Christoph R. Loeser¹, Luke Reid², Nicole Reeves², Eva M. Sweeney², Sebastian Cotofana²

¹ Skin Cancer Center, Ludwigshafen Hospital, Ludwigshafen, Germany

² Department of Anatomy, Ross University School of Medicine, Roseau, Commonwealth
of Dominica

Introduction

The nail apparatus of the human is highly underestimated in terms of importance, clinical relevance and therapeutic options, if affected by disease. However, the nail apparatus is crucial to daily life activities including touch sensation and any form of digital manipulations and reaches out towards distal phalanx stability. Its complex nature may be one of the reasons why there are deficiencies in the current understanding of nail embryology, anatomy, pathology and therapeutic interventions.

Therefore an overview shall be given of all relevant aspects for a better understanding of the nail apparatus.

Comparative Anatomy

The anatomy of the distal limb integumentary structures is highly variable among mammals, even those of different genera within the same family [1]. Based on analyses of the distal/terminal phalanges of early fossil mammals, the diversification in distal limb appendages can be traced back to the initial adaptive radiation of mammals after the Cretaceous-Paleogene mass extinction [2]. With the selective pressures of non-avian dinosaurs lifted, mammals were able to inhabit a wider range of environments, adapting various foraging and locomotor strategies [3] Thus, in modern mammals, the adult form of the distal phalanx and the integumentary structures vary based on the function of the fore- and hind-feet in food procurement activities (e.g. searching for food, moving between food sources, acquiring food). A broad categorization of these keratinized appendages is made with reference to “nails,” “hooves,” and “claws.”

Hooves are characterized by relatively short, broad distal phalanges, which are adaptive for animals that move primarily on flat substrates [2]. Clawed animals generally have curved distal phalanges and associated keratinized structures (falculae), which can be useful for interlocking with substrates as in climbing or hanging; they can also be robust and elongated to assist in digging behaviors. Reduction in claw size is associated with higher frequency encounters with small diameter tree branches, as evidenced by comparative analyses of the thin nails (ungulae) of arboreal rodents, marsupials, carnivores, and callitrichid primates [4]. The fossil record further suggests that the earliest primates were also small bodied and tree dwelling, suggesting that claw reduction to thin nails was an early adaptation to the environment. In modern humans, nails protect the distal aspect of the digits, assist in fine motor tasks (e.g. picking up small objects), and enhance the aesthetic appearance of the hands.

Embryology

The embryological development of the human limb occurs between 4 and 8 weeks of development, by the end of the week 4 with buds on the ventrolateral body wall [5]. Limb bud formation is initiated when 2 layers of mesoderm (somatic and lateral plate) travel laterally. Somatic mesoderm cell will differentiate into muscle, nerve and vasculature, while lateral plate mesoderm will form cartilage, bone and tendon [6,7]. The forelimb develops 1 to 2 days later,  prior to the hindlimb. By week 6, the distal portion of the limb bud becomes flattened to form the hand- and footplates, with a circular constriction separating it from the proximal portion [8]. The zone of polarizing activity (ZPA) and the expression of the sonic hedgehog compound (Shh) determine the craino-caudal axis (digit I-V axis) development of the hand- and footplate [7]. The territory of ZPA is the location for digit five, with digits four, three, two and one developing further away. It has been demonstrated that the location of the ZPA influences the order of digit development, as seen by the grafting of ZPA cells into the cranial (anterior) limb bud, inducing mirror-image digit duplication [5]. The fingers and toes begin to form by day 48, due to areas of programmed cell death (apoptosis) in the apical ectodermal ridge AER. The continued outgrowth of the digits is the result of an intact AER and is complete by day 56.

Fig. 1: Macroscopic anatomy of the nail. A representation of a longitudinally sectioned fingertip is shown. The nail plate can be observed invaginating into the proximal nail fold and the cuticle is visible projecting from this fold onto the dorsal surface of the plate. Note the close relationship of the underlying nail matrix and bed to the distal phalanx.

