Tumors in Domestic Animals E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 3826

Veröffentlichungsjahr: 2016

Beschreibung

Tumors in Domestic Animals, Fifth Edition is a fully revised new edition of the most comprehensive and authoritative reference on veterinary tumor pathology in common domestic animals, now in full color throughout with the most current advances in research and diagnostics.

• Now in full color with hundreds of exquisite new images showing diagnostic features, pathogenesis, and techniques
• Adds new sections on relevant clinical pathology and oncology
• Updated throughout to include the very latest advances in research and diagnostics
• Takes a logical, user-friendly system approach
• Written by leading experts on animal tumor pathology

Leseprobe

Table of Contents

Cover

Title Page

List of Contributors

Preface

1 An Overview of Molecular Cancer Pathogenesis, Prognosis, and Diagnosis

Fundamentals of cancer biology

The hallmarks of malignancy

References

Veterinary cancer incidence and molecular approaches to diagnosis and prognosis

References

2 Trimming Tumors for Diagnosis and Prognosis

Specimen sizing

Orientation of trimmed specimens

Margin evaluation

Skin tumors

Canine soft tissue sarcomas and mast cell tumors

Digital amputations

Limb amputations

Ears

Eyelids

Intraocular tumors

Hemimandibulectomies/maxillectomies

Gastrointestinal tumors

Tumors of parenchymal organs

Tumors of lobar parenchymal organs

Lymph nodes

References

3 Immunohistochemistry

Introduction

References

The immunohistochemical test

References

Antigen retrieval

References

Antigens and antibodies

References

Detection methods

References

Storage and handling of reagents

References

Controls in immunohistochemistry

References

Standardization (optimization) and validation of a new IHC test

References

Immunohistochemical report and interpretation

References

Troubleshooting the IHC test

References

Approach to the immunohistochemical characterization of tumors

Biomarkers in diagnostic immunohistochemistry of neoplasms

References

Cancer of unknown primary site

References

The future of immunohistochemistry in veterinary oncology

References

4 Epithelial and Melanocytic Tumors of the Skin

General references

EPITHELIAL NEOPLASMS WITHOUT SQUAMOUS AND ADNEXAL DIFFERENTIATION

Basal cell neoplasms (Table 4.1)

References

NEOPLASMS OF THE EPIDERMIS

Papilloma (cutaneous papillomatosis)

References

References

Squamous cell carcinoma

References

Basosquamous carcinoma

NEOPLASMS WITH ADNEXAL DIFFERENTIATION

Follicular neoplasms

Reference

Sebaceous and modified sebaceous gland neoplasms

Hepatoid gland neoplasms

Apocrine and modified apocrine gland neoplasms

Anal sac gland neoplasms

References

Eccrine adenoma and carcinoma

Clear cell adnexal carcinoma

References

Merkel cell tumor

Reference

MELANOCYTIC NEOPLASMS

Melanocytoma

Melanoacanthoma

References

NAILBED (SUBUNGUAL) NEOPLASMS

Subungual malignant melanoma

References

Subungual keratoacanthoma (nailbed keratoacanthoma)

Subungual squamous cell carcinoma

References

HAMARTOMAS

Epidermal hamartoma

Follicular hamartoma

Apocrine hamartoma

Fibroadnexal hamartoma (adnexal nevus, focal adnexal dysplasia, folliculosebaceous hamartoma)

CYSTS

Infundibular cyst (epidermoid cyst, epidermal cyst, epidermal inclusion cyst)

Isthmus cyst

Dilated pore

Panfollicular (trichoepitheliomatous) cyst

Dermoid cyst (dermoid sinus)

Sebaceous duct cyst

Subungual epithelial inclusion cyst

Apocrine cyst(s) (apocrine cystomatosis)

Ceruminous cysts

Ciliated cyst

TUMOR‐LIKE LESIONS

Seborrheic keratosis

Reference

Squamous papilloma

Pressure point comedones

Cutaneous horn

Sebaceous hyperplasia (senile nodular sebaceous hyperplasia)

Fibroepithelial “polyp” (cutaneous tag, skin tag, acrochordon)

NEOPLASMS COMMONLY METASTATIC TO THE SKIN

Feline pulmonary carcinoma with digital metastases

Mammary carcinoma

Prostatic carcinoma, transitional cell carcinoma, and colonic carcinoma

References

5 Mesenchymal Tumors of the Skin and Soft Tissues

References

Fibroma

Keloidal fibroma/fibrosarcoma

Fibrosarcoma

Injection‐site sarcomas

Canine maxillary well‐differentiated fibrosarcoma

References

Equine sarcoid

Feline sarcoid (feline fibropapilloma)

References

Pleomorphic sarcoma (anaplastic sarcoma with giant cells, malignant fibrous histiocytoma)

References

Myxoma and myxosarcoma

Tumor‐like lesions

References

Canine hemangiopericytoma (myopericytoma, perivascular wall tumor)

Peripheral nerve sheath tumor (nerve sheath tumor)

Leiomyoma (piloleiomyoma and angioleiomyoma)

References

Lipoma

Liposarcoma

References

Hemangioma

Hemangiosarcoma

Lymphangioma and lymphangiosarcoma

Angiomatosis

Canine cutaneous histiocytoma

Reactive histiocytosis

Histiocytic sarcoma complex

Xanthoma

References

Plasma cell tumor (plasmacytoma, extramedullary plasmacytoma)

Lymphoma

Canine transmissible venereal tumor

6 Mast Cell Tumors

General considerations

Canine mast cell tumors

References

Feline mast cell tumors

References

Mast cell tumors in other species

References

7 Tumors of the Hemolymphatic System

INTRODUCTION

LYMPHOID TUMORS

Biological implications of tumor classification

Types of lymphoma by species

Molecular considerations

References

Precursor B‐cell neoplasms

References

Mature peripheral B‐cell neoplasms

References

References

Myeloma

References

Marginal zone lymphoma

References

Mantle cell lymphoma

References

Follicular lymphoma

Burkitt’s type lymphoma

Diffuse large B‐cell lymphoma

References

T‐cell‐rich large B‐cell lymphoma

Angiocentric B‐cell lymphoma with reactive T cells (lymphomatoid granulomatosis)

References

T‐CELL LYMPHOMAS

Precursor T‐cell lymphoblastic leukemia/lymphoma

References

T‐cell chronic lymphocytic leukemia/small cell lymphocytic lymphoma and large granular lymphocyte types

References

T‐cell prolymphocytic leukemia

References

T‐cell granular lymphocytic leukemia/lymphoma

References

Peripheral T‐cell lymphoma not otherwise specified

References

T‐zone lymphoma

References

Intestinal T‐cell lymphoma

References

References

Intravascular large T‐cell lymphoma, subcutaneous panniculitis‐like T‐cell lymphoma, angioimmunoblastic T‐cell lymphoma, aggressive NK‐cell leukemia/lymphoma

Aggressive NK‐cell leukemia and blastic lymphoma

References

Adult T‐cell leukemia/lymphoma

References

Anaplastic large cell lymphoma

References

MYELOID NEOPLASMS

Diagnostic steps

Categories of myeloid neoplasms

Myelofibrosis

Summary

References

THYMOMA

Paraneoplastic syndromes

Pathology

References

TUMORS OF THE SPLEEN

Vascular tumors

References

Mesenchymal tumors

References

8 Canine and Feline Histiocytic Diseases

Histiocytic differentiation and canine histiocytic diseases

Immunophenotyping in hematopoietic neoplasia

CANINE HISTIOCYTIC DISEASES

FELINE HISTIOCYTIC DISEASES

References

9 Tumors of Joints

Introduction

References

MALIGNANT TUMORS

Does synovial cell sarcoma exist in animals?

