SKIN TUMORS WITH APOCRINE DIFFERENTIATION

Moderators: Dr. B.Triveni ( Professor) Dr. N.Chary ( Associate Professor) Dr.N.Neelaveni(Assistant Professor) Dr.B.S.Chaithanya (PG)

TOPICS Introduction Classification of Appendageal Skin tumors Tumors with Apocrine Differentiation

INTRODUCTION
Introduction

History

Embryology

Histological classification

HISTORY
Time line 1880 1891 1892 1893 1956 1962 1980 Contribution by Malherbe Allaire Nasse Andrew Ross Robinson Hermann Pinkus Headington and French Lopansri and Mihm Contribution Describe pilomatricoma as calcifying tumor Reported Ocular sebeceous carcinoma First case of mixed cutaneous tumor Described Eccrine hidrocystoma First Described Eccrine Poroma First designated Trichilemmoma as a neoplasm of outer root sheath Designated the term pilomatrixoma carcinoma

EMBRYOLOGY

Component Epidermis Melanocytes Langerhans cells Merkel cells Dermis Hair follicles

Origin Surface ectoderm Neural crest cells in cranio-caudal direction Bone marrow Epithelial cell of early fetal epidermis Condensation and differentiation of the underlying mesenchyme derived from the dermatome of the somite's. Hair germs develop from basophilic cell of basal cell layer of the epidermis . Dermal hair papillae is derived from mesenchyme Middle bulge of ectodermal cells of hair follicle Upper bulge of hair follicles that are in the early bulbous peg stage . Basophilic cells in the basal layer of epidermis .

Sebaceous glands Apocrine glands Eccrine glands

HISTOPATHOLOGICAL CLASSIFICATION

1) Eccrine 2)Apocrine 3)Sebacous 4)Follicular 5)Mixed

ADNEXA

Adnexa structures accessory to a main organ in which they may be found. In the skin there are epithelial structures of adnexa (hair follicles, and sebaceous, eccrine and apocrine units) and non-epithelial structures of adnexa (blood vessels, nerves and muscles of hair erection). Skin appendages They are represented by three histologically distinct structures . 1) Pilosabeceous unit 2) Eccrine sweat glands 3) Apocrine glands

GLAND
What is a gland?

CLASSIFICATION OF GLANDS

CLASSIFICATION OF GLANDS

TYPES

TYPES

TYPES

CLASSIFICATION OF GLANDS ACCORDING TO MODE OF SECRETION

APOCRINE GLAND

HOLOCRINE

APOCRINE GLAND

Sebaceous and apocrine glands emanate from the primary follicle and reside within the adjacent dermis. Virtually, all follicles sport sebaceous glands, whereas apocrine glands usually involute at most body sites, remaining detectable in genital and axillary sites, in periorbital and periauricular skin, and sometimes in skin of the scalp.

APOCRINE GLAND

In areas in which apocrine glands are preserved, the apocrine duct juts from the lower infundibulum just superior to the insertion of the sebaceous duct and spirals downward to join the secretory portion of the apocrine gland, which is situated in the deep reticular dermis and subjacent subcutis. The secretory elements are arranged as tubules lined by cuboidal and columnar cells with ample eosinophilic cytoplasm that often appears finely granular in conventional sections. At the luminal border, a papillated or decapitation pattern is often present, reflecting holocrine secretion.

CLASSIFICATION OF SKIN TUMORS

WHO classification of skin tumors
1) Keratinocytic tumours 2) Melanocytic tumours 3) Appendageal tumours 4) Haematolymphoid tumours 5) Soft tissue tumours 6) Neural tumours 7) Inherited tumour syndromes

MALIGNANT TUMORS

GENERAL FEATURES

The histopathological classification of apendegeal tumors may be classical or it may be mixed as the tumors arise from primitive cell and the degree of differentaition depends upon 1) molecular pathways 2) Microenvironment 3)The degree of vascular supply Site specific tumors are Extremities 1) Papillary digital adenocarcinoma 2) Papillary eccrine adenoma

GENERAL FEATURES

Axillae Apocrine carcinoma Vulva and perineum Hidradenoma papilliferum Extramammary pagets disease Ductco papillary apocrine carcinoma.

