Pediatric dermatohistopathology--histopathology of skin diseases in newborns and infants.

Minireview Submitted: 16.10.2014 Accepted: 29.1.2015 Conflict of interest None

Marion Wobser 1, Karen Ernestus2, Henning Hamm1 (1) Department of Dermatology, Venereology, and Allergology, Würzburg University Hospital (2) Institute of Pathology, Julius Maximilian University Würzburg

DOI: 10.1111/ddg.12651

Pediatric dermatohistopathology – histopathology of skin diseases in newborns and infants Summary While neonatal skin physiology has been thoroughly examined using non-invasive techniques in recent years, only few systematic studies and review articles addressing the histopathology of neonatal skin have been published thus far. In most cases, histopathological findings of dermatoses in neonatal skin do not significantly differ from those seen in adult skin. Nevertheless, a comprehensive knowledge of embryonic and fetal skin development as well as the microanatomical structure of neonatal skin can contribute to a better understanding of various dermatoses of infancy. In the first part of this review article, we present the histopathological features of such skin diseases, which, though generally rare, almost exclusively appear during the first weeks of life due to distinctive structural and functional features of neonatal skin. The second part is dedicated to classic dermatoses of infancy and their histopathological features.

Introduction In recent years, the physiology of neonatal skin has been thoroughly elucidated using non-invasive examination techniques [1–3][2, 4, 5]. These analyses reveal that, at birth, the development and maturation of neonatal skin is still far from complete, even in term infants [6]. In fact, in the first postpartum days and weeks, the skin undergoes dynamic adaptation as a response to contact with the new environment [7–10]. Being an invasive diagnostic procedure, a biopsy for histological analysis is often deferred in neonates and infants, because a correct diagnosis is frequently possible by merely assessing the typical clinical presentation of neonatal dermatoses. In addition, supplementary noninvasive diagnostic measures such as microbiological swabs, dermatoscopy, diascopy, and ultrasound to corroborate the visual clinical diagnosis. In light of the above, there are only few systematic studies on the microanatomical structure of the skin in the first months of life. In the first part of this review, we present the distinctive histopathological features of neonatal and infantile dermatoses. As fetal skin development provides clues to the pathogenesis of some infantile dermatoses, it is summarized in a brief introductory section. In the second part, we illustrate the histopathology of some additional infantile dermatoses, of which microscopic findings hardly do differ from

those encountered in adulthood, but that typically manifest at this early stage of life. Table 1 summarizes the most important dermatoses, with special emphasis on its histopathology, the diagnoses shaded in blue are addressed in detail in the following review.

Embryonic and fetal skin development Figure 1 offers a tabulated overview of embryonic and fetal skin development. The skin, serving as a barrier between organism and environment, is formed from two germ layers. The epidermis and skin appendages (sweat and sebaceous glands, hair follicles, nails) are formed from the ectoderm (outer germ layer), while the dermis is derived from the mesoderm (middle germ layer). The complex development of skin and its appendages from the embryonic stages to the birth of a viable newborn follows a highly regulated ontogenetic program.

Epidermis Detectable from the 10th-14th gestational day onwards, the ectoderm initially gives rise to the double-layered primitive embryonic epidermis. From the 4th to the 20th gestational week (GW), the latter is covered by the glycogen-rich periderm, which is then sloughed off into the amniotic fluid

© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1306

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Minireview Pediatric dermatohistopathology – histopathology of skin diseases in newborns and infants

Table 1 Some “classic“ neonatal and infantile dermatoses. The histopathological features of the dermatoses. Dermatoses attributable to distinctive microanatomical features of neonatal and infantile skin Immature sweat glands/appendages

Miliaria

Immature dermoepidermal anchoring

Sucking blisters

Immature adipose tissue

Subcutaneous fat necrosis of the newborn, sclerema neonatorum

Immature hematopoietic system

Blueberry muffin baby

Congenital dermatoses Malformations

Fistulas and cysts: - congenital dermoid cyst - branchial and bronchogenic fistula - medial and lateral neck cyst

Accessory malformations: - accessory tragus - supernumerary nipple - supernumerary digit Aplasia cutis congenita Nasal glioma Acrochordon Omphalocele Genodermatoses and neurocutaneous syndromes

Epidermolytic ichthyosis Epidermolytic palmoplantar keratoderma (type Vörner) Epidermolysis bullosa simplex; junctional and dystrophic epidermolysis bullosa

Neurocutaneous syndromes/phacomatoses: - Incontinentia pigmenti - Tuberous sclerosis - Neurofibromatosis Nevi, hamartomas, malformations

Organoid nevi: - Sebaceous nevus - Inflammatory linear verrucous epidermal nevus (ILVEN)

Melanocytic nevi: - Congenital melanocytic nevi - Dermal melanocytosis

Vascular malformations: - Blue rubber bleb nevus syndrome - Angioma serpiginosum Continued