Synovial cell sarcoma

References

Histiocytic sarcoma

References

Other sarcomas

References

BENIGN TUMORS

Synovial myxoma

Synovial hemangioma

Periarticular fibroma

Giant cell tumor of tendon sheath

References

NON‐NEOPLASTIC LESIONS

Synovial chondromatosis

References

Synovial cysts

References

Vascular hamartoma

References

Synovial pad proliferation

References

Calcinosis circumscripta

References

10 Tumors of Bone

General considerations

References

BENIGN TUMORS OF BONES

Osteoma, ossifying fibroma, and fibrous dysplasia

References

Osteochondroma

Feline osteochondromatosis

Chondroma

Hemangioma of bone

Non‐ossifying fibroma

References

MALIGNANT TUMORS OF BONES

General considerations

References

Osteosarcoma

References

Chondrosarcoma

Fibrosarcoma

Hemangiosarcoma

References

Giant cell tumor of bone

Liposarcoma

Multiple myeloma

Malignant lymphoma of bone

References

SECONDARY TUMORS OF BONES

Metastatic bone disease

Invasive tumors of bones

References

TUMOR‐LIKE LESIONS OF BONES

Exuberant fracture callus

Fibrodysplasia ossificans progressiva

Cysts

References

11 Tumors of Muscle

TUMORS OF SMOOTH MUSCLE

General considerations

References

References

Smooth muscle tumors of the gastrointestinal system

References

Smooth muscle tumors (leiomyoma) of the gall bladder

Smooth muscle tumors of the urinary system

References

Smooth muscle tumors of the genitalia

Multicentric leiomyomas/leiomyosarcomas of the female genital tract

References

Smooth muscle tumors of the skin and subcutis

Leiomyoma/leiomyosarcoma of the spleen and liver

Smooth muscle tumors (leiomyoma) of the respiratory tract

Leiomyomas and leiomyosarcomas at other sites

References

TUMORS OF SKELETAL MUSCLE

General considerations

Classification and general histological features

References

Clinicopathologic features

Special diagnostic procedures

Ultrastructural features of tumors of skeletal muscle

Immunohistochemistry of tumors of skeletal muscle

References

Rhabdomyoma

Laryngeal rhabdomyoma and rhabdomyosarcoma

References

Rhabdomyosarcoma

Embryonal rhabdomyosarcoma

References

References

Non‐myogenic tumors of skeletal muscle

References

TUMORS OF CARDIAC MUSCLE

Cardiac rhabdomyoma

Cardiac rhabdomyosarcoma

Cardiac hemangiosarcoma

Cardiac lymphoma

Cardiac angioleiomyoma in cattle

Tumor‐like cardiac lesions

References

DIFFERENTIAL DIAGNOSIS AND APPROACH TO DIAGNOSIS OF TUMORS OF MUSCLE

12 Tumors of the Respiratory Tract

NASAL CAVITY AND PARANASAL SINUS TUMORS OF THE DOG

NASAL CAVITY AND PARANASAL SINUS TUMORS IN OTHER SPECIES

Cat

Horse

Sheep and goats

NASAL AND NASOPHARYNGEAL POLYPS

Nasopharyngeal and middle ear polyps in cats

TUMORS OF THE LARYNX AND TRACHEA

Larynx

Trachea

References

TUMORS OF THE LUNG

Epithelial tumors

Molecular lesions associated with pulmonary neoplasia in domestic animals

Feline pulmonary adenocarcinoma

Retroviral pulmonary tumors of sheep: ovine pulmonary adenocarcinoma

Mesenchymal tumors primary to lung

References

13 Tumors of the Alimentary Tract

INTRODUCTION

ORAL TUMORS

References

Epithelial neoplasia of the oral cavity

References

Mesenchymal tumors of the oral cavity

References

Melanocytic neoplasms

References

Non‐neoplastic oral tumors

References

Tumors of the tongue

References

Tumors of the tonsils

References

Odontogenic tumors and cysts

Non‐neoplastic tumors

References

Tumors of the salivary glands

References

TUMORS OF THE ESOPHAGUS

Epithelial tumors

Mesenchymal tumors

Non‐neoplastic tumors

References

Tumors of the bovine forestomachs

Tumors of the ovine forestomachs

References

TUMORS OF THE STOMACH

References

Epithelial tumors

References

Mesenchymal tumors

References

Non‐neoplastic tumors

References

TUMORS OF THE INTESTINE

References

Epithelial tumors

References

Mesenchymal tumors

References

References

References

Non‐neoplastic intestinal tumors

References

TUMORS OF THE RECTUM

Epithelial tumors of the canine rectum

Other tumors of the canine rectum

Rectal tumors in other species

References

TUMORS OF THE PERITONEUM AND RETROPERITONEUM

Mesothelioma

Retroperitoneal neoplasms

Non‐neoplastic tumors of the peritoneum

References

TUMORS OF THE EXOCRINE PANCREAS

Epithelial tumors

Other pancreatic neoplasms

Non‐neoplastic tumors

References

14 Tumors of the Liver and Gallbladder

EPITHELIAL NEOPLASMS OF THE LIVER

Nodular hyperplasia

Regenerative nodules

Hepatocellular adenoma

Hepatocellular carcinoma

Mixed hepatocellular and cholangiocellular carcinoma

Hepatoblastoma

References

BILIARY NEOPLASMS

Cholangiocellular adenoma (biliary adenoma)

Cholangiocellular carcinoma (biliary carcinoma, bile duct carcinoma)

References

Adenomas and carcinomas of the gallbladder

Cystic mucinous hyperplasia of the gallbladder

References

Hepatic carcinoids

References

MESENCHYMAL TUMORS OF THE LIVER

Hemangiosarcoma

Sarcomas and other mesenchymal tumors

Hepatic myelolipoma

References

METASTATIC NEOPLASIA

References

15 Tumors of the Urinary System

RENAL TUMORS

Epithelial tumors

References

Nodular dermatofibrosis and renal cell tumors

Embryonal tumors

References

Mesenchymal tumors

References

Etiology

References

Metastatic tumors

Tumor‐like lesions

References

TUMORS OF THE RENAL PELVIS AND URETER

TUMORS OF THE URINARY BLADDER AND URETHRA

References

Epithelial tumors

Transitional cell carcinoma – urothelial carcinoma

Squamous cell carcinoma

Adenocarcinoma

Undifferentiated carcinoma

References

Etiology

References

Mesenchymal tumors

References

Tumor‐like lesions

Urethral tumors

References

16 Tumors of the Genital Systems

INTRODUCTION AND EMBRYOLOGY

TUMORS OF THE OVARY

Introduction

Epithelial tumors

Sex cord stromal tumors

Germ cell tumors

Other tumors

Cysts

Vascular hamartoma

Ovarian hematoma

Ovarian choristoma

References

TUMORS OF THE UTERINE TUBE (OVIDUCT) AND UTERUS

Epithelial tumors

Mesenchymal tumors

Hyperplastic and tumor‐like lesions of the uterus

Miscellaneous uterine cysts

References

TUMORS OF THE CERVIX, VAGINA, AND VULVA

Epithelial tumors

Mesenchymal tumors

Tumor‐like lesions of the vagina and vulva

References

TUMORS OF THE TESTICLE

Introduction

Sex cord stromal tumors

Germ cell tumors

Mixed tumors of the testicle

Other tumors of the testicle

Tumor‐like lesions of the tissues adjacent to the testicle

References

TUMORS OF THE SPERMATIC CORD, EPIDIDYMIS, AND ACCESSORY SEX GLANDS

Tumors of the spermatic cord and epididymis

Tumors and tumor‐like lesions of the prostate

TUMORS OF THE MALE EXTERNAL GENITALIA

Epithelial tumors

Mesenchymal tumors

Other tumors

References

17 Tumors of the Mammary Gland

Epidemiology

Clinical presentation

References

Normal anatomy, histology, and immunohistochemistry

References

Hormones and growth factors

References

CLASSIFICATION OF MAMMARY TUMORS

Molecular classification of canine and feline mammary carcinomas

References

Grading of canine mammary tumors

References

CLASSIFICATION OF CANINE MAMMARY TUMORS

Hyperplasia/dysplasia

Benign mammary neoplasms

Complex adenoma (adenomyoepithelioma)

Benign mixed tumor

Malignant epithelial neoplasms

Malignant epithelial neoplasms – special types

Malignant mesenchymal neoplasms (sarcomas)

Carcinosarcoma (malignant mixed mammary tumor)

Neoplasms of the nipple

References

FELINE MAMMARY GLAND TUMORS

Grading of feline mammary tumors

References

CLASSIFICATION OF FELINE MAMMARY GLAND TUMORS

Hyperplasia and dysplasia

Benign neoplasms

Malignant epithelial neoplasms

Malignant epithelial neoplasms – special types

Malignant mesenchymal neoplasms

References

GENERAL INTRODUCTION TO PROGNOSTIC FACTORS

Canine prognostic factors

Feline prognostic factors

References

SPONTANEOUS MAMMARY TUMORS OF OTHER SPECIES

References

18 Tumors of the Endocrine Glands

TUMORS OF THE PITUITARY GLAND

Functional corticotroph (chromophobe) adenoma in pars distalis

Nonfunctional chromophobe adenoma in pars distalis

Adenoma of the pars intermedia

Acidophil adenoma of pars distalis

Pituitary chromophobe carcinoma

Craniopharyngioma (intracranial germ cell tumor)

Basophil adenoma of pars distalis

Metastatic tumors to the pituitary gland

References

TUMORS OF THE ADRENAL GLAND

Tumors of the adrenal cortex: adenoma, carcinoma, myelolipoma

Ectopic adrenal cortex

References

Tumors of the adrenal medulla: pheochromocytoma, neuroblastoma, ganglioneuroma

References

TUMORS, HYPERPLASIA, AND CYSTS OF THYROID FOLLICULAR CELLS

Tumors of thyroid follicular cells: adenoma, carcinoma

Transgenic animal models of thyroid carcinogenesis

Thyroid carcinogenesis and radiation

Hyperplasia of thyroid follicular cells: hyperplastic, colloid, nodular, and congenital goiter

Tumors of thyroglossal duct remnants

References

Tumors of thyroid C cells (parafollicular cells; ultimobranchial derivatives): adenoma, carcinoma

References

TUMORS OF THE PARATHYROID GLAND

Chief cell adenoma and carcinoma

Non‐neoplastic parathyroid cysts (Kürsteiner’s cysts)

References

CANCER‐ASSOCIATED HYPERCALCEMIA

Humoral hypercalcemia of malignancy (pseudohyperparathyroidism)

References

TUMORS OF THE PANCREATIC ISLET CELLS

Beta cell (insulin‐secreting) tumors: islet cell adenoma (insulinoma), carcinoma (malignant insulinoma)

Non–beta cell tumors of the pancreatic islets

Gastrin cell (gastrin‐secreting) tumors: islet cell adenoma (gastrinoma) and carcinoma (malignant gastrinoma)

Alpha cell (glucagon‐producing) islet cell adenoma (glucagonoma)

