L-10 Pathology of skin tumors

• Study notes on Skin Tumors include information on benign dermal and epithelial tumors, vascular tumors and tumors with cellular migrants producing skin lesions.

Benign Dermal and Epithelial Tumors

• Benign Fibrous Histiocytoma (Dermatofibroma), Dermatofibrosarcoma Protuberans and Xanthomas are examples of benign dermal and epithelial tumors.

Benign Fibrous Histiocytoma (Dermatofibroma)

• Lineage is uncertain and indolent, with an unknown cause.
• Usually seen in adults.
• Commonly found on the legs of young and middle-aged women.
• Often asymptomatic, but can present with tenderness.
• Size may increase or decrease over time.
• Associated with a history of antecedent trauma.
• Abnormal response to injury and inflammation occurs.
• Tumors contain FXIIIa-positive dermal dendritic cells.
• Neoplasms appear as firm, tan to brown papules.
• Actively growing lesions are less than 1 cm in diameter, but can reach several centimeters.
• Often become flattened over time.
• Lesions contain a well-circumscribed dermal proliferation of benign-appearing spindle cells.
• The overlying epidermis may show hyperplasia.
• Fibroblasts tend to surround individual collagen bundles.

Dermatofibrosarcoma Protuberans

• Well-differentiated primary fibrosarcoma of the skin.
• Slow-growing and locally aggressive.
• Can recur, but rarely metastasizes.

Pathogenesis of Dermatofibrosarcoma Protuberans

• Molecular hallmark is translocation.
• Gene encoding for collagen 1A1 (COL1A1) and platelet-derived growth factor-β (PDGFB) are involved.
• Juxtaposition of COL1A1 promoter sequences and the coding region of PDGFB occurs due to a resulting rearrangement.
• Overexpression and increased secretion of PDGFβ drives tumor cell growth through an autocrine loop.
• The tumor consists of a flesh-colored fibrotic nodule on sectioning.
• Lesion often infiltrates the subcutis like "Swiss cheese".
• Storiform, or swirling alignment of the spindled cells, is apparent.

Xanthomas

• Involves intracellular accumulation of cholesterol within macrophages.
• Seen in acquired and hereditary hyperlipidemic states.
• Consist of foamy cell clusters.
• These clusters occur in the subepithelial connective tissue of the skin and tendons.
• Associated with conditions like cholestasis.
• Cholestasis can be caused by extrahepatic or intrahepatic obstruction of bile channels or defects in hepatocyte bile secretion.
• Xanthomas are depositions of yellowish cholesterol-rich material.
• Can appear anywhere in the body in various disease states.

Benign Vascular Conditions

• Study notes on benign vascular conditions includes information of two conditions; ectasia and telangiectasia.

Vascular Ectasias

• Ectasia is a local dilation of a structure.
• Telangiectasia is a permanent dilation of preexisting small vessels.

Vascular Tumors

• These include Spider Telangiectasias, Hereditary Hemorrhagic Telangiectasia and Juvenile Hemangiomas.

Spider Telangiectasias

• Arrays of dilated subcutaneous arteries or arterioles.
• They have a central core that blanches with pressure.
• Appear radial and pulsatile.
• Typically located on the face, neck, or upper chest.
• Associations include hyper-estrogenic states and liver cirrhosis.

Hereditary Hemorrhagic Telangiectasia

• Also known as Osler-Weber-Rendu disease.
• This is an autosomal dominant disorder.
• Mutations occur in TGF-β signaling pathway genes.
• Malformations are composed of dilated capillaries and veins.
• Usually present at birth.
• Widely distributed in the skin, oral mucous membranes, respiratory, gastrointestinal, and urinary tracts.
• Spontaneous rupture can occur.
• Estimated frequency of manifestations include spontaneous, recurrent epistaxis (90%), skin telangiectases (75%), hepatic or pulmonary involvement (arteriovenous malformations) (30%), gastrointestinal (GI) bleeding (15%), and CNS lesions.

Juvenile Hemangiomas

• Also known as "Strawberry type" hemangiomas of the newborn.
• Occur in 1 in 200 births.
• Can be multiple.
• Arise in the skin and grow rapidly for a few months.
• Fade by 1 to 3 years of age.
• Completely regress by age 7 in majority of cases.

Pyogenic Granulomas

• These are Capillary Hemangiomas.
• Rapidly growing red lesions.
• They can occur on the skin, gingiva, and oral mucosa.
• Bleed easily and ulcerate.
• Develop after trauma.
• Have typical size of 1 to 2 cm within a few weeks.
• Curettage and cautery is usually curative.

Malignant Vascular Tumors

• Angiosarcoma is a malignant tumor.

Angiosarcoma

• Organ associated or cutaneous in form.
• Endothelial neoplasm.
• Affects older adults, with equal gender predilection.
• Tumor may occur at any site.
• Often involves skin, soft tissue, breast, and liver.
• Associated with carcinogenic exposures.
• Include arsenic (e.g., in pesticides), Thorotrast (radioactive contrast agent formerly used for radiologic imaging), and Polyvinyl chloride (a widely used plastic).

