Histology, Dermis

Structure

The dermis is a connective tissue layer of mesenchymal origin located deep in the epidermis and superficial to the subcutaneous fat layer.[1] The composition of the dermis is mainly fibrous, consisting of collagen and elastic fibers. Between the fibrous components lies an amorphous extracellular "ground substance" containing glycosaminoglycans, such as hyaluronic acid, proteoglycans, and glycoproteins. The dermis is divided into 2 layers: the papillary dermis and the reticular dermis. The papillary dermis is the superficial layer, lying deep into the epidermis. The papillary dermis is composed of loose connective tissue that is highly vascular. The reticular layer is the deep layer, forming a thick layer of dense connective tissue that constitutes the bulk of the dermis. 

Collagen is the principal component of the dermis. Specifically, type I and type III collagen are found in abundance. Elastic fibers also play an important structural role within the dermis. Elastic fibers are composed of elastin and fibrillin microfibrils. In contrast to collagen, the biochemical configuration of elastin allows for gliding, stretching, and recoiling of fibers.[2] The reticular dermis comprises thick elastic fibers. Two subtypes of elastic fibers are worth further discussion: elaunin and oxytalan fibers.[3] Elaunin fibers are horizontally arranged elastic fibers found near the junction of the papillary and reticular dermis. Oxytalan fibers are perpendicular elastic fibers found in the papillary dermis.[4] The dermis houses blood vessels, nerve endings, hair follicles, and glands. There are many cell types found within the connective tissue of the dermis, including fibroblasts, macrophages, adipocytes, mast cells, Schwann cells, and stem cells.[5] Fibroblasts are the principal cells of the dermis. Mast cells are typically found surrounding dermal capillaries.

Function

Skin Support and Protection

The structure of the dermis provides a connective tissue framework for strength, flexibility, and protection of the deeper anatomical structures. Collagen and extracellular components like hyaluronic acid fortify the skin and facilitate an anchor for the epidermis via hemidesmosomes and other adhesive basement membrane zone (BMZ) components.[6] Oxytalan fibers may also play a role in anchoring the epidermis. Elastic tissue also helps support the skin and provides flexibility. The blood vessels in the dermis are crucial for the maintenance of the epidermis and epidermal appendages. Nutrients via blood support the epidermis, hair follicles, and sweat glands. The vascular network further permits the dermis to host an inflammatory response via the recruitment of neutrophils, lymphocytes, and other inflammatory cells. The dermal blood supply also plays a role in temperature regulation discussed below. 

Thermoregulation

Vasoactive dermal vessels regulate body temperature. Specialized structures called glomus bodies also take part in thermoregulation through AV shunt formation.[7] Glomus bodies are complexes of glomus cells, vessels, and smooth muscle cells that predominate in the digits, palms, and soles.[8] Although often within the dermis, eccrine sweat glands are ectoderm-derived epidermal appendages that invaginate into the deeper tissue of the dermis and subcutaneous layer.[9] 

Sensation

Several mechanoreceptors are present in the dermis. Nerve endings in the dermis surround hair follicles. These nerve endings sense hair movement and act as mechanoreceptors, allowing sensation to extend beyond the skin's surface. Deep pressure receptors also exist. Pacinian corpuscles are large, lamellar, ovoid structures found in the deep dermis and they provide deep pressure and vibratory sensation. Meissner's corpuscles, located in the dermal papillae of the papillary dermis, respond to low-frequency stimuli. Meissner's corpuscles are concentrated in glabrous (hairless) skin.[10] 

Cells of the Dermis and Their Function

The dermis contains many cell types. Fibroblasts, the principal cell of the dermis, handle the synthesis of collagen, elastic and reticular fibers, and extracellular matrix material. Histiocytes are tissue macrophages present within the connective tissue that assist the immune system. Mast cells are inflammatory cells located in the perivascular areas of the dermis. Mast cells secrete vasoactive and proinflammatory mediators important in inflammatory reactions, collagen remodeling, and wound healing.[11] Dermal adipocytes are a distinct cell population from the subcutaneous adipose tissue. Dermal adipocytes not only provide insulation and energy storage but also assist in hair follicle regeneration and wound healing.[12][13]

Tissue Preparation

The dermis is examined using a standard skin biopsy. The tissue sample should first be fixated with formalin to preserve tissue structure. After fixation, the specimen is dehydrated with an alcohol (eg, ethanol) to remove water. The alcohol agent is then cleared using xylol. After, the tissue sample is embedded in paraffin. After hardening of the paraffin medium, a microtome slices the specimen. The tissue specimen may be stained according to hematoxylin and eosin (H&E) staining protocols. 