Nail development begins at week 10 with a thickening of ectoderm producing a primary nail field. This nail field migrates from the tips of the digit to the dorsal aspect, along with the vasculature and innervation from the ventral aspect. When the nail field locates its dorsal position the surrounding epidermis folds on the lateral and proximal sides, giving rise to nail folds. Cells of the proximal nail field proliferate and keratinize, consolidate, flatten and producing a nail plate at the nail root. Firstly, the nail plate is covered with a layer of epidermis, the eponychium. This layer degenerates except at the root where the remnants form the cuticle. Fingernails continue to grow reaching the fingertip by 32 weeks, while the toenail only reaches the toe tips by 36 weeks.

Macroscopic Anatomy

The nail apparatus is comprised of the nail matrix, nail bed, hyponychium, nail folds and the underlying dermis of the matrix (Fig. 1). The nail plate is a laminated rectangular structure that is continuously produced, as the nail matrix epithelial cells differentiate and become keratinized. Distally, the hyponychium marks the junction of the nail bed and skin of the fingertip; this region also allows detachment of the nail plate so that it may continue distally as a free edge. The plate is partially enveloped by the lateral and proximal nail folds. The lateral nail folds are continuous with the skin of the digit at the sides of the nail and with the nail bed [9]. The proximal nail fold is invaginated by the nail plate such that the fold has dorsal and ventral surfaces. The dorsal surface of the proximal fold, the eponychium, produces the cuticle which projects from the recess of the proximal fold and adheres to the dorsal surface of the nail plate thus sealing the recess of the proximal nail fold. The ventral floor of the proximal fold harbors cells of the nail matrix. The nail matrix can be considered in dorsal (proximal), intermediate (distal) and ventral regions. The distalmost part of the matrix is marked by the distal border of the lunula, a white half-moon shaped region underlying the proximal visible portion of the nail plate [10]. The vascularity of the nail bed confers a pinkish appearance to the nail distal to the whitish lunula. In this distal part of the nail plate, one can also observe the transverse onychocorneal and onychodermal bands just proximal to the distal free margin. The former marks the distalmost attachment of the nail plate to the bed, and the latter separates the onychocorneal band from the free edge of the plate.

During growth the plate is pushed distally by the continuous production of new nail plate by the matrix and by the slow movement of the nail bed as it too grows distally [11]. The proximal portion of the matrix forms the more superficial layers of the nail plate, the middle matrix forms the intermediate layer of the plate and the distal matrix, the deeper layer. The ventral (deep) surface of the nail plate is considered to be partly composed of the nail bed. The nail bed provides a strong link between the nail and the underlying dermis which in turn is adherent to the proximal bony phalanx. The superficial aspect of the nail bed possesses a thin keratinized layer that allows the nail plate to move across the bed. The nail bed epithelium also bears parallel rete ridges to aid attachment. The plate thickens as it progresses distally whereas thickness increases with age and is dependent on the length of the nail matrix and bed. The nail plate possesses transverse and horizontal curvatures which correlate to the shape of the underlying phalanx. The shape of the free border correlates to the curvature of the lunula [10].

Fig. 2: Repeated filling and spontaneous resolution of a mucoid pseudocyst leads to frequent changes in nail deformation over time and is a strong hint for the diagnosis. The cyst is localized below or, as it was in this case, above the nail-matrix.

The arterial vascular supply is provided by the superficial and deep palmar arches, which also contribute to the common palmar digital arteries which divide at the clefts of the fingers into proper palmar digital arteries that run on the opposing sides of adjacent fingers. Proximal to the distal interphalangeal joint the proper palmar digital arteries provide a branch that runs dorsally to form the superficial arcade that supplies the nail fold and proximal matrix. The nail bed epithelium possess 4-6 layers of capillaries that run in transverse layers from proximal to distal [12].

Histology

Nails are plates of keratinized cells containing hard keratin, with an arched structure on both the fingers and toes [13]. The hardness of the nails is attributed to the densely packed keratin filaments embedded in an amorphous keratin matrix with high sulfur content. The nail matrix is a group of epithelial bulbs and contains melanocytes, epithelial cells, stem cells, Merkel’s and Langerhans’ cells. It consists of two parts, an apical and ventral region [14]. The ventral part produces the majority of the nail plate, the apical matrix forms thin dorsal parts of the nail plate. A prekeratogenous zone is comprised of both layers from the keratogenous zone and the basal compartment, and is well defined in the ventral part, however is diffuse in the apical matrix [14]. The nail bed is a series of epithelial cells continuous with the stratum basale and stratum spinosum of the epidermis [15]. The nail bed is thought to not produce nail substance, and much like the eponychium and hyponychium only express epidermal keratins [13]. The hyponychium present at the fingertip is an epidermal-type of horny layer, and contributes to sealing the distal nail apparatus [16]. The isthmus is an area of transition between the nail bed and hyponychium, produces small keratinous areas. This complex area has thin granular and parakeratotic corneocyte layers, which adhere to the ventral surface of the plate, producing a seal on the distal aspect of the nail apparatus. Seals around the proximal and lateral edges are formed by the nail folds and are morphologically similar to other parts of the skin [13].