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Table 1 Continued Dermatoses attributable to distinctive microanatomical features of neonatal and infantile skin - Glomus tumor/glomuvenous malformation - Lymphangioma

Fibrohistiocytic and mesenchymal hamartomas: - Smooth muscle hamartoma - Fibrous hamartoma of infancy Tumors and benign proliferations

Vascular tumors: - Infantile hemangioma - Kaposiform hemangioendothelioma - Pyogenic granuloma

Langerhans cell and non-Langerhans cell histiocytoses: - Langerhans cell histiocytosis - Juvenile xanthogranuloma - Benign cephalic histiocytosis - Reticulohistiocytoma Cutaneous mastocytoses Pilomatricoma Hibernoma, lipoblastoma, lipoma

Fibrohistioytic and mesenchymal tumors and proliferations - Dermatomyofibroma - Giant cell fibroblastoma, dermatofibrosarcoma protuberans - Infantile fibromatoses

as vernix caseosa. From the 15th GW onwards, the epidermis is finally multilayered and characterized by a differentiated keratin pattern largely analogous to that of adult skin [11] (Figure 2a). The keratinization of the fetal epidermis begins around the 20th GW [12]. Starting in the 34th week of pregnancy, the “cornified envelope” is formed which provides the basis for the organism’s important barrier and protective function to the outside world. Desmosomal intercellular bridges ensure the continuity and integrity of the epidermis [13, 14]. While the components of the dermoepidermal junction such as hemidesmosomes, anchoring filaments and fibrils are detectable as early as the 8th -10th week [15, 16], the interdigitation of epidermis and dermis remains fragile until birth due to only slight papillomatosis with flat epidermal rete ridges (Figure 3a).

Dermis The mesoderm (middle germ layer) is detectable from the 18th day onwards. The embryonic dermis arising from the mesoderm consists of a loose network of undifferentiated mesenchymal cells in a hydrated hyaluronic acid-rich matrix predominantly containing “fetal” type III collagen, which provides numerous ligands to drive subsequent differentiation (Figure 2b). Dermal fibroblasts begin to form collagen type II and elastin in the 12th GW, and the enddifferentiation into the papillary and reticular layer, each marked by a distinct connective tissue structure, commences. While the dermis is initially mucinous and highly cellular, it is subsequently more and more replaced by fibrous connective tissue.


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Figure 1 Overview of embryofetal skin development and postnatal adaptation.

Adnexal structures and other components of fetal skin Influenced by mutual interactions between components of the ectodermal epidermis and the mesenchymal dermis with tightly regulated signaling and differentiation pathways, skin appendages (hair follicles, nails, glands) as well as blood vessels and nerves start forming in the 9th week of gestation [17] (Figure 2c). Beginning in the 15th GW, intrauterine sebum production contributes to the formation of the lipids of vernix caseosa and the cornified envelope [18]. Until the 28th GW, all of the more than three million eccrine sweat glands have already been formed. In the 8th GW, melanocytes start migrating from the neuroectoderm, the neural crest, into the skin. Merkel cells and Langerhans cells are detectable in the epidermis from the 10th–15th GW onwards [19]. Subcutaneous adipose tissue starts forming in the 18th GW (Figure 2d).

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Even though all structures of the epidermis, dermis, and skin appendages have been fully established by the 24th GW, numerous additional processes – especially under the influence of various environmental factors such as temperature changes, exposure to air, and bacterial colonization – have to take place postpartum with respect to differentiation and adaptation. These primarily relate to the further development of the mechanical resistance of the skin as a barrier between the organism and the outside world. The increase in thickness of the stratum corneum and epidermis in response to mechanical forces, the formation of marked papillomatosis, the increase in elastic fibers, and the replacement of “fetal” type III collagen (50–60 % of neonatal skin) by “adult” type I collagen (80–90 % of the adult skin) can be interpreted as a response to cope shear forces. In the 28th week of gestation, the microanatomical structure of sweat gland lobules and ducts already largely resembles that of a newborn. However,



Figure 2 Histopathology of fetal skin. Fetal skin in the 28th gestational week. The stratified epidermis shows basketweave orthokeratotic cornification (hematoxylin & eosin stain, magnification x400) (a). The dermis is highly cellular and glycogen-rich. There is incipient demarcation between papillary and reticular dermis (hematoxylin & eosin stain, magnification x100) (b). Adnexal structures are completely formed, yet not fully differentiated (hematoxylin & eosin stain, magnification x100) (c). Apart from mature adipocytes, there is an abundance of lipoblasts in fetal adipose tissue (hematoxylin & eosin stain, magnification x200) (d).

the sweat glands are not yet functional due to incompletely developed innervation, thus resulting in anhidrosis. Along with the complete maturation of the microanatomical structures of the skin, adaptation of other functional processes such as lipid formation and pH regulation occurs, which are important for the barrier function of the stratum corneum, temperature regulation, microcirculation, and innervation [4, 5, 12]. In the first few days and weeks postpartum, maturation of immunological processes of the skin’s innate and adaptive immune response as well as the formation of the cutaneous microbiome also takes place [10].