GENERAL FEATURES

Tumors showing potential multiplicity 1) Cylindroma 2) Syringoma 3) Poroma 4) Trichoepithelioma 5) Trichilemmoma (Cowdens syndrome 6) 6) sabeceous tumor (Muir-Torre syndrome )

GENERAL FEATURES

Child hood tumors Syringoma Syringocystadenoma papilliferum Poroma Cylindroma Pilomatrixoma Trichoepithelioma

GENERAL FEATURES

Clues to eccrine tumor Ductal or Tubular differentaition Tubules not line by corneocytes in crenulate pattern ( sabeceous ducts ) Not lined by cells with decapitation secretion

GENERAL FEATURES

BENIGN NEOPLASMS

Hidrocystoma
Definition Hidrocystomas are cystic proliferations of the sweat glands. They have either apocrine or eccrine differentiation, with the majority being of apocrine nature.
Apocrine hidrocystomas are cystic adenomas that arise from the apocrine secretory coil, while eccrine hidrocystomas represent retention cysts of the eccrine cyst duct.

BENIGN TUMORS

Synonyms apocrine gland cyst, papillary apocrine gland cyst , apocrine cystadenoma . Epidemiology Extremely rare 1:1000 skin biopsies submitted. Hidrocystomas usually affect middle-aged.

Localization Hidrocystomas have a predilection for the face and neck, mainly the periorbital area, but may also affect other parts of the body such as the perineum.

BENIGN TUMORS

Clinical features Hidrocystomas present as domeshaped, cystic firm papules or nodules, with a slightly blue colouration. In some cases the content of the cyst is brown or black. Etiology The exact cause of hidrocystomas is not known. They have been reported to be exacerbated with high temperatures and to completely disappear with cold weather and atropine therapy . There is an increased incidence of hidrocystomas in hyperthyroid patients, perhaps related to hyperhidrosis.

BENIGN TUMORS

BENIGN TUMORS

Macroscopy The lesions are of variable size ranging from 0.5-1.0 cm, although lesions of up to 7.0 cm have been reported. Hidrocystomas are usually located in the dermis, but in some cases they may be present in the subcutaneous fat. The cut surface reveals a well-circumscribed, unilocular or multilocular cyst. Histopathology Hidrocystomas can be uni or multilocular and are usually lined by a double layer of epithelium. The inner layer contains large columnar cells with eosinophilic cytoplasm which has luminal decapitation secretion, while the outer layer is flat and composed of myoepithelial cells. The term papillary apocrine gland cyst has been applied for hidrocystomas with papillary projections of epithelium into the lumen .

BENIGN TUMORS

Immunoprofile -Hidrocystomas express epithelial membrane antigen (EMA) -carcinoembryonic antigen (CEA) decorates the luminal cells -There is expression of cytokeratins 7,8,18,19 in the luminal cell layer and cytokeratins 1,5,10,14 in the basal and luminal cell layers. S-100 protein is positive in the secretory portion of normal eccrine glands and in the myoepithelial cells of apocrine glands. Prognosis and predictive factors Complete excision is usually curative. Topical atropine or scopolamine has also been used.

BENING TUMORS

Hidradenoma
Definition Hidradenoma is a benign adnexal neoplasm, closely related to poroma, that displays a limited degree of ductal differentiation. While historically considered eccrine, recent evidence suggests that hidradenoma can be either apocrine or eccrine. Synonyms Clear cell hidradenoma, nodular hidradenoma, poroid hidradenoma, acrospiroma, solid-cystic hidradenoma Epidemiology Hidradenomas are sporadic with no sex predilection. Most develop in adults

BENIGN TUMORS

Localization Hidradenomas commonly develop on the scalp, trunk, and proximal extremities, and rarely on the hands and feet. Eyelid lesions have also been noted. Clinical features Hidradenomas lack any distinctive clinical features, presenting as skin-coloured to red-brown nodules.