Delta cell (somatostatin‐producing) islet cell adenoma (somatostatinoma)

Pancreatic polypeptide‐secreting islet cell carcinoma

References

TUMORS OF THE CHEMORECEPTOR ORGANS

Aortic and carotid body: adenoma (chemodectoma), carcinoma (malignant chemodectoma)

Extra‐adrenal paraganglioma

References

19 Tumors of the Nervous System

INTRODUCTION

General considerations

References

PRIMARY TUMORS OF THE CENTRAL NERVOUS SYSTEM

Astrocytoma

Other nonclassified glial neoplasms

References

Oligodendroglioma

References

Oligoastrocytoma (mixed glioma)

References

Ependymal tumors

References

Choroid plexus tumors

References

Neuronal and mixed neuronal–glial tumors

References

References

References

Embryonal tumors: primitive neuroectodermal tumors

References

Ectopic nephroblastoma of the canine thoracolumbar spinal cord

References

Meningiomas

References

Meningioangiomatosis

References

Granular cell tumor

References

Lymphoma and neurolymphomatosis

References

Intravascular lymphoma

References

Histiocytic sarcoma of the CNS

References

Suprasellar germ cell tumors

References

References

Tumors of the cranial and paraspinal peripheral nerves

References

METASTATIC (SECONDARY) TUMORS OF THE CNS

References

20 Tumors of the Eye

TUMORS OF THE OCULAR SURFACE TISSUES

Tumors of meibomian gland origin

Conjunctival melanoma

Bovine squamous cell carcinoma

Equine squamous cell carcinoma

Canine and feline squamous cell carcinoma

Adenocarcinoma of the gland of the third eyelid in dogs and cats

Feline conjunctival surface adenocarcinoma (mucoepidermoid carcinoma)

Hemangioma and hemangiosarcoma of all species

Conjunctival lipogranuloma of cats

Papillary conjunctival tumors of dogs

The histiocytic proliferative disorders of the lids, conjunctiva, and globes of dogs

References

TUMORS OF THE GLOBE

Canine ocular melanoma

Feline diffuse iris melanoma

Equine melanocytic tumors

Iridociliary epithelial tumors in dogs and cats

Canine uveal schwannoma in blue‐eyed dogs

Primitive neuroectodermal tumors and medulloepithelioma of dogs, cats, and horses

Feline post‐traumatic sarcoma, three variants: spindle cell, lymphoma, osteosarcoma/chondrosarcoma

Lymphoma

Metastatic ocular neoplasia

References

TUMORS OF THE OPTIC NERVE AND ORBIT

Orbital meningioma of dogs

Glioma/astrocytoma of the optic nerve or retina

Feline restrictive orbital myofibroblastic sarcoma

Canine lobular orbital adenoma

Canine orbital hibernoma

Canine orbital rhabdomyosarcoma

Other orbital mass lesions of dogs and cats

References

21 Tumors of the Ear

General considerations

INTERNAL EAR

Tumors

References

MIDDLE EAR

Epithelial tumors

References

Guttural pouch

References

Non‐epithelial tumors

References

Aural inflammatory polyps

References

Tympanokeratomas (cholesteatomas)

Cholesterol granulomas

References

Mucoperiosteal exostoses (otolithiasis)

References

EXTERNAL EAR

Epithelial tumors

References

Ceruminous gland tumors

Squamous cell carcinomas

Carcinomas of undetermined origin

References

Aural melanomas

Spindle cell tumors

Cartilage tumors

Round cell tumors

Hemangiosarcomas

References

Temporal odontomata (dentigerous cyst)

Auricular chondritis

Auricular chondrosis

Ceruminous cystomatosis

References

Appendix: Diagnostic Schemes and Algorithms

Introduction

Mitotic count

References

Canine melanomas and melanocytic neoplasms

References

Histologic grading of canine cutaneous mast cell tumors

References

Prognosis of canine cutaneous mast cell tumors

References

Canine subcutaneous mast cell tumors

References

Cytologic grading of canine cutaneous mast cell tumors

References

Feline cutaneous mast cell tumors

References

Evaluation of regional lymph node metastasis in canine cutaneous mast cell tumors

References

Canine oral perioral mast cell tumors

References

Canine soft tissue mesenchymal tumor (sarcoma)

References

Canine soft tissue mesenchymal tumor: Future?

References

Joint tumors in dogs

References

Lymphoma and lymphoid leukemia prognoses

References

Enlarged lymph node evaluation in dogs

Bone marrow evaluation

PARR (PCR for antigen receptor rearrangement)

References

Canine and feline nasal tumors

Reference

References

Scoring system and prognosis for canine lung tumors

References

Histologic grading and prognosis for feline lung tumors

References

Mammary

Urothelial (transitional) cell carcinoma (UC)

Summary

References

Skin masses

Canine breed predispositions for epidermal and melanocytic tumors

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Selected veterinary paraneoplastic syndromes and associated neoplasms

Chapter 03

Table 3.1 Steps in an immunohistochemical test

Table 3.2 Cross‐reactivity of antibodies among different species

Table 3.3 Markers used for the differential diagnosis of major tumor categories

Chapter 04

Table 4.1 Revised classification of basal cell neoplasms

Table 4.2 Canine papillomaviruses and clinical symptoms

Table 4.3 Points of differentiation between viral and squamous papillomas

Table 4.4 Histological features of sebaceous neoplasms

Chapter 07

Table 7.1 Categories of myeloid neoplasms

Table 7.2 Dog leukocyte antigens detectable by immunochemistry

Chapter 08

Table 8.1 Canine and feline histiocytic diseases

Table 8.2 Cell markers useful for diagnosis of leukocytic proliferative diseases in formalin‐fixed tissues of dogs and cats

Chapter 10

Table 10.1 Summary of key features of osteoma, ossifying fibroma, and fibrous dysplasia in domestic animals

Table 10.2 Comparison of reactive and “neoplastic” bone in histological sections

Chapter 11

Table 11.1 Three hundred sixty‐six tumors diagnosed as leiomyoma of the dog, cat, cow, and horse in which the specific site of origin was identified in the Cornell files from 1977 to 1997

Table 11.2 One hundred eighty‐two tumors diagnosed as leiomyosarcoma of the dog, cat, and horse in which the specific site of origin was identified in the Cornell files from 1977 to 1997

Table 11.3 Sixteen cases of rhabdomyoma or rhabdomyosarcoma

Chapter 12

Table 12.1 Immunohistochemical markers useful in differentiating pulmonary carcinoma patterns

Chapter 13

Table 13.1 TMN classification and staging of oral neoplasms

Table 13.2 Odontogenic tumors and cysts

Chapter 14

Table 14.1 Identification of nodular lesions of the liver. These are generalizations that are characteristic of the lesions; exceptions are not listed

Chapter 15

Table 15.1 Renal neoplasia

Table 15.2 Primary renal neoplasia in dogs

Table 15.3 Primary renal neoplasia in cats

Table 15.4 Urinary bladder neoplasia

Table 15.5 Canine primary urinary bladder tumors

Table 15.6 Feline primary urinary bladder tumors

Table 15.7 Bovine urinary bladder tumors with enzootic hematuria

Chapter 16

Table 16.1 Expected immunohistochemical labeling of testicular neoplasms

Chapter 17

Table 17.1 Direct normal and altered lymph drainage in canine and feline mammary glands

Table 17.2 Immunohistochemistry of normal canine and feline mammary gland

Table 17.3 Differentiating benign from malignant mammary tumors

Table 17.4 Molecular classification of canine and feline mammary tumors

Table 17.5 Histologic grading of canine mammary neoplasms

Table 17.6 Grading of feline mammary carcinomas

Table 17.7 Staging of canine mammary tumors

Table 17.8 Staging of feline mammary tumors

Chapter 18

Table 18.1 Comparison of major classes of hormones

Chapter 19

Table 19.1 Immunophenotyping findings in primary and metastatic tumors in the CNS in FFPE tissues using routine diagnostic antibodies to cell‐specific markers

Table 19.2 Differential diagnosis of peripheral nerve sheath tumor subtypes (PNST) using routinely available antibodies to various cell‐specific markers in FFPE tissues

Table 19.3 Differential features and criteria for distinguishing between subtypes of peripheral nerve sheath tumors

Chapter 20

Table 20.1 Comparison of fixatives for ocular tissues

Table 20.2 Skin tumors of the eyelids in domestic animals

Table 20.3 Primary tumor of the globe

Table 20.4 Stages in the development of feline diffuse iris melanoma

List of Illustrations

Chapter 01

Figure 1.1 Tumor cell heterogeneity. Although tumors arise from a single cell, the inherent genetic instability in tumor cells gives rise to additional mutations and a heterogeneous population of cells with different genetic characteristics. Some mutations are lethal to developing cell lines and they die, but other mutations provide various features that facilitate the emergence of viable cell lines which may contain malignant characteristics including the ability to metastasize.

Figure 1.2 Tumor doubling. Tumor growth starts with a single cell that expands clonally. It takes approximately 30 doublings to form a 1 g mass, at which time most lesions can be detected clinically. Only 10 more doublings are needed to form a 1 kg mass, considered to be a lethal burden in humans. Likely, a smaller mass would be lethal in dogs or cats.