Cutaneous Angiosarcoma

• Begins as multiple deceptively small nodules.
• Develops into asymptomatic red papules.
• Becomes fleshy masses of red-tan to gray-white tissue.
• Margins blur surrounding structures.
• Has central areas of necrosis and hemorrhage.

Microscopic Level of Vascular Tumors

• Tumors range from plump, atypical endothelial cells forming vascular channels.
• Can mimic undifferentiated tumors, showing a solid spindled appearance with no discernible blood vessels.
• Difficult to distinguish from carcinomas and melanomas.

Special Stains

• Special stains are useful for determining the Endothelial Origin, showing markers like CD31 and von Willebrand factor.

Tumors with Cellular Migrants Producing Skin Lesions

• Include Mycosis Fungoides / Sézary Syndrome and Langerhans Cell Histiocytosis.

Mycosis Fungoides / Sézary Syndrome

• T Cell lymphoma that presents in the skin and progresses to lymphoma.
• Characterized by erythematous plaques that appear early in the disease.
• Plaques and Nodules can occur on the trunk, extremities, face, and scalp.
• Nodules correlate with the spread of disease.

Morphology of Mycosis Fungoides

• Hallmark is the presence of the Sézary-Lutzner cell.
• Characterized by Malignant T-helper cells - CD4+.
• Forms band-like aggregates within the superficial dermis.
• Invades the epidermis as single cells and small clusters.
• Pautrier microabscesses are present.
• Cerebriform nuclei contour is also evident.

Pathology of Mycosis Fungoides

• Pautrier's Microabscess can be observed.
• Convoluted nuclei (cerebriform) with dense chromatin occur.

Sézary Syndrome

• Represents a continuum from erythrodermic Mycosis fungoides.
• Considered as being aggressive.
• Exfoliative Erythroderma occurs.
• Characterized by diffuse erythema and scaling of the entire body surface.
• Lymphadenopathy can occur.

Langerhans Cell Histiocytosis

• Historical term is Histiocytosis X.

Langerhans Cell Histiocytosis

• Includes Letterer-Siwe disease (Multifocal Multisystem), Hand-Schüller-Christian Syndrome (Multifocal Unisystem), and Localized Eosinophilic Granuloma (Unifocal Lesions).
• A group of idiopathic disorders.
• Characterized by cells similar to bone marrow-derived Langerhans cells, with a backdrop of hematopoietic cells including T-cells, Macrophages, and Eosinophils.

LCH Cells

• Marker Expression is present.
• Resting Epidermal Langerhans cells show CD1a, intracellular major histocompatibility complex II [MHCII] expression.
• Resting Epidermal Langerhans cells show Birbeck granules which functions in receptor-mediated endocytosis, similar to clathrin-coated pits.
• Activated Langerhans cells express CD54 and CD58.
• Pathologic cells of LCH represent Langerhans cells in arrested maturation.
• May be caused by a disease of mononuclear phagocyte dysregulation.
• Widespread positivity for CD1a exists.
• Langerhans cells and lymphocytes are present in the epidermis and the papillary dermis shown through hematoxylin and eosin staining.
• Rodlike Birbeck granules with characteristic periodicity and dilated terminal end can be observed through a electron micrograph.
• Birbeck granules contain Pentalaminar tubules, often with a dilated terminal end producing a tennis racket-like appearance which contain the protein langerin

Pathogenesis of LCH

• Largely unknown.
• Activating and associated Mutations are present.
• Valine-to-glutamate substitution at residue 600 in BRAF, TP53, RAS, and the tyrosine kinase MET can be seen.
• Homing of Neoplastic Langerhans Cells are evident.
• Aberrant expression of chemokine receptors CCR6 (normal) and CCR7 occurs.
• CCR6 binds CCL20 in skin and bone while CCR7 binds CL19 and 21 in lymphoid organs.

Clinicopathologic Entities

• Letterer-Siwe disease occurs before age 2 / occasionally adults.
• Dominant Clinical Feature includes Cutaneous lesions resembling a seborrheic eruption, that Infiltrates of LCs; front / back of the trunk, scalp Hepatosplenomegaly, Lymphadenopathy, and Pulmonary lesions.

Letterer-Siwe disease

• Characterized by Destructive osteolytic bone lesions and Extensive infiltration of the marrow.
• Anemia and Thrombocytopenia are also evident.
• Predisposition to recurrent infections exists.
• Tumor cells can become anaplastic, referred to as Langerhans cell sarcoma.
• Untreated disease is rapidly fatal.
• LCH can also be associated with Hand-Schüller-Christian Syndrome and Localized Eosinophilic granuloma.
• On a plain skull radiograph, lesions are typically lytic, with sharp borders and a punched out appearance.