Histopathology Hidradenoma is a mostly dermal neoplasm with a nodular, circumscribed pattern at scanning magnification. Sometimes an epidermal attachment can be identified. The intervening stroma is often sclerotic and may be highly vascularized with ectatic vascular channels. Hidradenoma is composed of several types of cells: Clear or pale cells, which contain abundant glycogen, and show distinct cell membranes . The number of clear cells varies from lesion to lesion. When these cells predominate, the name clear cell hidradenoma is appropriate.

BENIGN TUMORS

Squamoid cells are polygonal with a central vesicular nucleus and eosinophilic cytoplasm, and often are arranged in whorls . Mucinous cells are the least common component. They are large cells with fine basophilic granular cytoplasm. Cuboidal or columnar cells line the tubules and show evidence of apocrine differentiation . Transition between different types of cells is frequent. The cells are arranged in sheets, punctuated by ducts and glandular areas which may show apocrine differentiation. Hybrid lesions including compact poroid cells with prominent ductal differentiation have been referred to as poroid hidradenomas.

BENIGN TUMORS

BENIGN TUMORS

Prognosis Complete excision is curative.

Hidradenoma papilliferum
Definition Hidradenoma papilliferum is a benign cystic and papillary neoplasm that almost always develops in the vulval andperianal regions of middle-aged women. Epidemiology The age of presentation ranges from 20-90 years. Localization The skin of the vulva and perianal regions are the most frequently involved areas.

BENIGN TUMORS

Clinical features

The lesion appears as a slow-growing cystic dermal nodule, usually asymptomatic,although it sometimes ulceratesand bleeds. The neoplasm is a unilateralskin-coloured nodule, papule or polypoid exophytic lesion, most commonly locatedon the labius majus.

BENIGN TUMORS

Histopathology At scanning magnification, hidradenoma papilliferum consists of a cystic neoplasm composed of elongated tubules and large papillary structures with a frond-like pattern. The papillae are composed of a central axis of connective tissue lined by two layers of epithelial cells. The basal layer is composed of pale staining cuboidal myoepithelial cells and the luminal layer is made up by columnar cells with decapitation secretion. The cystic cavity and the lumina of the tubular structures contain apocrine secretions in the form of eosinophilic homogeneous material.

BENIGN TUMORS

Histopathology The stroma surrounding the cystic cavity is composed of compressed fibrous tissue that is separated from the normal adjacent dermis by clefts. These clefts are responsible for the tendency of the neoplasm to shell out easily after incision of the epidermis. In contrast with syringocystadenoma papilliferum, hidradenoma papilliferum is not connected with follicular infundibulum and there are not plasma cells in the axis of connective tissue of the papillations. Sometimes, neutrophils are scattered within the connective tissue framework.

BENIGN TUMORS

Immunoprofile
Immunohistochemical studies demonstrated that epithelial cells lining the papillations express low-molecular weight cytokeratins.
The luminal border of the cells lining tubular structures is also decorated by carcinoembryonic antigen, epithelial membrane antigen and gross cystic disease fluid protein-15. Immunostains for S-100 protein and high-molecular-weight keratins are negative. Neoplastic epithelial cells lining tubules and papillations also express strong immunoreactivity for androgen and oestrogen receptors.

BENIGN TUMORS

Prognosis and predictive features Hidradenoma papilliferum is a benign neoplasm cured by simple excision.

Syringocystadenoma papilliferum
Definition Syringocystadenoma papilliferum is a benign adnexal neoplasm that occurs in association with an organoid naevus such as naevus sebaceous in at least one-third of cases.