Histochemistry and Cytochemistry

Immunofluorescence of tissue samples is an important diagnostic tool in autoimmune blistering diseases such as bullous pemphigoid and dermatitis herpetiformis. For example, linear deposition of immunoglobulin (Ig) G  and complement (C3) along the dermoepidermal junction is characteristic of bullous pemphigoid. Granular deposits of IgA in the dermal papillae are characteristic of dermatitis herpetiformis.[14]

Microscopy, Light

Light microscopic analysis of H&E-stained samples delineates the epidermis, dermis, and subcutaneous adipose. The epidermis is easily visualized due to the presence of basophilic keratinocytes. Scanning across the tissue sample, one can appreciate the alternating dermal papillae and rete ridges. Dermal papillae are the protrusions of dermal connective tissue into the epidermal layer. Rete ridges are the extensions of the epidermis into the dermal layer. This undulating pattern is more apparent in the thick skin of the hands and palms. There is no clear line of distinction between the papillary and reticular dermis. Collagen patterns are mostly horizontal throughout. The superficial papillary dermis possesses thinner elastic fibers compared to the thicker elastic fibers of the reticular dermis. The papillary dermis is composed of loose connective tissue (LCT) and is highly vascular. The reticular dermis shows thick collagen bundles and forms the bulk of the dermal layer.

Hair follicles, glands, and ducts can be seen throughout the epidermis, dermis, and hypodermis. A higher magnification view can further distinguish sebaceous, apocrine, and eccrine sweat glands. Meissner's corpuscles and Pacinian corpuscles can also be distinguished by light microscopy. Pacinian corpuscles in the deep dermis or hypodermis have an onion-like appearance on cross-sectional views. Meissner corpuscles are seen in the dermal papillae as oblong structures with neurons in a spiral orientation surrounded by a fibrous capsule.[10] Polarizing light microscopy is useful in the diagnosis of depositional diseases such as amyloidosis and gout. Tissue samples stained with Congo red dye may be examined under polarized light, producing a characteristic apple-green birefringence of protein deposits in amyloidosis.[15] Similarly, polarized light microscopy is used to differentiate urate crystal and calcium deposition.[16]

Microscopy, Electron

Electron microscopy (EM) can be used to visualize the ultrastructural features of the skin. Most importantly, EM has been used to visualize the basement membrane zone of the dermoepidermal junction. EM shows ultrastructural components of hemidesmosomes, the lamina lucida (LL), the lamina densa (LD), and various anchoring fibrils.[17]

Pathophysiology

There are numerous diseases that affect the skin. The following discussion describes some common and uncommon diseases that affect the dermis. This discussion is not all-inclusive but demonstrates the importance of understanding the normal structure and function of the genetic diseases that can affect dermal structure and function. Ehlers-Danlos syndrome is a group of genetic connective tissue disorders caused by various mutations in collagen. The mutations in dermal collagen result in skin hypermobility and fragility. Osteogenesis imperfecta is a genetic disorder of type I collagen, causing decreased dermal collagen and impaired skin elasticity.[18] Marfan syndrome is another genetic condition caused by a defect in the FBN1 gene encoding the fibrillin-1 protein. While skin complaints are not required for diagnosis, patients are prone to the development of striae distensae (stretch marks) due to rapid growth phases in adolescence.[19] These 3 genetic disorders, along with other inherited diseases, may rarely cause reactive elastosis perforans serpingosa, in which transepithelial elimination of elastic fibers manifests clinically as papules in an annular or serpiginous pattern.[20] 

Cushing syndrome, chronic glucocorticoid use, and pregnancy are other conditions causing striae distensae. Glucocorticoids inhibit fibroblasts, thus disrupting the synthesis of collagen and ECM material. Histology of striae distensae reveals flattening of the epidermis with loss of rete ridges and changes in the architecture of collagen bundles coupled with elastin degeneration throughout the dermis.[21] The overactivity of fibroblasts has been implicated in many skin-related diseases. Myofibroblasts, expressing alpha-smooth muscle actin (a-SMA), have been implicated in both hypertrophic scars and keloids.[22][23] A careful histopathological examination is required to differentiate among keloids, hypertrophic scars, dermatofibromas, dermatofibrosarcoma protuberans, and scleroderma due to similar histopathologic findings.[24] Lichen sclerosis is an inflammatory disorder involving abnormal fibroblast function in the papillary dermis, causing fibrosis of the superficial dermis and epidermis.[25] Acanthosis nigricans results from increased growth factor receptor signaling causing proliferation of epidermal keratinocytes and dermal fibroblasts, leading to hyperkeratosis and papillomatosis ("peaks and valleys") on histopathology.[26][27] Researchers have also observed persistent activation of fibroblasts in the dermis in morphea and nephrogenic systemic fibrosis.[28]