Histopathology of skin diseases attributable to distinctive microanatomical features of neonatal and infantile skin The dermatoses mentioned below can be attributed to the incomplete maturation of the structure and/or function of the skin, including skin appendages, during fetal development until birth. Accordingly, these skin diseases occur in newborns, more often in preterm than term infants (Table 1). In adults, these skin disorders regularly do not appear.

Figure 3 Distinctive histopathological features (structure, degree of maturation) of neonatal skin give rise to specific dermatoses (suction blisters, subcutaneous fat necrosis of the newborn, infantile hemangioma). Normal skin of a 4-week-old newborn shows a horizontally arranged basal cell layer, lack of papillomatosis, and loose dermal connective tissue. Artificial detachment of the epidermis (caused by processing of the histological specimen) is an indication of the mechanical fragility of neonatal skin (hematoxylin & eosin stain, magnification x400) (a). Subcutaneous fat necrosis of the newborn with characteristic crystalline inclusion bodies within xanthomized giant cells (hematoxylin & eosin stain, magnification x200) (b). Lobular capillary proliferations of monomorphic vessels in the early stages of infantile hemangioma (hematoxylin & eosin stain, magnification x200) (c). Endothelial cells are Glut-1positive (d).

Sucking blisters The neonatal skin has a stratum basale running horizontally to the surface (Figure 3a). This leads to increased vulnerability of the skin and sensitivity to shear forces, which results, for instance, in the formation of sucking blisters on the lips and erosions upon band-aid removal.

Subcutaneous fat necrosis of the newborn (SFNN) Within the first six weeks of life, extensive subcutaneous fat necrosis may occur, which is possibly attributable to the distinct lipid composition of brown neonatal fat with its reduced compensation mechanisms to trauma, hypoxia, and especially hypothermia [20]. Histology reveals necrotizing lobular panniculitis with secondary granulomatous “foam-cell-like” inflammation, fibrosis, and calcification (saponification). Subcutaneous fat necrosis of the newborn is characterized by stellate formations of fatty acid crystals in giant cells (Figure 3b)


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and, rarely, intracytoplasmic eosinophilic globules. Rapid diagnosis can be lifesaving, as this allows for prompt workup to rule out life-threatening hypercalcemia often associated with SFNN and, if indicated, immediate initiation of adequate treatment [21].

Infantile hemangioma Infantile hemangioma is the most common vascular tumor in neonates and infants, with an increased incidence in preterm babies. Hypoxia-induced aberrant signaling via the vascular endothelial growth factor (VEGF) in incompletely differentiated vascular stem cells appears to be of pathogenetic relevance [22]. In early stages, infantile hemangioma displays proliferating capillary blood vessels arranged in lobules (Figure 3c) [23]. The endothelial cells express the Wilms tumor antigen 1 (WT-1) and glucose transporter 1 (Glut-1) (Figure 3d). The latter is a marker for immature endothelial cells, and may thus be used as the most important histopathological criterion for differentiating vascular malformations from congenital vascular tumors [24]. During the regression phase, infantile hemangioma exhibits increasing fibrosis with possible loss of adnexal structures, intravascular microthrombi, and regression of capillaries. In the propranolol era, a biopsy or excision with histological confirmation is only performed in exceptional cases, such as to rule out differential diagnoses and due to cosmedical reasons

Histopathology of congenital dermatoses Malformations Dermoid cyst: Unlike the much more common acquired inclusion cysts (epidermal/infundibular cyst, trichilemmal cyst/ isthmus-catagen cyst) or retention cysts (hidyrocystoma), a dermoid cyst is a rare congenital cystic malformation along embryonic fusion lines [25, 26]. Usually presenting at birth or in the first year of life, dermoid cyst is clinically characterized by a firm, elastic, dome-shaped cutaneous-subcutaneous protrusion at cranial predilection sites [27, 28]. The cyst’s lumen is unilocular and lined by stratified, orthokeratotic epithelium with stratum granulosum (Figure 4a). Recent studies have shown that dermoid cysts have a characteristic cytokeratin profile, which suggests that they originate from the follicular infundibulum [29]. However, lesions also frequently show “sawtooth” cornification, as seen in sebaceous gland ducts and steatocystoma (Figure 4b). Since dermoid cysts arise from sequestered cutaneous tissue of both ectodermal and mesodermal origin, they possess additional elements such as sebaceous glands, apocrine and eccrine sweat glands, fibrolipomatous connective tissue as well as vellus hairs and arrector pili muscles (Figure 4c) [30], yet – unlike mature