Non-traumatic pathologies of the nail apparatus and their surgical treatment

In the following section, the most frequent and surgically treatable disorders of the nail apparatus will be discussed in relation to the primary anatomical structures involved. These will include the bone of the distal phalanx, the distal inter-phalangeal joint, the nail matrix, nail bed, nail plate and the nail fold.

The Bone of the distal phalanx

Symptoms: A solid tumor, slowly growing in the nail bed, finally arising from it and lifting, sometimes grotesquely distorting or destroying the nail plate, can usually be linked to the bone of the distal phalanx.

Differential diagnosis: Any localized and slowly growing pain in the nail bed, usually affecting the great toe, is suggestive for possible diagnosis of a subungual exostosis [17]. In early stages, symptoms and site can be misleading. Other painful benign tumors originating in the nail bed, e.g. glomus tumor or glomangioma, usually do not lead to distortion of the nail plate.

Diagnostic strategy: Patients usually present, when the problem is advanced. Diagnostics should largely be based on radiography.

Therapy: The protruding mass can be removed surgically in local anesthesia by using a chisel or rongeur forceps. The nail plate should not be touched if possible. Healing is facilitated by secondary intention.

Comments: Minimal trauma is suspected as causative for subungual exostosis, and is frequently seen in children on their great toe [18]. Biopsies can be misleading and should be avoided. Post-operative radiography will document successful removal. Relapse can occur and should be explicitly discussed with the patient before surgery.

The distal interphalangeal joint

Symptoms: If there is a leakage of synovial fluid into tissue surrounding the joint, a nodule can form, imitating a cyst. Interestingly, this always affects the dorsal part of the digit, despite the fact that the tissue there is much denser than on the palmar/plantar side. However, the fluid will form a cavity either below the matrix or – more often – in the proximal nail fold. Depending on the thickness of the epidermis and the overlying horny layer, sometimes just a nearly translucent layer of tissue covers the nodule. The thinner the tissue above the pseudocyst, the higher is the risk of a rupture. Depending on size and site, patients experience pain and/or nail plate deformation.

Differential diagnosis: The pseudocyst can be mistaken for other tumors of the nail bed, e.g. glomus tumor, when it is situated below the matrix or, even more uncommon, in the nail bed. A strong hint at a pseudocyst is a periodically increased alteration of the nail plate due to changes in size over time. (Fig. 2)

Diagnostic strategy: A spillage of gel like fluid is usually diagnostic as well as the clinical picture. High resolution MRI can help detect subungual sites. Radiography can reveal the formation of an osteophyte in some cases.

Therapy: There is a plethora of therapies with a considerable rate of recurrences. They range from repeated puncture (Fig. 3, 4) up to surgical removal [19, 20]. Scar formation permanently seals the leak and is therefore crucial for success. A delicate excision of the pseudocyst in local anesthesia and thereby removing the culprit might be favorable, followed by local flap transposition to cover the site and seal the leak. Variations of this technique were described by de Berker et al. [21].

Comments: Since there is just condensed tissue surrounding the mucoid fluid and there is no cystic wall, the correct term should be (mucoid) pseudocyst. Employing methylene blue solution to visualize the cyst [21] might increase the risk of permanent tattooing or even anaphylaxis. Magnifying lenses during surgical procedures have been shown to be efficient.

The Nail matrix

Symptoms: Linear changes of color in the nail-plate can originate from the nail matrix. They are often brown or black in color due to deposition of pigment (melanonychia) or red (erythronychia) due to impaired growth with consecutive eversion of parts of the nail bed into the nail plate. These changes are especially bothersome when the linear coloration of the nail plate increases in size proximally. This is a sign for growth and therefore suspicious for malignancy.