Figure 1.3 Histologic evolution of a carcinoma. The cellular development of cancer is a multistep process in most cases. There are several phenotypic steps in the evolution of colonic carcinoma including areas of hyperproliferation/hyperplasia, then dysplasia, followed by adenoma and, in a subset of these, carcinomas. The distribution of different phenotypes is not uniform throughout individual lesions and regions with different phenotypes may be seen when a lesion is sampled. Spontaneous growth arrest or resolution of tumors may occur, as overexpression of oncogenes can drive cellular senescence in some circumstances.

Figure 1.4 Hallmarks of cancer. These features are key elements of malignancies.

Figure 1.5 RAS oncogene. An example of proto‐oncogene activation is shown in this overview diagram of the typical RAS signaling cascade. When a growth factor binds to its transmembrane receptor the receptor becomes activated. Receptor binding triggers activation of RAS via a bridging protein. Inactive RAS, which is bound to guanosine diphosphate (GDP), becomes activated via an exchange (red arrow) for guanosine triphosphate (GTP). Activated RAS acts through intermediary proteins to activate mitogen‐activated protein kinases (MAP kinases) that lead to altered nuclear signal transduction and cell mitosis. In normal cells GTPase‐activating protein (GAP) stimulates dephosphorylation of activated RAS to an inactive form that curtails signaling (blue arrow). Mutant RAS does not interact with GAP normally and consequently stimulates cell proliferation in an unchecked fashion.

Figure 1.6 Raleigh chromosome. In human leukemias, a characteristic chromosome is the Philadelphia chromosome (Ph). This derivative chromosome, also referred to as the Philadelphia translocation, is the result of reciprocal translocation between human chromosomes 9 and 22, bringing the genes

BCR

and

ABL

(panel A) together to create activation of the tyrosine kinase of c‐ABL. The evolutionarily conserved translocation (panel B) has been detected in canine leukemias, the result of a reciprocal translocation between regions of dog chromosomes 9 and 26 (shown in panel C). The canine event is referred to as the Raleigh chromosome and has been detected in chronic myelogenous leukemia and chronic myelomonocytic leukemia. Within these patients, the frequency of cells with the Raleigh chromosome has been shown to decrease in response to tyrosine kinase inhibitor treatment, indicating that its presence may be used to monitor cytogenetic remission.

Figure 1.7 Tumor suppressor protein pRB. When pRB is hyperphosphorylated by cyclin‐dependent kinases it releases members of the transcription factor E2F family that then bind to DNA and stimulate progress from G

1

into the S phase of the cell cycle. When pRb is hypophosphorylated it binds E2F and interacts with histone‐modifying proteins, histone deacetylase and histone methyltransferase, inhibiting progress through the cell cycle. When the ability of pRB to bind E2F is disrupted by mutations or viruses, the checkpoint is eliminated and cells may then proliferate in an uncontrolled fashion.

Figure 1.8 Tumor suppressor protein, p53. The tumor suppressor gene (

TP53

) encodes a protein, p53, which is crucial for repair or apoptosis of genetically damaged cells. Signaling is mediated through growth arrest and DNA damage‐inducible protein (GADD45) that allows for DNA repair and cyclin‐dependent kinase inhibitor 1 (CDKN1 or p21) that inhibits phosphorylation of cell cycle‐related kinases and arrests progression through the cell cycle. When genetic damage is too severe to be repaired p53 can initiate apoptosis via activation of the apoptosis‐stimulating gene

BAX

. Alternatively, activation of p53 in severely damaged cells can also trigger transcription of microRNAs (miRNA) that drive cell senescence. When

TP53

is damaged by chemicals, radiation, viruses, or inherited defects, p53 production may be abrogated or a mutant p53 protein produced. Mutant p53 does not function normally and affected cells with damaged DNA do not arrest the cell cycle to enable DNA repair. Mutated cells are able to progress though the cell cycle giving rise to daughter cells with mutations and eventual tumor formation. Thus, when the gene

TP53

is damaged or absent, tumor suppression is compromised.

Figure 1.9 Telomerase. Telomerase is an enzyme that enables cells to replicate in an unlimited fashion. Cells with repressed telomerase activity such as somatic cells eventually reach senescence after a finite number of mitoses and undergo cellular senescence, a permanent growth arrest state, or apoptosis. Telomerase adds back short sections of DNA that were lost from the chromosomal telomeres (repetitive nucleoprotein sequences at the ends of chromosomes) during normal DNA replication cycles. Cells with telomerase activity such as stem cells, germ cells and cancer cells can potentially proliferate indefinitely and are potentially immortal.

Figure 1.10 Angiogenesis. Tumor angiogenesis is a critical step for the growth of the primary mass as well as metastatic masses. Tumor cells release angiogenic factors that stimulate budding of new vessels that deliver oxygen and nutrients to the growing tumor cells and provide venous drainage to remove waste products. New vessels also provide an avenue for vascular metastasis. Tumor size is limited to approximately 1 mm in diameter without supporting blood vessels.

Figure 1.11 Tumor cell and stromal interactions. Interactions between tumor cells and the adjacent stroma play a key role in many facets of tumor evolution. Multiple interactions between the tumor cells and stromal and inflammatory cells mediate tumor growth, differentiation, and metastasis, as well as host tissue responses.

Figure 1.12 Metastasis. Invasion and metastasis are hallmarks of malignant tumors. Each step in the process of metastasis can involve progressive histological changes and/or molecular alterations, some of which are illustrated here.

Figure 1.13 Lymphoma cytogenetic prognostic assay. Multicolor FISH of canine interphase nuclei of cells aspirated from lymph nodes of (A) a healthy dog and (B) a dog with lymphoma. Enumeration of the five differentially labeled single locus probes indicates that in (A) all five have a normal copy number of 2, while in (B) the two probes labeled in red and aqua (arrows) both have an abnormal copy number of 3. Probe enumeration in 100 cells allows derivation of mean copy number value for each probe. With standard‐of‐care doxorubicin‐based chemotherapy for lymphoma, 95% of dogs with low mean copy number (<1.6) of both probes labeled in red and aqua have shorter first remission times (<90 days), and 95% of dogs with higher mean copy number (>2.5) have remission times over 9 months. Assays like this will help oncologists and owners make informed decisions on how an individual patient with lymphoma may respond to specific therapy (theranostics).

Figure 1.14 Histiocytic sarcoma cytogenetic assay. Three‐color FISH of canine interphase nuclei designed to detect cells with DNA copy number aberrations characteristic of cells derived from a canine histiocytic malignancy. This assay was designed to help differentiate canine histiocytic sarcoma from lymphoma. (A) Nucleus of peripheral lymphocyte of a healthy dog. (B) Nuclei of cells derived from a fine‐needle aspirate of canine lymph node from a dog with a confirmed histiocytic neoplasm. The three probes comprising the FISH assay represent regions of CFA 2 (red, R), CFA 16 (green, G), CFA 31 (yellow, Y). Although all three probes have a copy number of

n

 = 2 in the healthy cell (i.e., R2/G2/Y2), it is clear from panel B that the cells labeled a–d each have one or more numerical abnormalities with copy numbers as follows: (a) R1/G0/Y0, (b) R2/G2/Y1, (c) R1/G1/Y0, and (d) R2/G2/Y1. Enumeration of >100 cells yields mean copy numbers for each probe of <2.0 in >90% of histiocytic neoplasms, while >90% of canine lymphomas a have a balanced or mean copy number >2.0 for each probe.

Figure 1.15 Cytogenetic signature of canine urothelial carcinoma. Four‐color FISH of canine interphase nuclei designed to detect cells with DNA copy number aberrations characteristic of cells derived from canine urothelial carcinoma. (A) Nucleus of peripheral lymphocyte of a healthy dog. (B) Nucleus of a cell voided in the urine of a dog with a confirmed urothelial carcinoma. The four probes comprising the FISH assay represent CFA (

Canis familiaris

) 8 (yellow), CFA 13 (red), CFA 19 (green), and CFA 36 (pink). While all four probes have a copy number of

n

 = 2 in the healthy cell, panel

A

, it is clear from panel B that there are several abnormalities. In this case the neoplastic cell has the expected two copies of CFA 8 (internal control), but has the urothelial carcinoma signature of copy number increases of 13 and 36 and loss of 19: in this example there are five distinct signals representing CFA 13, one signal representing CFA 19, and at least eight distinct signals representing CFA 36. This assay will help detect and or confirm urothelial carcinoma in a free‐catch sample of urine.

Chapter 02

Figure 2.1 Excisional biopsy. The entire mass is removed by the biopsy. Margin evaluation can be performed.

Figure 2.2 Incisional biopsy. Only a portion of the mass is removed by the biopsy. Margin evaluation is not possible.

Figure 2.3 Cell Safe™ cassette containing endoscopic intestinal samples. Samples this small are difficult to orient. Tissues in FFPE block may need to be rotated to obtain correct orientation.

Figure 2.4 (A) Perpendicular margin. The tissue is cut perpendicular to the surgeon’s plane of cut. (B) When placed on the glass slide, the histologic tumor‐free margin (HTFM) and mass can both be visualized and the distance between edge of the tumor and non‐neoplastic tissue estimated or measured and reported as M1–M4.

Figure 2.5 Perpendicular margin, pictogram. Serial sections or “bread/bologna slicing” of the entire mass. This technique will assess approximately 1–5% of the circumferential margin depending on the size of the tumor and the number of sections taken at specified intervals, none of which is standardized for animal tumors.

