

·       Trichoepithelioma (Malignant): p63 ++; AE1/AE3 +; CK(8,15,19,34) +/-

·       Tricholemmoma (Inferior Type): CD34 +; CK15 & CK19 +/-

·       Tricholemmoma (Isthmic Type): CK15 +; CK19 +/-

·       Pilomatricoma: p63 ++; AE1/AE3 +

 

DIFFERENTIAL DIAGNOSIS:

·       IKA:

·       Cutaneous inverted papilloma (I-V01): Hydropic degeneration, koilocytes, abnormal keratohyaline granules, inclusion bodies

·       Trichofolliculomas (I-N02), cutaneous horns, squamous cell carcinoma (I-N04), and cysts

·       Trichoepithelioma:

·       Panfollicular cyst: Simple smooth wall lined by stratified squamous epithelium

·       Bulb type tricholemmoma:

·       Basal cell carcinoma (clear cell variant): Lobules of basal cells, multifocally continuous with the epidermis, large cell aggregates

·       Granular cell trichoblastoma: Granular cells more clear, peripherally displaced nuclei

·       Isthmus type tricholemmoma:

·       IKA: Has a well-defined central cyst with secondary cysts

·       Trabecular trichoblastoma: Presence of prominent peripheral palisading, absence of foci of tricholemmomal keratinization

·       Pilomatricoma:

·       Trichoepithelioma: Cystic structures are smaller; contain zones of nonmatrical squamous epithelium rarely seen in pilomatricomas

 

COMPARATIVE PATHOLOGY:

·       Guinea pigs: Trichofolliculoma/trichoepithelioma (I-N02) are most common

·       Hamster: Hair follicle epitheliomas are induced by hamster polyoma virus (HaPyV)

·       Humans: Pilomatrixomas that show trichilemmal or hairlike differentiation

 

References:

1.     Barthold SW, Griffey SM, Percy, DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA. Wiley Blackwell; 2016:176-177, 250.

2.     Goldschmidt MH, Goldschmidt KH. Mesenchymal tumors of the skin and soft tissues. In: Meuten DJ ed. Tumors in Domestic Animals. 5th ed. Ames, IA: John Wiley & Sons, Inc; 2017: 99-107.

3.     Goldschmidt MH, Munday JS, Scruggs JL, Klopfleisch R, Kiupel M. In: Kiupel M, ed. Surgical Pathology of Tumors of Domestic Animals, Volume 1: Epithelial Tumors of the Skin. Washington DC, C.L Davis Foundation; 2019: 83-119.

4.     Gross TL, Ihrke PF, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Publishing; 2005: 616-625.

5.     Kok MK, Chambers JK, Ong SM, Nakayama H, Uchida K. Hierarchical Cluster Analysis of Cytokeratins and Stem Cell Expression Profiles of Canine Cutaneous Epithelial Tumors. Vet Pathol 2019; 55(6):821-837.

6.     Lazar AJF, Murphy GF. The skin. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Saunders Elsevier; 2015:1152-1153.

7.     Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 714-17.

8.     Miller WH, Griffin CE, Campbell KL. Small Animal Dermatology. 7th ed. St. Louis, MO: Elsevier; 2013: 778-779, 785-8.

9.     Pieper JB, Stern AW, LeClerc SM, Campbell KL. Coordinate expression of cytokeratins 7, 14, and Bcl-2 in canine cutaneous epithelial tumors and cysts. J Vet Diagn Invest. 2015;27(4):497-503.

10.  Rissi, DR. Cutaneous Pilomatrical Carcinosarcoma in a Dog. J Comp Path. 2019;170:22-25.

11.  Welle MM, Wiener DJ. The hair follicle: A comparative review of canine hair follicle anatomy and physiology. Toxicol Pathol. 2016;44(4):564-74

 

 

 

 

 

 

 

 

 

Tumor

Keratinization

Ghost cells

Histologic features

Origin

IHC Stain

IKA

Gradual keratinization

No

Central keratin-filled pore

 

Complex cyst wall has mucinous matrix

Infundibulum/ Isthmus

CD34+

Bcl-2

Trichoepithelioma

Gradual & abrupt keratinization

Yes

Can differentiate to all 3 segments of the hair follicle; abortive trichogenesis

Hair matrix cells; inner & outer sheath

Benign: CD34+; CK8,CK15 +/-

 

Malignant: p63 ++; AE1/AE3 +; CK(8,15,19,34) +/-

Pilomatricoma

Abrupt keratinization

(a small amount of gradual possible as well)

Yes

Basaloid polygonal cells that surround a central zone of ghost cells

 

Pigment

 

Bone and mineral possible

Hair matrix cells; inner sheath

p63 ++; AE1/AE3 +

Tricholemmoma

Some central tricholemmal keratinization

No

Abundant pale "glassy" cytoplasm

 

Brightly eosinophilic basement membrane

Isthmus/ Inferior

Ist: CD34 +; CK15 & CK19 +/-; PAS

 

Inf: CK15 +; CK19 +/-

Trichoblastoma

No keratinization

No

Variable patterns include undulating ribbons, medusoid

Hair matrix cells

CK8 ++; CK15 +; CK19 +/-

 


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