Aging and chronic sun exposure can weaken the dermis. Solar elastosis is due to chronic ultraviolet (UV) radiation exposure, resulting in damage to elastic fibers. Histology reveals basophilic degeneration of elastic fibers in the dermis.[29] The reduction of connective tissue in aging, usually with concomitant UV damage, causes actinic purpura (i.e., senile purpura), where the dermis cannot support its vasculature. As a result, minor trauma can lead to extravasation of blood.[30] Similar manifestations may be seen in chronic glucocorticoid users. Glomus tumors can also occur within the dermis and deeper tissues, especially within the digits and palms where glomus bodies are concentrated.[31]

Urticaria is an inflammatory dermatosis characterized by vascular hyperpermeability, causing superficial dermal edema with resultant lymphatic dilation. The pathogenesis of urticaria often involves degranulation of mast cells and immunoglobulin E-dependent pathways; however, this is not true for all cases.[32] Mastocytosis describes a spectrum of rare diseases involving an increase in mast cells within the skin and other organs. Urticaria pigmentosa is the most common cutaneous form of mastocytosis and predominately occurs in childhood.[33] Granulomatous diseases such as sarcoidosis, granuloma annulare, necrobiosis lipoidica, and mycobacterial infections (tuberculosis, leprosy) involve histiocytes within the dermis. Mycobacterium leprae infects Schwann cells of peripheral nerves, leading to diminished or absent cutaneous sensation in leprosy.[34] Lymphocytic infiltration of the dermis causes diseases such as polymorphous light eruption, a common photosensitive dermatosis.[35] Cutaneous manifestations of hematologic malignancy, such as leukemia cutis, also involve leukocytic infiltration into the skin layers. Sweet syndrome is a rare condition associated with neutrophilia and neutrophilic infiltration into the reticular dermis.[36] Other disorders involve the deposition of foreign material within the dermis, such as cholesterol in xanthelasma and protein fibrils in amyloidosis.[37] Burns and ulcers are important to consider as the depth of burn or wound involvement affects patient diagnosis and management. Partial-thickness burns, also known as second-degree burns, destroy the epidermis and extend into the dermis.[38] Similarly, stage II pressure ulcers, as described by the NPUAP, expose the dermis.[39] 

Clinical Significance

The clinical significance of the microanatomy and function of the dermis is a broad and complex topic. Below is a brief list of diseases that involve the dermis. Please note many of these diseases can affect other cutaneous layers and organs of the body. Understanding the normal anatomy and physiology of the dermis is paramount in mastering the cutaneous manifestations of the diseases listed below. 

Structural Disorders

• Structural disorders of the dermis include inherited and acquired diseases of collagen, elastic tissue, and fibroblasts.
  • Solar elastosis
  • Actinic, or senile, purpura
  • Striae
  • Scars, hypertrophic scars, and keloids
  • Burns or wounds (eg, puncture or laceration)
  • Dermatofibroma and dermatofibrosarcoma protuberans
  • Morphea
  • Nephrogenic systemic fibrosis
  • Genetic diseases (eg, Ehlers-Danlos syndrome, osteogenesis imperfecta, and Marfan's syndrome)

Inflammatory and Autoimmune Disorders

• Autoimmune blistering diseases (eg, dermatitis herpetiformis)
• Drug eruption
• Granulomatous disease (eg, sarcoidosis, granuloma annulare, mycobacterial infections)
• Lichen sclerosis
• Leukemia cutis
• Mastocytosis (eg, urticaria pigmentosa)
• Polymorphous light eruption
• Sweet syndrome
• Urticaria and eczematous dermatitis

Depositional Disorders

• Cutaneous depositional diseases involve the deposition of endogenous or exogenous substances in the dermis or subcutaneous tissue.[40] The respective deposited substance is listed in parentheses.  
  • Amyloidosis (protein)
  • Calcinosis cutis (calcium)
  • Gout (uric acid)
  • Myxedema (mucopolysaccharides)
  • Xanthoma/xanthelasma (cholesterol)