Fig. 3: Painless puncture, usually without need for local anesthesia, is a fast and easy office procedure to relieve the pressure of a mucoid pseudocyst.

Fig. 4: Outward aimed pressure revealed a droplike blob of mucoid substance, thereby proving the diagnoses. Application of constant gentle pressure afterwards with a tape bandage might lead to remission.

Differential diagnosis: Melanonychia can be caused by benign lentiginous lesions, nevi or melanoma in the nail matrix. Erythronychia is caused primarily by Bowen’s disease of the nail or subungual warts.

Diagnostic strategies: Dermoscopy can be supportive [22]. While observation and watchful waiting can be considered, only histological analysis is diagnostic.

Therapy: The treatment depends on the diagnosis. Whenever the diagnosis of invasive melanoma is established in melanonychia, complete removal of the nail organ with microscopically controlled surgery is mandated [23]. Careful biopsy of benign lesions can lead to clearing of the melanonychia. In Bowen’s disease of the nail, targeted excision (as biopsy) can be sufficient. (Fig. 5, 6, 7) Stringent follow up is mandatory in all cases.

Comments: There is a wide range of clinical changes of the nail plate due to processes in the nail matrix. While quite difficult in itself, obtaining a suitable specimen for histologic evaluation is only half the battle. Extensive knowledge of the histology of the nail is necessary in order to interpret the very subtle changes in the matrix correctly. Tremendous changes in the nail plate clinically can correspond to very little substrate detectable in the tissue microscopically.

The Nail bed

Symptoms: A painful blueish discoloration beneath the nail plate is in most cases caused by a benign growth in the nail bed. Histology might confirm either glomus tumor or glomangioma.

Differential Diagnosis: Causes for localized subungual pain could also be early stage exostosis and subungual warts. In rarer cases we find malignant tumors or tumors of peripheral nerves among many others.

Diagnostic strategy: While the clinical picture can be suggestive, an ischemia test was previously proposed [24]. MRI also proved useful.

Fig. 5: Erythronychia with a thin longitudinal band showing redness above the matrix with distal onycholysis and some brown streaks from bleading.

Fig. 6: Intraoperative site (of Erythronychia shown in Fig. 5) with a distal access through incision of the nail plate and longitudinal excision of parts of the nail bed, matrix and underside of the nailplate. The nailplate was repositioned after surgery. Histology revealed Bowens disease of the nail.

Fig. 7: Follow up two years after surgery (compare Fig. 5 and 6) in a close up. Almost complete resolution. Note healing and almost perfect growth despite extensive removal of tissue including distal matrix due to gentle and nail-plate preserving surgery.

Therapy: When glomus tumor is correctly suspected, diagnosis and treatment can be combined in a one-step-approach. First, the nail plate is cut and lifted. Then the nail-bed will be incised and the glassy nodule carefully removed. After the nailbed is sutured back in place, the nail plate can be repositioned.

Comments: Complete removal of a glomus tumor can be achieved by careful preparation, but recurrence should be considered.

The Nail fold

Symptoms: Human papilloma virus can cause wart-like growth on the lateral and proximal nailfold. It can laterally involve the nail bed and bring destruction to the whole nail organ over time.

Differential Diagnosis: Warts have to be distinguished from malignant epithelial tumors like Bowen’s disease and squamous cell carcinoma. In some cases benign hyperplasia such as knuckle pads or clavus can mimic warts.

Diagnostic strategy: Whenever suspected, warts should be removed and histological analyses should be performed, especially if the patient is beyond child-age. Non healing “eczema” on a single digit should be always explored by biopsy.

Therapy: Warts can be removed with conservative means or ablative modalities, like Argon-plasma-coagulation (APC), Cryosurgery or LASER. Histology should be obtained after removal. Bowen’s disease, squamous cell carcinoma and other malignant tumors should be removed using microscopically controlled surgery based on national guidelines.

Comments: Often the nail plate and sensible parts like matrix and nail bed can be preserved by using a gentle path. When malignant invasive growth involves parts of the nail bed or matrix the whole nail apparatus has to be excised. When microscopically controlled surgery is employed, amputation does not increase overall survival. Complete or partial removal of the digit is only performed, when there is involvement of bone and/or joint.

The recommendations for diagnosis, therapy and outcome presented here are based on the experience of the first author and should be therefore interpreted as such.