BENIGN TUMORS

Epidemiology Syringocystadenoma papilliferum occurs with equal frequency in both sexes. It is a tumour of childhood or adolescence. Clinical features The majority of syringocystadenomas affect the head and neck area, typically as one or more warty papules, sometimes in a linear array, or as a solitary grey or red plaque. Scalp and neck are favoured sites; those on the scalp are typically alopecic.

BENIGN TUMORS

Histopathology

Histologically, endophytic invaginations of epithelium extend from the epithelial surface into the dermis. Typically squamous epithelium is present at the surface of the invaginations, and is contiguous with a double layer of cuboidal and columnar epithelium in the deeper portions of the lesion. Within the dermis, broad villous projections protrude into cystic spaces. Columnar epithelium is present toward the lumen of the spaces and simple cuboidal epithelium can be seen at the periphery. Decapitation secretion of luminal cells is a frequent finding. Plasma cells are consistently numerous within the stroma, and are a highly reproducible finding in the stroma of syringocystadenomas.

BENIGN TUMORS

Syringocystadenoma papilliferum

hidradenoma papilliferum,

Syringocystadenoma papilliferum is a almost always develops in the vulval benign adnexal neoplasm that occurs in and perianal regions of middle-aged association with an organoid naevus women. such as naevus sebaceous, It is a tumour of childhood or adolescence. The majority of syringocystadenomas affect the head and neck area. The papillary stroma contains plasma cells hidradenoma papilliferum is not connected with follicular infundibula and there are not plasma cells in the axis of connective tissue of the papillations.

BENIGN TUMORS

Histogenesis Syringocystadenomas show differentiation that is predominantly apocrine in pattern, but eccrine origin has been suggeste in some cases, as exemplified by immunohistochemical labelling with eccrine marker IKH-4. Prognosis and predictive factors Syringocystadenonas are benign and simple excision is curativ e.

BENIGN TUMORS

Tubular and tubular papillary adenoma

Definition Tubular apocrine adenoma is a benign dermal adnexal neoplasm demonstrating apocrine differentiation that typically occurs in a broad age group of women on the scalp region. Synonyms Apocrine adenoma, tubular adenoma, tubulopapillary hidradenoma, papillary tubular adenoma. Epidemiology Tubular apocrine adenomas occur sporadically with a female predilection . A broad age group may be affected.

BENIGN TUMORS

Localization Tubular apocrine adenomas commonly occur on the scalp and less often at other sites including the leg, trunk, axillary and anogenital areas . Clinical features Tubular apocrine adenomas present as asymptomatic solitary nodules that are skin-coloured to pink-red in appearance with either a smooth or irregular appearance . Most tumours range in overall dimension between 1 to 2 cm.

BENIGN TUMORS

Histopathology Tubular apocrine adenomas are well-circumscribed dermal neoplasms that may extend into the subcutis. They have an overall lobular architecture and are typically encased by a fibrous stroma. The lobules consist of multiple irregularly shaped tubular structures that have a double to several layered epithelial lining. The peripheral epithelial layer consists of cuboidal to flattened cells (myoepithelial) and the luminal layer of columnar cells that demonstrate decapitation secretion. In some tubules papillary cellular extensions that are devoid of stroma project into the lumina. Additionally, cellular debris and eosinophilic granular material are identified within some lumina . The neoplasm lacks cytologic atypia and mitotic activity. Overlying epidermal hyperplasia may be present.

BENIGN TUMORS

The differential diagnosis includes apocrine adenocarcinoma and papillary eccrine adenoma. In contrast to apocrine adenocarcinoma tubular apocrine adenomas lack cytologic atypia, are well circumscribed and possess a peripheral myoepithelial layer . Tubular apocrine adenomas resemble papillary eccrine adenomas in many respects and previously these were believed to be related neoplasms . However on the basis of morphologic criteria (papillary eccrine adenomas lack decapitation secretion) and enzyme histochemistry and ultrastructural analysis demonstrating differences in differentiation (apocrine versus eccrine) they are now believed to represent distinct neoplasms.