Figure 2.6 (A) Perpendicular margin. Two cuts are made at right angles to evaluate five components of the margin: four lateral (“points of the compass” cut) and the ventral margin. (B) Perpendicular margin. Modified “points of the compass” cut in an oversized mass to evaluate the margin in five directions. In this modification the specimen is too large to include the margin and mass in the same section so the histologic tumor‐free margin (HTFM) cannot be observed directly and measured or estimated on the glass slide. These type of sections can be reported as M4, >5 mm. Standard histopathology cassettes are 3.0 cm × 2.5 cm.

Figure 2.7 (A) Parallel or

en face

margin, pictogram. The tissue is cut parallel to the surgeon’s plane of cut. This technique prioritizes examination of the outermost tissues supplied by the surgeon. A second or third section must be obtained from the tumor to establish the diagnosis. The cuts (sections) in this pictogram are made in a vertical plane;

en face

sections in a horizontal plane are seldom done in animal tumors but will yield tumor and peripheral margin until the deep margin is reached. (B) Parallel or

en face

margin placed on the glass slide. More surface(s) on the margin are examined but the relationship between the mass and the margin is not visible on the slide.

Figure 2.8 (A) Epithelial tumor, pictogram. Benign types grow as a cohesive sphere of connected cells with even edges. Carcinomas may be infiltrative. The natural surface of both types can be compared to the “tip of an iceberg.” (B) The margin is easily observed in perpendicular section but the HTFM may vary in different parts of an asymmetrical tumor or infiltrative carcinomas. The HTFM in the lower panel is narrower than the upper panel.

Figure 2.9 (A) Round cell tumor, pictogram. The tumor grows as a sphere of unconnected cells with an irregular edge. (B) The tumor appears completely excised in the upper panel but tumor cells infiltrate the margin in another section deeper in the block.

Figure 2.10 (A) Soft tissue sarcoma, pictogram. The sarcoma grows as an asymmetrical mass with highly irregular edges consisting of concentric lamination or finger‐like extensions similar to a root ball of a tree. (B) The tumor appears completely excised in the upper panel but deeper in the block sections reveal tumor cells infiltrating the margin.

Figure 2.11 (A) Digital amputation phase 1. Prior to decalcification; soft tissue sections of the mass and two

en face

sections of the surgical margin. (B) Digital amputation phase 2. After decalcification; perpendicular section through the nailbed and

en face

section through the phalanx at the surgical margin.

Figure 2.12 Ear masses. (A) Partial distal amputation of the pinna. One perpendicular section through the mass for diagnosis and one

en face

or cross‐section of the surgical margin to evaluate completeness of excision. (B) Total ear canal ablation (TECA) for excision of malignant tumors in the ear canal. One cross‐section through the mass for diagnosis and an

en face

or cross‐section of the TECA specimen at the surgical margin for completeness of excision.

Figure 2.13 Eyelid masses. (A) V‐plasty surgery removed a small wedge of section with the deep margin at the apex. (B) Wedge section resulting from the V‐plasty. One perpendicular section through the mass to the apex is the most practical.

Figure 2.14 (A) Ocular enucleation with a mass in the iris. Locate the optic nerve and long posterior ciliary artery. (B) Ocular enucleation trimming. Cut the globe superior to inferior, cranial to caudal. Discard the lateral collates and embed the central section with the optic nerve laterally in the cassette.

Figure 2.15 Hemimandibulectomy specimen. One perpendicular section of the soft tissue of the mass should be taken prior to decalcification, followed by two

en face

sections of the cranial and caudal margins.

Figure 2.16 (A) Full‐thickness wedge biopsy of the intestine. (B) Orientation of full‐thickness intestinal biopsy for evaluation of all layers of the bowel wall.

Figure 2.17 (A) Observable intestinal mass. (B) Resection and anastomosis for an observable intestinal mass. (C) Anastomosis and trimming of intestinal mass. Take

en face

sections of both orad and aborad ends of the resection specimen. A cross‐section and longitudinal section through the mass permits evaluation of the serosal surfaces for radial spread of the tumor.

Figure 2.18 (A) Sampling small splenic masses. Complete cross‐sections through masses should include the interface between the mass and normal adjacent spleen. (B) Sampling large splenic masses. Multiple sections of larger masses are needed to increase the likelihood of collecting diagnostic tumor tissue due to the almost constant presence of necrosis and or hemorrhage in splenic tumors.

Figure 2.19 (A) Testicle cut longitudinally on the midline. Examine multiple cut surfaces and look for changes in color or consistency and sample these regions if found. (B) Testicular tumor subsampled to fit into processing cassette.

En face

or cross‐section of the spermatic cord trimmed for margin evaluation. There is no standardization of where to trim the cord so take a cross‐section close to the proximal end of the specimen. Finding tumor cells in the spermatic cord of primary testicular tumors is rare.

Figure 2.20 Partial lobectomy for evaluation of liver nodules. Perpendicular or cross‐section through the mass for diagnosis followed by

en face

section of the liver at the surgical margin to assess completeness of excision.

Figure 2.21 Longitudinal section of a lymph node for evaluation of micrometastasis. Be sure to sample the subcapsular sinus. Total number of sections is not standardized. Gauge number of sections based on size of the lymph node. Examine multiple cut surfaces to look for changes in color or consistency and sample these regions if found.

Chapter 03

Figure 3.1 Effects of formalin fixation on proteins. Formalin fixation produces conformational changes in proteins secondary to cross‐links between protein groups and the fixative. The use of antigen retrieval (heat‐induced epitope retrieval, HIER) is intended to revert those changes.

Figure 3.2 Effects of fixation on antigen expression. Antigens are affected by fixation differently. (A,B) Horse, fetus lung infected with

Bartonella

sp. (A) Fixation for 2 days: antigen (arrowheads) is easily detected. (B) Fixation for 11 weeks: Antigen detection is lost. (C,D) Dog, skin. Cytokeratins. (C) Fixation for 2 days: Strong detection in adnexal structures. (D) Fixation for 7 weeks: Significant loss of immunoreactivity. Immunoperoxidase‐DAB.

Figure 3.3 Effects of inadequate fixation. Dog, lymph node. Diffuse large B cell lymphoma. This sample was submitted without slicing, resulting in incomplete penetration of fixative and inadequate staining. (A) Reduced staining with hematoxylin in the center of the sample. (B) Lack of staining for CD79a in the center of the sample. Immunoperoxidase‐DAB.

Figure 3.4 Structure of an immunoglobulin molecule. In immunohistochemistry, both the variable (antigen‐binding site) and the Fc (antibody‐binding site) regions are necessary for proper detection of the antigen–antibody reaction.

Figure 3.5 (A) Avidin–biotin complex (ABC) method. The primary antibody (in black) binds the antigen on the tissue section followed by incubation with biotinylated antibody (in red). Avidin–peroxidase molecules then will bind biotinylated immunoglobulins. The antigen–antibody reaction is detected by a colored reaction produced when the enzyme molecules (e.g., peroxidase) interact with a substrate and a chromogen. (B) Polymer method. This detection system does not rely on the binding of avidin to biotin. The second antibody (in red) is attached to a polymer containing numerous molecules of enzyme.

Figure 3.6 Variation of immunoreactivity among animal species. (A) Dog, skin. Melanoma. (B) Horse, skin. Melanoma. Both samples were stained with an antibody to Melan‐A. The melanocytic neoplasm reacts strongly with this antibody in dogs (A) but not in horses (B). Immunoperoxidase‐DAB.

Figure 3.7 Antibody standardization for IHC. Three sets of sections (five slides per set) are used. Two‐fold dilutions (1/25 through 1/200) were made (first four slides on each group; the last slide is the negative reagent control). (A) Sections in each set were treated with (A) no antigen retrieval (AR), (B) enzyme digestion (proteinase K [PK]), or (C) heat‐induced epitope retrieval (HIER) with citrate buffer, pH 6.0. Immunoperoxidase‐DAB, hematoxylin counterstain.

Figure 3.8 Each antigen has a different tissue distribution. (A) Dog, urinary bladder. Cytokeratins have a cytoplasmic localization. (B) Dog, oral melanoma. RACK1 is expressed in the cytoplasm of neoplastic cells. (C) Dog, urinary bladder urothelial carcinoma. A distinct membranous and less intense cytoplasmic expression for uroplakin III is observed in numerous neoplastic cells. (D) Dog, liver. Arginase‐A is expressed in both the nucleus and cytoplasm. (E) Dog, urinary bladder urothelial carcinoma. Most urothelial cells have nuclear expression of GATA‐3. (F) Dog, smooth muscle. Collagen IV is expressed in the interstitium. Immunoperoxidase‐DAB.

Figure 3.9 Antigen expression variation. Dog, cutaneous histiocytoma. (A) H&E. (B–D) E‐cadherin immunoperoxidase‐DAB. (B) The upper portion of the tumor has strong membranous reactivity. Epidermis (star) is also positive. (C) Middle portion of the tumor with weaker membranous reactivity. (D) Bottom of tumor. E‐cadherin reactivity is weak and mostly cytoplasmic or paranuclear.

Figure 3.10 Cell type staining variation. Dog, thyroid medullary carcinoma. Pax8 is strongly expressed in the nuclei of entrapped follicular cells (arrowheads). Medullary cells (arrowheads) have weaker expression of this marker. Immunoperoxidase‐DAB.