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Figure 4 Dermoid cyst, histopathology. The wall of a unilocular dermoid cyst is lined by stratified, cornifying epithelium. The cavity of the cyst contains lamellated horny material and vellus hair shafts (hematoxylin & eosin stain, magnification x100) (a) Associated with the cyst wall, there are vellus hairs, glandular structures and smooth muscle bundles (hematoxylin & eosin stain, magnification x200) (b, c).

cystic teratomas – no cartilage or bone tissue. Associations with hamartomas [31], basaloid differentiation of the cystic epithelium [32], and malignant transformation of dermoid cysts [33] are utterly rare. Supernumerary nipples: Analogous to normal nipple tissue, there is an increased number of sebaceous gland lobules arising from a partially exophytic papillomatous epidermis. Underneath it, embedded in fibrotic connective tissue, apocrine acini with a double-layered epithelium and acidophilic secretion in the cystic lumen can be seen (Figure 5a). An excision is usually performed due to cosmetic reasons, and rarely due to a clinical misdiagnosis of dermal nevus or fibroma. Aplasia cutis congenita: Various endogenous and exogenous factors that affect the fragile embryofetal development of the skin in utero may be the underlying cause of aplasia cutis congenita [34]. Clinically, the disorder is characterized by a solitary scalp lesion – present at birth – that is either eroded/ulcerated or even scarred. Histological findings range from circumscribed epidermal defects to the complete absence of all adnexal structures with cicatricial fibrosis (Figure 5b). Elastic fibers are absent, and the reepithelialized epidermis is thin and flattened.

Hereditary skin disorders Incontinentia pigmenti (Bloch-Sulzberger syndrome): Incontinentia pigmenti (OMIM # 308300) is an X-linked



Figure 6 Histopathology of epidermolytic palmoplantar keratoderma (type Vörner). Epidermolytic keratinocytes with coarse keratohyalin granules as well as marked orthohyperkeratosis (hematoxylin & eosin stain, magnification x200 (a), x400 (b)). Figure 5 Histopathology of supernumerary nipple, aplasia cutis and incontinentia pigmenti (vesicle smear). Supernumerary nipples are histologically characterized by apocrine glands beneath a papillomatous epidermis (hematoxylin & eosin stain, magnification x200, inlet x400) (a). Congenital aplasia cutis histologically shows scar tissue with loss of adnexal structures and elastic fibers (hematoxylin & eosin stain, magnification x200) (b). Vesicle smear in incontinentia pigmenti revealing numerous eosinophils (hematoxylin & eosin stain, magnification 1,000x) (c).

dominant multisystem disorder as first presenting sign frequently exhibiting cutaneous manifestations. The hotspot mutation in the NEMO gene, detectable in 85 % of cases, leads to deregulation of NFκB-dependent signaling pathways with subsequent impairment of immunological function, cell adhesion and regulation of apoptosis [35]. Initial vesicular lesions along Blaschko’s lines appear shortly after birth and reflect a disturbed intracellular signaling. Histology shows eosinophilic spongiosis of the epidermis. The Tzanck test with evidence of abundant eosinophils within a blister (Figure 5c) is a rapid, minimally invasive method for early diagnosis in newborns, especially for the purpose to rule out an infectious disorder such as herpes simplex infection. A biopsy is not required. Pathogenetically, tissue eosinophilia is caused by the deregulated, NFκB-dependent expression of cytokines and chemokines – including eotaxin – in keratinocytes, which subsequently leads to recruitment of eosinophils into the skin [36]. Epidermolysis bullosa: Hereditary epidermolysis bullosa is caused by genetic impairment, or even loss of function, of structural proteins of the dermoepidermal anchoring zone with subsequent blistering. Depending on the cleavage site, two entities are distinguished: epidermolysis bullosa simplex with cleavage within the basal keratinocytes, and junctional (dystrophic) epidermolysis bullosa with cleavage along and beneath the basement membrane [37]. Histology of a fresh blister or perilesional skin with evidence of a loss of

dermoepidermal adherence, yet without a significant inflammatory infiltrate, can already provide important clues for a hereditary bullous disorder. However, antigen mapping by immunofluorescence staining of cryosections and mutation analysis are the two key diagnostic measures. Ichthyosis and palmoplantar keratoderma: Similar to hereditary bullous disorders, histopathology is of limited value in the diagnostic classification of ichthyosis and other hereditary disorders of cornification; exceptions are epidermolytic ichthyosis and palmoplantar keratoderma both exhibiting the histological pattern of epidermolytic hyperkeratosis. The latter is characterized by varying degrees of perinuclear vacuolization with coarse basophilic keratohyalin granules in the stratum granulosum and stratum spinosum, up to blister formation (Figure 6a, b) [38].

Nevi, hamartomas, and malformations Dermal melanocytosis: Usually discernible at birth, dermal melanocytosis is presumed to be caused by inhibition of melanocyte migration from the neural crest into the skin during embryonic skin development. Histologically, dermal melanocytosis is characterized by horizontally arranged spindle-shaped melanocytes, diffusely interspersed between collagen fibers (Figure 7a). The association of blue nevi [39] or neurocristic hamartomas [40] with dermal melanocytosis is rare, but not surprising given their assumed common molecular background (activating GNAQ mutations) [41, 42]. Sebaceous nevus: At birth, sebaceous nevi present as solitary, yellow-orange plaques on the scalp or face. Only rarely is there a more generalized distribution along Blaschko’s lines in the context of syndromal diseases (Schimmelpenning syndrome, phacomatosis pigmentokeratotica). This complex, organoid nevus is histologically characterized by a variable extent of epidermal changes (hyperkeratosis, acanthosis, papillomatosis, rarely also germinal follicles) in combination


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Figure 7 Histopathology of dermal melanocytosis and sebaceous nevus. Dermal melanocytosis is characterized by horizontally arranged spindle-shaped and dendritic melanocytes with prominent pigmentation (hematoxylin & eosin stain, magnification x400) (a). Sebaceous nevus (on the head of a sixmonth-old infant) with papillomatous, acanthotic epidermis with germinative follicular structures, mimicking the embryofetal hair papilla, as well as small keratocysts and hyperplastic apocrine glands. Complete lack of terminal hairs (hematoxylin & eosin stain, magnification x200) (b). Hyperplastic sebaceous glands open directly into the epidermis (hematoxylin & eosin stain, magnification x200) (c).

with alterations of glandular structures. An important clinical and histological feature is the absence of terminal hairs. Thus, sebaceous glands – usually increased in number and/ or size – open directly into the epidermis without being associated with hair follicles (Figure 7b, c). It should be noted that the histological changes in sebaceous nevi may vary depending on their location on the body and also based on agedependent, hormonally controlled sebaceous gland activity. Rarely and usually in adulthood, benign secondary tumors such as trichoblastoma or syringocystadenoma papilliferum, and infrequently also malignant epithelial tumors such as basal cell carcinoma, may arise from sebaceous nevi. By contrast, newly developing tumors in childhood histologically usually turn out to be either verruca vulgaris or pyogenic granuloma. From a molecular genetic standpoint, sebaceous nevi are characterized by postzygotic mutations in the HRAS (95 %) or KRAS (5 %) gene [43]. Congenital melanocytic nevus: Histologically, superficial and deep congenital melanocytic nevi display a band-like or more nodular accumulation of monomorphic melanocytes that show full differentiation towards the base of the lesion (Figure 8a, b). Melanocytes situated at deeper levels may exhibit neuroid differentiation, and individual junctional

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Figure 8 Histopathology of congenital melanocytic nevus. Congenital melanocytic nevus with band-like subepidermal accumulation of monomorphic adnexotropic melanocytes and ascent of individual cells into the junctional zone (hematoxylin & eosin stain, magnification x100) (a). Higher magnification shows perineural (b) and perifollicular (c) arrangement of nevus cells (hematoxylin & eosin stain, magnification x400). Periadnexal arrangement with involvement of deeper dermal layers (d) (hematoxylin & eosin stain, magnification x200).

melanocytes may ascend to higher epidermal layers, which should not be misinterpreted as melanoma. Orientation of nevus cells along adnexal structures, muscle fibers, blood vessels, and nerves is characteristic for the congenital structural pattern of melanocytic nevi (Figure 8c, d). This reflects the migration of primitive neuroectodermal stem cells along these guiding structures during embryonic development [44, 45]. Excision is usually performed due to cosmetic reasons. Glomus tumor/glomuvenous malformation: Histogenetically, glomus tumors are derived from the neuromyoarterial, temperature-regulating glomus apparatus (SucquetHoyer canal) [46, 47]. Depending on the presence of various tissue components (glomus cells, myoid spindle cells, endothelium-lined blood vessels), three entities may be distinguished: solid glomus tumors, glomuvenous malformation (formerly known as glomangioma), and glomangiomyoma. Glomuvenous malformation usually presents as a congenital solitary blue plaque or papule located on the extremities; excision with histological confirmation is often performed due to pain and tenderness. In contrast to the blue rubber bleb nevus syndrome (cavernous angiomas), a major clinical differential diagnosis, there is no visceral involvement [48, 49]. Histologically, glomuvenous malformation is characterized by dilated dermal blood vessels, which are surrounded by monomorphic, cuboidal glomus cells (Figure 9a). Consistent