Figure 3.11 Distinguishing specific from nonspecific staining. Dog, thyroid medullary carcinoma. (A) Most of the cells are labeled with antibody to calcitonin. Note the variable staining among cells, typical for this marker. (B) Same tumor was incubated with antibody to thyroglobulin, producing a diffuse, homogeneous nonspecific staining. Immunoperoxidase‐DAB.

Figure 3.12 Dog, lymph node. Insufficient antibody applied to the slide. Part of the slide (asterisk) was not covered by the primary antibody, resulting in no reaction. CD79a immunoperoxidase‐DAB.

Figure 3.13 Effects of antigen retrieval (AR) on IHC. Dog, esophagus. (A) No AR. Myoglobin expression is detected as expected in skeletal muscle (circle) and there is no labeling of the epithelium (arrowhead). Smooth muscle (asterisk). Vessel (V). (B) Proteinase K. Background develops in mucosal epithelium, plasma, and smooth muscle. (C) HIER with citrate buffer. There is nonspecific nuclear labeling of the mucosal epithelium and smooth muscle (insets). Immunoperoxidase‐DAB.

Figure 3.14 Inadequate level of AR solution. Horse, liver. The jar holding the AR solution cracked during the procedure, leaking part of the solution and resulting in incomplete retrieval. (A) Subgross, showing lack of staining of the upper portion of the tissue section. (B,C) Minimal reactivity in the portion not exposed to HIER solution (asterisks). Equine herpesvirus 1 immunoperoxidase‐DAB.

Figure 3.15 Background due to primary antibody concentration. Cat, intestine. B cell lymphoma. (A) The antibody titer was too concentrated, producing diffuse nonspecific background. (B) Optimal dilution showing specific labeling only in areas with T lymphocytes. CD3 immunoperoxidase‐DAB.

Figure 3.16 Inadequate rinsing of DAB solution. DAB precipitate covers the tissue section.

Figure 3.17 Algorithm to tumor diagnosis using immunohistochemistry as an aid.

Chapter 04

Figure 4.1 (A,B) Basal cell tumor, cat. (A) The mass is multilobulated with central necrosis in the center of the lobules. (B) At the periphery of the mass the neoplastic cells are small, round with chromatic nuclei. These neoplastic cells exhibit no nuclear or cellular pleomorphism. Within the interstitial stroma are numerous melanophages. (C–F) Basal cell carcinoma – infiltrative type, cat. (C) There is an association with the overlying epidermis. The neoplastic cells are infiltrative of the dermis. (D) At the base of the neoplasm the invasive neoplastic basal cells incite a desmoplastic response. (E) There is an association with the overlying epidermis. (F) The neoplastic cells form large islands with central areas of necrosis similar to feline basal cell tumors (see Figure 4.1A). (G) Feline basal cell carcinoma – clear cell type.

Figure 4.2 (A) Bovine papillomavirus infection, multicentric. (Image courtesy of Perry Habecker.) (B) Equine papillomavirus infection, multicentric. (Image courtesy of Perry Habecker.) (C) Canine papilloma, cut surface of gross lesion. (D) Bovine papilloma, histopathology with epidermal hyperplasia, compact orthokeratotic hyperkeratosis, enlarged keratohyaline granules and several koilocytes. (E) Canine papilloma histopathology with cells in the upper spinous and granular cell layer with a viral cytopathic effect (see below). (F) Canine papilloma histopathology with parakeratosis and numerous cells in the upper spinous layer with basophilia to the cytoplasm of the cells (viral cytopathic effect). (G) Canine papilloma – infundibular subtype with marked viral cytopathic effect at the base of the infundibulum and accumulation of parakeratotic keratinocytes within the infundibular lumen. (H) Canine papilloma – infundibular subtype, immunohistochemistry (DAB). (I) Canine papilloma – Le Net subtype. (J) Canine papilloma – Le Net subtype with marked clumping of the cytoplasmic keratin tonofilaments and basophilic intranuclear viral inclusion bodies. (K) Canine papilloma – regressing, with extensive infiltration of the basal and suprabasal epidermis by small lymphocytes and several apoptotic keratinocytes in the spinous layer.

Figure 4.3 (A) Canine inverted papilloma, cut surface of gross lesion. (B) Canine inverted papilloma with papilliform projections extending into the center of the mass.

Figure 4.4 (A–D) Canine pigmented plaques. (B) With an abrupt transition from normal to hyperplastic epidermis. (C) Transition zone between normal and hyperplastic epidermis with occasional koilocytes and enlarged keratohyaline granules. (D) Immunohistochemistry to demonstrate papillomavirus within the granular cell layer (DAB). (E) Equine aural plaque with histopathology.

Figure 4.5 (A–E) Feline squamous cell carcinoma

in situ

. (B) Proliferation of neoplastic keratinocytes within the epidermis and follicular infundibulum but without invasion through the basement membrane into the dermis. (C) Disorganized keratinocytes within the epidermis and follicular infundibulum. (D) Keratinocytes exhibiting viral cytopathic effects. (E) Progression to invasive squamous cell carcinoma.

Figure 4.6 (A) Bovine squamous cell carcinoma, multifocal. Note the lack of periocular epidermal pigment. (B) Feline SCC, focal, early lesion involving nonpigmented, sparsely haired skin. (C) Feline SCC, advanced lesion with destruction of the pinnal cartilage and extensive hemorrhage. (D) Canine SCC, advanced lesion with marked ulceration and destruction of the nasal planum. (E) Well‐differentiated SCC. (F) Well‐differentiated SCC with parakeratosis. (G) Invasive SCC with desmoplasia and focal neural invasion. (H) Acantholytic variant of SCC.

Figure 4.7 Basosquamous carcinoma, canine. (A) Low magnification. The peripheral neoplastic cells are basaloid with central squamous differentiation. (B) High magnification. The squamous cells show mild pleomorphism and there are occasional interspersed melanocytes.

Figure 4.8 Normal canine hair follicle histology.

Figure 4.9 (A–C) Infundibular keratinizing acanthoma, canine. Note the accumulation of keratin in the lumen of the cyst (A).

Figure 4.10 (A,B) Tricholemmoma – isthmus type, canine, at low (A) and higher (B) magnification. (C,D) Tricholemmoma – inferior type, canine, at low (C) and high (D) magnification.

Figure 4.11 Trichoblastoma. (A) Ribbon type, canine. (B) Medusoid type, canine. (C) Solid type, canine. (D) Granular cell type, canine. (E) Trabecular type, feline. (F) Spindle cell type, feline.

Figure 4.12 Trichofolliculoma, feline, with a large central lumen containing keratin with numerous hair follicles and small sebaceous glands at the periphery.

Figure 4.13 (A–C) Trichoepithelioma, canine. (A) The cut surface reveals multiple small white foci of neoplastic tissue within interstitial fibrous stroma. (B) Multiple islands of neoplastic cells with trichogenic differentiation surrounded by an edematous fibrous stroma. (C) Higher magnification of Figure 4.13B with incomplete and abortive trichogenesis. (D,E) Trichoepithelioma – cystic variant, canine. There are several large cysts with trichogenic differentiation. (E) Higher magnification of Figure 4.13D. The basal lamina is thickened, the peripheral cells are palisaded and there is accumulation of shadow cells within the cyst lumina.

Figure 4.14 Malignant trichoepithelioma, canine. (A) Large islands of basaloid‐like cells are invasive with central trichogenic differentiation. (B) Higher magnification of Figure 4.14A. Occasional cells have brightly eosinophilic trichohyalin granules within their cytoplasm.

Figure 4.15 Pilomatricoma, canine. (A) Note the peripheral rim of basophilic cells and abrupt transition to the internal shadow cells. In the center is a fibrous stroma that contains numerous multinucleated giant cells. (B) Higher magnification of Figure 4.15A. (C) This shows foci of osseous metaplasia and aggregates of shadow cells surrounded by multinucleated giant cells.

Figure 4.16 (A) Sebaceous adenoma, canine. At the periphery of the lobules are small reserve cells with differentiation to sebocytes. (B) Sebaceous ductal adenoma, canine. There is a preponderance of sebaceous ducts with fewer sebocytes and reserve cells. (C) Sebaceous epithelioma, canine. There is a preponderance of reserve cells with occasional sebaceous ducts and sebocytes. (D) Sebaceous carcinoma, canine. The neoplastic cells in the multilobulated neoplasm have intracytoplasmic lipid droplets, large pleomorphic nuclei with prominent nucleoli.

Figure 4.17 Meibomian adenoma with marked squamous epidermal hyperplasia.

Figure 4.18 (A–E) Hepatoid gland adenoma, canine. (A) Hepatoid gland adenoma arising in the perianal area. (B) Cut surface. The mass on the left is well encapsulated. The mass on the right has areas of hemorrhage within the neoplasm but is well demarcated from the surrounding tissue. (C) The multilobulated mass has a rim of small reserve cells at the peripheral with central differentiation to large hepatoid cells. (D) Adenoma with focal ductal differentiation. (E) With extensive sebaceous differentiation. (F) Hepatoid gland epithelioma on the left with increased numbers of reserve cells and hepatoid gland adenoma on right with few reserve cells, canine. (G) Hepatoid gland carcinoma, canine. The neoplastic cells have a modest amount of cytoplasm. There are numerous mitotic figures.