Figure 9 Histopathology of glomuvenous malformation and fibrous hamartoma of infancy. In glomuvenous malformation, ectatic thin-walled vessels in the dermis and subcutaneous fat are surrounded by cuboid, nodular, monomorphic glomus cells with vesicular nuclei (hematoxylin & eosin stain, magnification x200) (a). Glomus cells stain positive for SMA (b), but negative for CD31 (c). An organoid pattern with admixture of different mesenchymal components is typical for fibrous hamartoma of infancy (d).

with vascular smooth muscle cells, glomus cells are positive for actin, vimentin, SMA (Figure 9b), and caldesmon, but negative for CD31 (Figure 9c), CD34, and D2–40. Moreover, there is no expression of WT-1 [50], which classifies glomangioma as a vascular malformation rather than a neoplasm (“glomus tumor”). A large percentage of cases are inherited in an autosomal dominant manner based on loss-of-function mutations in the glomulin gene (OMIM # 13800) [51], which regulates the proliferation and differentiation of vascular smooth muscle cells. Fibrous hamartoma of infancy: Present at birth, this hamartoma is – to varying degrees – composed of various mesenchymal components (coarse collagenous connective tissue, storiform and whorled fascicles of eosinophilic myofibroblasts, mature adipose tissue, and myxoid foci), and shows a characteristic organoid structure extending into the subcutaneous adipose tissue (Figure 9d) [52].

Tumors of infancy Kaposiform hemangioendothelioma Usually occurring early in life, kaposiform hemangioendothelioma is a semi-malignant vascular tumor. Immediate biopsy with histological analysis is of paramount importance, as delayed diagnosis poses the risk of potentially lifethreatening consequences (Kasabach-Merritt syndrome with

Figure 10 Histopathology of kaposiform hemangioendothelioma. Spindle-shaped endothelial cells in lobular arrangement und slit-like blood vessels in a newborn with kaposiform hemangioendothelioma and associated Kasabach-Merritt syndrome (hematoxylin & eosin stain, magnification x200) (a). Slit-like vessels in the periphery of the lesion are a characteristic feature (hematoxylin & eosin stain, magnification x400) (b).

disseminated intravasal coagulation [DIC]). Histologically, nodular spindle cell aggregates (Figure 10a, b) with slit-like, CD31-positive blood vessels and surrounding SMA-positive pericytes are found in the dermis, extending into the subcutaneous adipose tissue [47, 53]. Intravascular microthrombi may also be seen in the periphery of the tumor lobules. Infantile hemangioma and Kaposi’s sarcoma, the latter one being rarely encountered in childhood, are the most important clinical and histological differential diagnoses. Unlike hemangioma, kaposiform hemangioendothelioma is always Glut-1 and LeY-negative, but stains positive for vascular and lymphatic markers (CD34, CD31, D2–40, Prox-1, LYVE-1, Fli-1); nuclear expression of HHV-8, pathognomonic for Kaposi’s sarcoma, is missing. In contrast to vascular malformations, kaposiform hemangioendothelioma is positive for WT-1. Given that kaposiform hemangioendothelioma and tufted angioma display a similar histological architecture with a nodular growth pattern (cannon ball pattern) as well as a similar immunohistological profile, and because they can both induce Kasabach-Merritt syndrome, these two vascular tumors are thought to be closely related [54, 55].

Langerhans cell histiocytosis Histologically, skin involvement in Langerhans cell histiocytosis [56] is characterized by dense dermal infiltrates of histiocytes, which often reveal marked epidermotropism and folliculotropism accompanied by an eosinophil-rich inflammatory response an adnexal destruction. Multinucleated giant cells or xanthomization are rarely found. Unlike their normal cutaneous counterparts, pathological Langerhans cells do not have a dendritic morphology, but exhibit ample eosinophilic cytoplasm with a large indented reniform


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Figure 12 Histopathology of cutaneous mastocytoma. Nodular mast cell infiltrates in the dermis. (hematoxylin & eosin stain, magnification x200) (a). Basal hyperpigmentation of the overlying epidermis. Mast cells are positive for c-kit (CD117) (b).

Figure 11 Histopathology of Langerhans and non-Langerhans cell histiocytoses (juvenile xanthogranuloma). Dense epidermotropic dermal infiltrates of Langerhans cells with characteristic reniform nuclei in an infant with cutaneous Langerhans cell histiocytosis (hematoxylin & eosin stain, magnification x400) (a). Langerhans cells express CD1a (b). While the early stages of juvenile xanthogranuloma predominantly exhibit spindle-shaped CD68 and factor XIIIa-positive histiocytes and only few multinucleated giant cells (hematoxylin & eosin stain, magnification x200, x400) (c, d), fully developed lesions are distinctly xanthomatous (hematoxylin & eosin stain, magnification x400) (e, f).

nucleus (Figure 11a). Langerhans cells express S-100, CD1a (Figure 11b), and langerin. Electron microscopy reveals characteristic Birbeck granules in the cytoplasm. Given that Langerhans cell histiocytosis is caused by constitutive oncogenic activation of the MAPK signaling pathway, which in half of the cases is due to an activating BRAF V600E mutation [57, 58], targeted therapeutic strategies may possibly become a treatment option in the future [59].