Figure 4.19 (A) Apocrine adenoma, canine. There are apocrine blebs on the luminal surface of the neoplastic cells. (B) Apocrine papillary adenoma, canine. (C) Apocrine ductal adenoma, canine. The duct lumina, of varying shapes and sizes, are lined by a double layer of epithelial cells. (D) Apocrine ductal adenoma with focal squamous differentiation, canine. (E) Apocrine ductal adenoma, feline. The neoplasm has many similarities with a feline basal cell tumor (Figure 4.1A). However, there are aggregates of cells with a more abundant eosinophilic cytoplasm and occasional cells lining small lumina at the base of the photomicrograph. (F) Apocrine carcinoma with dermal lymphatic invasion, canine. (G) Apocrine carcinoma with dermal invasion and desmoplasia, canine. (H) Apocrine ductal carcinoma with focal squamous differentiation, canine.

Figure 4.20 (A) Ceruminous adenoma, canine. (B) Ceruminous carcinoma, feline.

Figure 4.21 (A) Anal sac gland carcinoma – solid type, canine. (B) Anal sac gland carcinoma – rosette type, canine. (C) Anal sac gland carcinoma – tubular type, canine. (D) Anal sac gland carcinoma – clear cell type, canine.

Figure 4.22 (A–C) Clear cell adnexal carcinoma, canine. (B) Higher magnification of Figure 4.22A. (C) Immunohistochemistry to demonstrate positive staining for cytokeratins (AE1/AE3) (DAB).

Figure 4.23 (A,B) Merkel cell tumor, feline. (A) AFIP/JPC WSC 2008–2009 slide #59 Merkel cell carcinoma. (B) AFIP/JPC WSC 2008–2009 slide #59 at higher magnification.

Figure 4.24 (A) Melanocytoma, equine. (B) Melanocytoma, canine. Compound melanocyte tumor with intraepidermal and dermal proliferation of neoplastic melanocytes. (C) Melanocytoma – round cell type, canine. (D) Melanocytoma – round cell type, bleached section, canine. The neoplastic cells have an abundant amount of cytoplasm, peripheral nuclei, and occasional multinucleated cells. (E) Melanocytoma – spindle cell type, canine. (F) Melanocytoma – spindle cell type with neuroidal differentiation, canine. (G) Melanocytoma – polygonal (epithelioid) type, canine. (H) Melanocytoma – mixed type, canine. There are occasional cells with a clear cytoplasm, seen with a balloon cell melanoma.

Figure 4.25 (A) Melanoacanthoma, canine. Have feature of both a melanocytoma and a benign follicular neoplasm. (B) Higher magnification of panel A.

Figure 4.26 (A) Malignant melanoma, equine. Individual neoplastic cells are present within the epidermis and in the dermis form variably sized nests separated by a fibrovascular stroma. (B) Malignant melanoma, footpad, canine. Nests of neoplastic melanocytes are present within the epidermis and dermis. At one margin the neoplastic melanocytes are present in the basal layer with no dermal involvement. This is the horizontal growth phase of malignant melanoma. (C) Malignant melanoma, canine. The epidermis is hyperplastic and within the superficial dermis are. neoplastic melanocytes forming small nests with variable intracytoplasmic melanin pigment. (D) Malignant melanoma, canine. The epidermis is hyperplastic and within the dermis the neoplastic melanocytes form sheets. Neoplastic cells have large nuclei with prominent nucleoli but there is no intracytoplasmic melanin.

Figure 4.27 (A) Normal nailbed. The nailbed is on the right and the bone of P3 on left of photomicrograph. (B) Subungual malignant melanoma, canine. The neoplastic melanocytes extend between the nailbed epithelium and bone of P3 with focal invasion of bone. (C) Nests of neoplastic melanocytes are present within the nailbed epithelium and adjacent tissue.

Figure 4.28 Subungual keratoacanthoma, canine. (A) There is marked expansion of the nailbed and loss of bone from P3. (B) The neoplastic keratinocytes have not breached the basement membrane and there is no infiltration of the subungual connective tissue.

Figure 4.29 Subungual squamous cell carcinoma, canine. (A) There is invasion and destruction of P3 but the articular cartilage of P3 remains intact. P2 and P1 are normal. (B) The neoplastic cells have infiltrated and destroyed the bone of P3 but the articular cartilage is intact.

Figure 4.30 (A) Follicular hamartoma, canine. (B) Sebaceous hamartoma, canine. (C) Apocrine hamartoma, canine. (D) Fibroadnexal hamartoma, canine.

Figure 4.31 (A) Infundibular cyst, canine. (B) Isthmus cyst, canine. (C) Dilated pore, feline. (D) Panfollicular cysts, canine. (E–G) Dermoid cyst, canine. (E) Pilonidal sinus. (F) Dermoid cysts. (G) Dermoid cyst/pilonidal sinus. (H) Sebaceous duct cyst, canine. (I) Subungual epidermal inclusion cysts, canine. (J) Apocrine cysts, canine. (K) Ceruminous cysts, feline. (L) Ciliated cyst, feline.

Figure 4.32 (A) Seborrheic keratosis, canine. (B) Squamous papilloma, canine. (C,D) Pressure point comedones, canine. (E) Cutaneous horn, bovine. (Image courtesy of Perry Habecker.) (F) Cutaneous horn, footpad, feline. (G) Sebaceous hyperplasia, canine. (H) Cutaneous tag, canine.

Figure 4.33 (A,B) Metastatic pulmonary carcinoma, digit, feline.

Chapter 05

Figure 5.1 Fibroma, skin, canine. Note the dense pattern of repetitive collagen.

Figure 5.2 (A) Keloidal fibroma, skin, canine. (B) Higher magnification of (A) showing smudgy pink “keloid”‐like collagen.

Figure 5.3 Fibrosarcoma, subcutis, canine. High nuclear density and paucity of collagen differentiate this from fibroma.

Figure 5.4 (A) Vaccine‐associated fibrosarcoma in the interscapular region, feline. (B) Vaccine‐associated sarcoma with giant cells. Note band of macrophages at top. Inset: Cytological preparation with a few macrophages and a giant cell with numerous nuclei. (C) Vaccine product in macrophages. This material is not birefringent.

Figure 5.5 (A,B) Well‐differentiated fibrosarcoma, maxilla, canine. (C) Note the bland fibrocytes of the neoplasm. Other examples will be more cellular.

Figure 5.6 Equine sarcoid. (A) Nodular sarcoid on the eyelid/canthus. (B) Verrucous sarcoid on ear. (Image courtesy of Perry Habecker.) (C) Proliferation of interwoven fibroblasts.

Figure 5.7 Feline sarcoid. Distinctive epidermal hyperplasia merging with a proliferating fibroblasts component is characteristic of feline and equine sarcoids. Both are associated with bovine papillomavirus DNA.

Figure 5.8 Malignant fibrous histiocytoma (pleomorphic sarcoma). (A) Storiform‐pleomorphic variant, subcutis, canine. (B) Giant cell variant, skin, canine.

Figure 5.9 Myxosarcoma, subcutis, canine. Nuclear density warrants the diagnosis of sarcoma, but the histologic distinction between myxoma and myxosarcoma can be subtle, and not clinically relevant as the behavior is the same for both.

Figure 5.10 Collagenous hamartoma, skin, canine. Note the haphazard arrangement of collagen that is similar to the adjacent normal collagen.

Figure 5.11 Nodular fasciitis, subcutis, canine. Center of lesion has streams of immature fibroblasts and mitotic figures, mimicking fibrosarcoma.

Figure 5.12 Canine myopericytoma, subcutis, canine. (A) Classic perivascular whorling. The cells arise from components of the vascular wall and adventitia. (B) Cytology specimen contains typical high cellular exfoliation and cohesion of the spindle cells. Note bi‐ and multinucleated cells, streams of cytoplasm, and considerable cellular and nuclear variability. PWT is a name for a group of spindle cell tumors. See the appendix on soft tissue mesenchymal tumor, page 957.

Figure 5.13 (A) Nerve sheath tumor, skin, feline. (B) Note the plexiform pattern involving several small nerves. (C) NST, grade 2, skin, canine.

Figure 5.14 (A) Piloleiomyoma, skin, canine. Tumors are usually in the superficial dermis adjacent to hair follicles and their arrector pili muscles. (B) Angioleiomyosarcoma, skin, canine. This tumor was intimately associated with dermal blood vessels, seen at the left side of the tumor. Nuclear density and pleomorphism are consistent with a sarcoma. Positivity for smooth muscle actin confirms the diagnosis.

Figure 5.15 Lipoma, subcutis, canine. (A) Lipoma. (B) Angiolipoma. (C) Infiltrative lipoma. Adipocytes infiltrate the skeletal muscle (red areas).

Figure 5.16 Liposarcoma, subcutis, canine

. (

A) Well differentiated. Most cells have large fat vacuoles but there is nuclear enlargement and mild pleomorphism. (B) Pleomorphic. Nuclei are highly pleomorphic and multinucleated cells are seen. Few cells retain fat vacuoles. (C) Myxoid. Rare lipid‐containing cells distinguish this tumor from a myxosarcoma.

Figure 5.17 (A) Hemangioma. (B) Higher magnification showing vascular channels containing red blood cells and lined by inconspicuous endothelial cells. (C) Gross appearance of solar‐induced hemangiomas, ventral abdomen, canine. (Images courtesy of Michael Goldschmidt.)