Juvenile xanthogranuloma Juvenile xanthogranuloma is the most common type of non-Langerhans cell histiocytosis in the first year of life [60]. In case of multiple xanthogranulomas in the context of neurofibromatosis (NF1), the increased risk of juvenile chronic myeloid leukemia should be considered. Histology shows dense non-epidermotropic infiltrates consisting of primarily spindle-shaped histiocytes (Figure 11c, d). The typical lipidized cytoplasm, which imparts the characteristic yellow hue, and xanthomatous multinucleated giant cells (Touton giant cells) only become visible after a while (Figure 11e, f). Unlike Langerhans cell histiocytosis, juvenile xanthogranuloma is positive for CD163, CD68, CD4, HLA-DR, and factor XI-

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IIa, but in almost all cases negative for S-100 and CD1a, consistent with dermal dendrocytes or plasmacytoid monocytes as their postulated cell of origin [61, 62]. Other non-Langerhans cell histiocytosis, such as benign cephalic histiocytosis (of childhood), differ in terms of their clinical, but not their histological, findings.

Cutaneous mastocytosis More than 10–25 % of all cutaneous mastocytosis cases occur in the first two years of life, predominantly as solitary mastocytoma [63]. Unlike adult mastocytosis, cutaneous mast cell proliferations in childhood are mostly reactive in nature rather than the result of an activating mutation in the c-kit gene [64, 65]. Histological confirmation of the diagnosis is only necessary in cases presenting with an ambiguous clinical picture. Within the dermis dense nodular infiltrates of monomorphic polygonal mast cells with ample cytoplasm and intracytoplasmic metachromatic granules can be found (Figure 12a). In their non-degranulated state, mast cells can be detected using special stains such as Giemsa and naphthol AS-D chloroacetate esterase, or immunohistochemically with antibodies directed against the c-kit / CD117 surface antigen (Figure 12b). Marked basal hyperpigmentation of the epidermis is the histological correlate of the brown hue in mastocytoma. It is due to melanocytic activation by the stem cell factor (SCF) produced by mast cells.

Pilomatricoma Pilomatricoma is a benign adnexal tumor with differentiation towards matrical cells of the hair follicle. Depending on its duration, pilomatricoma is histologically characterized by a variable extent of monomorphic, basaloid cells in the periphery of the lobules. Analogous to matrical cornification, they turn into “shadow cells” and form central eosinophilic horn masses (Figure 13a, b). In longstanding tumors,



Figure 13 Histopathology of pilomatricoma. Basaloid proliferation with matrical cornification and areas of “shadow cells” surrounded by multinucleated giant cells (b) (hematoxylin & eosin stain, magnification x100 (a), x400 (b)).

granulomatous inflammation and calcification (former term: calcifying epithelioma) are common. Activating mutations in the WNT signaling pathway have been reported as the underlying molecular mechanism [66]. Immunohistochemistry also shows accumulated nuclear β-catenin in basaloid matrical cells [67]. Multiple pilomatricomas occurs sporadically, but also in association with disorders such as myotonic dystrophy (Curschmann Steinert), Gardner’s syndrome/adenomatosis polyposis coli, and Rubinstein-Taybi syndrome as well as chromosomal aberrations.

Figure 14 Histopathology of lipoblastoma. Lipoblastoma is a lobulated tumor of adipose tissue with broad fibrous septa (hematoxylin & eosin stain, magnification x100) (a) composed of variably sized monomorphic adipocytes with various degrees of differentiation within a myxoid matrix (b, c). There are few lipoblasts (arrows) (hematoxylin & eosin stain, magnification x400).

Occurring in the first years of life, lipoblastoma is a rare benign tumor of adipose tissue, which may show rapid growth, necessitating histological confirmation to rule out malignancy [68, 69]. Aberrant oncogenic activation of PLAG1 during fetal histogenesis, which is exclusively expressed in primitive mesenchymal cells such as lipoblasts and fibroblasts, but not in mature tissues of mesenchymal origin [70, 71], is considered to be the pathogenetically plausible molecular basis for this tumor [72]. This also explains why this tumor may already develop in utero, whereas adult onset lipoblastoma is not observed. Clinically and histologically, lipoblastoma is frequently misdiagnosed as lipoma [73], especially since lipoblastoma of longer duration exhibits increasing adipocytic maturation. Accordingly, characteristic histological features are often found only focally following careful screening of the tissue sample. Histology shows a lipomatous tumor made up of variably sized hypocellular lobules separated by broad, fibrotic septa (Figure 14a). There is pronounced myxoid stromal loosening with interspersed spindle cells without nuclear atypia (Figure 14b) [74]. Individual lipoblasts are present within the tumor (Figure 14c).

developing after trivial trauma, presents as a rapidly growing, erythematous, exophytic, superficially eroded tumor. As pyogenic granuloma generally causes recurrent hemorrhage and shows no tendency for spontaneous healing, surgical removal is advisable. Apart from trauma, hormonal factors as well as drugs, microbiological colonization with bacteria or viruses [76] that produce proangiogenic cytokines such as VEGF [77] seem to be particularly relevant in the pathogenesis of reactive vascular proliferation, similar to Bartonella henselae-induced bacillary angiomatosis [75]. Histology reveals a lobular capillary tumor surrounded by a lateral epidermal collaret (Figure 15a, b). A larger afferent vessel (feeder vessel) is frequently seen at the base. Unlike bacillary angiomatosis, bacteria and neutrophils are only present in juxtaepidermal areas underneath the ulceration. In the early stages of pyogenic granuloma, an edematous stroma with thin septa between mitotically active proliferating vessels is the dominant feature, whereas later stages are characterized by broad fibrosclerotic septa with involution of vascular lobules (Figure 15c). Vascular endothelia are monomorphic, rarely epithelioid. Unlike infantile hemangioma, there is a lack of Glut-1 expression [78], even in rare cases of congenital lobular capillary hemangioma. However, in contrast to vascular malformations, there is positivity for WT-1 [79].

Pyogenic granuloma

Summary

Pyogenic granuloma (lobular capillary hemangioma), a reactive vascular neoplasm of infancy and early childhood

Compared adults, there is hardly any difference in histopathological findings of neonatal and infantile dermatoses.

Lipoblastoma


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the German Society of Dermatology (DDG), which granted Dr. Marion Wobser a scholarship for dermatohistology. Correspondence to Marion Wobser, M.D. Department of Dermatology, Venereology and Allergology Würzburg University Hospital Josef-Schneider-Straße 2 97080 Würzburg Germany Figure 15 Histopathology of lobular capillary hemangioma (pyogenic granuloma). Early stages of pyogenic granuloma show an ulcerated polypoid tumor composed of numerous capillary blood vessels within an edematous stroma (a) (hematoxylin & eosin stain, magnification x100). A neutrophil-rich infiltrate is usually present (b) (hematoxylin & eosin stain, magnification x400). Later stages exhibit fibrosclerotic involution with only few vessels and a sparse inflammatory infiltrate. Note the central “feeder vessel” (hematoxylin & eosin stain, magnification x200) (c)

Nevertheless, some diseases, including infantile hemangioma, subcutaneous fat necrosis of the newborn, and lipoblastoma, exclusively occur in the first years of life. These disorders reflect the immaturity of the skin organ. Although the histological analysis of skin diseases is usually omitted in infancy in favor of noninvasive methods, it is nevertheless indispensable in special cases, particularly in the differential diagnostic algorithm to rule out malignancy. Two examples thereof are Langerhans cell histiocytosis versus reactive inflammatory infiltrates, and kaposiform hemangioendothelioma versus benign vascular tumors or vascular malformations.

Acknowledgments We would like to thank all those who provided us with histological samples, as well as all our colleagues in the Department of Dermatology, Venereology and Allergology of Würzburg University Hospital and the Institute of Pathology at the University of Würzburg, who were involved in the clinical care or histological analysis of the aforementioned cases. A special thanks goes to Dr. Sandrine Benoit and Dr. Hermann Kneitz (Department of Dermatology, Venereology and Allergology, Würzburg University Hospital). We also thank the German Foundation for Dermatology of

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E-mail: [email protected]

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Single-incision pediatric endosurgery in newborns and infants.

[Dermatohistopathology in pediatric skin diseases].

Cholelithiasis in newborns and infants.

Endoscopic surgical management of inspiratory stridor in newborns and infants.

Urinary testosterone glucuronide and sulphate in newborns and young infants.

Oxidative Stress Related Diseases in Newborns.

Proton pump inhibitor prescribing patterns in newborns and infants.

Devastating metabolic brain disorders of newborns and young infants.

Risk of Wheezing Attacks in Infants With Transient Tachypnea Newborns.

Chemokines and skin diseases.

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Loracarbef vs. cefaclor in pediatric skin and skin structure infections.

Periostin in skin tissue and skin-related diseases.

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Insulin resistance and skin diseases.

Letter: description of skin diseases and white skin.

Vitamin D3 and skin diseases.

The Role of the Skin Barrier in Occupational Skin Diseases.

Pediatric infectious diseases.

Drug-induced skin diseases.

[Terminology in the context of anesthesia for preterm and term newborns and infants].

Manipulation and brace fixing for the treatment of congenital clubfoot in newborns and infants.

Inter-society consensus document on treatment and prevention of bronchiolitis in newborns and infants.

Genetic pediatric retinal diseases.