Figure 5.18 Hemangiosarcoma canine, skin. (A) Hemangiosarcoma, irregularly shaped and sized vessels with plump endothelial cells lining and filling trabeculae between lumens. (B) Epithelioid variant showing large polygonal cells and a glandular pattern.

Figure 5.19 (A) Ventral abdominal lymphangiosarcoma, feline. Note bruising due to extravasation of blood in the neoplasm. (B) Lymphangioma, skin, canine. Note thin, flat endothelium that lines collagen filled trabeculae, and lumens devoid of red blood cells. (C) Histology of ventral abdominal lymphangiosarcoma, feline.

Figure 5.20 Various histologic manifestations of angiomatosis lesions in dogs and cats. Note the haphazard arrangement of blood vessels, with muscle walls admixed with vascular clefts. (A) Progressive angiomatosis, skin, feline. (B) Vascular hamartoma, scrotum, canine (low magnification). (C) Vascular hamartoma, scrotum, canine (high magnification). Note the disorganized vascular stuctures of various calibers, some with smooth muscle walls.

Figure 5.21 Cutaneous histiocytoma. (A) Neoplastic cells immediately subjacent to the epidermis or infiltrating the epidermis are features of canine histiocytoma. (B) Cytology of neoplastic cells: fairly abundant light blue cytoplasm, round to oval‐shaped cells and nuclei. These tumors may have a high mitotic count and or lymphocytic inflammation associated with regression.

Figure 5.22 Reactive histiocytosis, skin, canine. Sheets of large bland histiocytes with a few plasma cells and lymphocytes in the background.

Figure 5.23 Histiocytic sarcoma, skin, canine. (A) Round cell variant with multinucleated cells. (B) Spindle cell variant. There is scattered nuclear pyknosis. (C) CD18 immunostaining is strongly positive.

Figure 5.24 Xanthoma, skin, feline. Sheets of lipid‐filled macrophages, with scattered cholesterol clefts, and background lymphocytes, plasma cells, and neutrophils.

Figure 5.25 Plasma cell tumor, skin, canine. (A) Sheets of round cells, often with hyperchromatic, eccentric nuclei and occasional perinuclear clear zones (Golgi). (B) Amyloid is present amidst the neoplastic cells in this tumor. When seen it is a helpful aid to the diagnosis but it is present in only about 10% of canine tumors.

Figure 5.26 Canine transmissible venereal cell tumor. (A) Multiple nodules and plaques cover the penis of this dog. (B) High magnification (oil) of sheets of uniform round cells with several mitotic figures. The mitotic count is typically high; some tumors will have lymphocytic inflammation. (C) Cytology showing uniform round cells with abundant light blue cytoplasm and vacuolation typical of TVT cells. Mitotic figure in lower left, spindle‐shaped cell is a supporting stromal cell. Images courtesy of D.J. Meuten.

Chapter 06

Figure 6.1 Mastocytosis, 8‐week‐old dog. This pup developed skin nodules at 3 weeks of age which increased in number and size over the next 10 weeks but then started to regress. All lesions spontaneously resolved by 35 weeks and at 2 years of age no lesions had recurred. The masses ranged from 1 to 5 cm in diameter and contained well‐differentiated mast cells on histology.

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Figure 6.2 Primary extracutaneous mast cell tumor, 9‐year‐old dog. (A) This is an enlarged lymph node that was located along the aorta that was expanded by infiltrating neoplastic mast cells. The location of the primary MCT was unknown, but spleen and liver were diffusely infiltrated by neoplastic mast cells. There was no history of a prior cutaneous MCT. (B,C) MCTs were also found in other unusual sites, such as periosteum of a rib (B) and spinal canal dorsal surface of the meninges (C). MCTs were widely disseminated in this dog: spleen, liver, lymph nodes. MCTs this widely disseminated are unusual in any species. It is not known if these are metastases or multicentric origin.

Figure 6.3 Cutaneous mast cell tumors, dog. (A) Multiple simultaneous cutaneous MCT in a boxer dog. (B) Large MCT with extensive cutaneous swelling and erythema. (C) Gastric hyperemia and hemorrhage in a dog with cutaneous MCT. Neoplastic mast cells can release histamine which may stimulate gastric H2 receptors, causing ulceration and bleeding through hypersecretion of hydrochloric acid. (D) Hairless, raised, well‐circumscribed, erythematous, and focally necrotic canine cutaneous MCT. (E) Ulcerated and erythematous MCTs arising on the nasal planum. (F) Multiple MCTs located periorally and along the mucocutaneous junction of the muzzle. MCTs located in the muzzle are often aggressive.

Figure 6.4 (A) Subcutaneous MCTs are located in the subcutis and are surrounded by adipose tissue. (B) A characteristic pattern of well‐differentiated MCTs are rows or ribbons of neoplastic mast cells. (C) Most subcutaneous MCTs are composed of well‐differentiated mast cells that are round, monomorphic, and have abundant basophilic granules in their cytoplasm. Nuclei are uniform and round, nucleoli are not visible, and mitoses are rare or absent. (D) A low Ki67 index is characteristic of the majority of subcutaneous MCTs; only one nucleus is labeled red in this field. (E) One large AgNOR as depicted here is typical for most nuclei in subcutaneous MCTs. (F) Perimembranous labeling of KIT is observed in most subcutaneous MCTs.

Figure 6.5 Cytology of canine cutaneous MCTs. (A) Mast cell granules fill the cytoplasm and are extracellular in this MCT, Wright’s stain. The cytoplasm of well differentiated MCTs stain intensely with Wright’s or Diff‐Quik. However, the granules in some MCTs will not stain reliably with Diff‐Quik or any aqueous stain. Most Romanowsky stains such as Wright’s or Wright–Giemsa are methanolic based and will stain granules in mast cells and basophils. Aqueous‐based stains such as the common “dip” stains may not stain cytoplasmic granules in mast cells, basophils, or large granular lymphocytes.

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(B) Poorly differentiated MCT in which some granules can be observed with Wright’s stain and another MCT (C) stained with aqueous Diff‐Quik in which granules are not visible. If a suspected MCT does not have visible granules with Diff‐Quik stain then consider staining additional slides with a methanolic‐based Rowmanosky stain such as Wright’s. See the appendix on Cytologic grading of canine cutaneous mast cell tumors (p. 952).

Figure 6.6 Margin evaluation of canine cutaneous MCT. (A) A combination of complete tangential margins for “cleanliness” and assessing distance of neoplastic cells to these margins based on radial sectioning is recommended for canine cutaneous MCTs. Areas of lateral skin margins are identified with red and deep tangential sections in white. Positions of radial cuts are identified by yellow lines. The sutures lines help orient the position of the mass in the animal. (B) Neoplastic mast cells extend to the inked margin, blue at base of image, H&E. Reports should state how many margins had tumor and a description of the neoplastic cells closest to the margin (e.g., neoplastic mass extending to margin; nests or individualized neoplastic cells extending to margin).

Figure 6.7 Prognostic flowchart for canine cutaneous MCTs. For detailed explanations please review the section on Prognostication.

Figure 6.8 Grading of canine cutaneous MCTs using the two‐tier system. (A) Low‐grade MCTs are composed of monomorphic, well‐differentiated mast cells with round nuclei and medium‐sized visible cytoplasmic granules. They do not contain any of the four features used to classify high‐grade MCTs. (B,C) High‐grade MCTs are composed of less‐differentiated mast cells, which often have a mitotic count of at least 7 mitotic figures in 10 HPF. High power field is 40× objective and a 10× ocular that equates to 2.37 mm

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The number of eosinophils infiltrating MCT is highly variable. They are numerous in these two examples of high‐grade MCTs, and eosinophils are not assessed as a criterion to grade MCTs. (D) Karyomegaly is a feature of high‐grade MCTs and is identified by 10% of neoplastic cells having a nuclear diameter that varies by at least two times. This is the most subjective criterion. (E) Another feature of high‐grade MCTs are at least 3 multinucleated (3 or more nuclei) cells in 10 HPF. (F) High‐grade MCTs can also be identified by having at least 3 bizarre nuclei in 10 HPF. High‐grade MCTs have one or more of the features listed in B, D, E, or F and low‐grade MCT have none of these.

Figure 6.9 Evaluating proliferation activity of canine cutaneous MCTs. (A) Regardless of the method of evaluation, a low Ki67 index (rare red nuclear labeling) has been associated with with longer survival times. (B) In contrast, a high Ki67 index (large numbers of cells with red nuclear labeling) has been associated with shorter survival times and a high risk of metastasis. (C) Low numbers of AgNORs per nucleus (1–2 black silver‐stained aggregates per nucleus) have been associated with less aggressive biological behavior, but statistically significant cut‐off values could not be established. (D) A large AgNOR number per nucleus (many nuclei with more than 4 black silver‐stained aggregates) has been associated with poor survival, but no significant cut‐offs could be established. Cut‐off values have been published for the combined AgNOR × Ki67 score and can be used to predict survival times as well as local recurrence.

Figure 6.10 KIT labeling patterns of canine cutaneous MCTs. (A) Pattern 1 is characterized by peri‐membrane labeling. (B) Pattern 2 is characterized by focal or stippled cytoplasmic labeling with decreased membrane labeling. (C) Pattern 3 has a diffuse cytoplasmic labeling. Patterns 2 and 3 have been associated with decreased survival time and increased incidence of local recurrence.