BENIGN TUMORS

Prognosis Tubular apocrine adenomas are benign slow-growing neoplasms. Simple excision is curative. Cylindroma Definition Cylindroma is a relatively undifferentiated benign adnexal neoplasm with a mosaic microscopical pattern. Cylindroma commonly occurs as a hybrid with spiradenoma, an event that has been referred to as cylindrospiradenoma or spiradenocylindroma

BENIGN TUMORS

Etiology The etiology is unknown. A link to chromosome 9 seems likely for multiple spiradenomas and cylindromas in the context of the Brooke-Spiegler syndrome, as the gene has been mapped to 9p21. Localization The vast majority of cylindromas occur on the scalp or face, especially in the vicinity of the ear. Clinical features Cylindromas are typically smooth, domeshaped hairless redbrown papules and nodules. Extensive scalp involvement can create clinical morphology resembling a headpiece (turban tumour).

Histopathology Cylindroma is a mostly dermal and sometimes subcutaneous neoplasm with a multinodular, circumscribed pattern at scanning magnification. Individual nodules are composed of mosaic nests of undifferentiated basaloid cells with small darkly-staining nuclei and scant cytoplasm; individual nests fit tightly and neatly within larger nodules in a pattern that has been likened to that of a jigsaw puzzle. The nests of cylindroma are commonly surrounded by a rim of densely eosinophilic PAS-positive basement membrane material, and the nests are also punctuated by small round droplets with similar staining qualities.

BENIGN NEOPLASMA

Prognosis and predictive factors Simple excision is usually curative. Malignant transformation is extremely uncommon.

Erosive adenomatosis of the nipple Erosive adenomatosis of the nipple (EAN) is a rare disease caused by a complex proliferation of the lactiferous ducts that affects primarily middle-aged women. It can be confused clinically with Pagets disease and histologically with malignant mammary neoplasia and sweat gland tumors.

BENIGN LESIONS

Clincal features a nodular, erythematous, friable lesion affecting the whole nipple with superficial ulceration and crusting in places . clinical axillary lymph node examination was negative.

BENIGN LESIONS

BENIGN TUMORS

Histological examination is fundamental for a diagnosis. Histologically, the lesion is characterized by intraductal proliferation invading the adjacent stroma. The most striking characteristic is the presence of two cell populations: an internal layer of cuboidal epithelial cells with an apocrine secretion and an external layer of contractile myoepithelial cells. erosion and ulceration may be present in 50% of cases, and keratin cysts in less than 50%. There are many differential diagnoses for EAN, including inflammatory, infectious and neoplastic diseases. Clinically, the most important differential diagnosis is with Pagets disease, while histologically it is with malignant mammary neoplasms and tumors of the apocrine glands.

BENIGN TUMORS

MALIGNANT TUMORS

Apocrine carcinoma Definition Apocrine carcinoma (AC) is a malignant sweat gland neoplasm with apocrine differentiation. Synonyms Apocrine adenocarcinoma, apocrine gland carcinoma Epidemiology AC is a rare tumour. Both genders are almost equally affected, and there appears to be no racial predilection.

MALIGNANT TUMORS

Localization Most AC arise in the axilla and, to a lesser extent, in the anogenital region. Rare locations include the scalp, face, chest, and distal upper extremities. Clinical features Most tumours are solitary, but a patient with bilatelal axillary AC has been reported. AC presents as single or multiple, firm or cystic nodules with a reddish or purplish hue of the ovelying skin, sizing between 1.5 and 8 cm . Ulceration and haemorrhage may be present. The patients age at presentation ranges from 25 to 91 years, with an average age of 57.9 years

MALIGNANT TUMORS

Histopathology AC is typically centred on the deeper dermis and tends to spread into the subcutaneous fatty tissue . Extension into the epidermis also occurs, occasionally in the form of extramammary Paget disease . The tumours are usually poorly circumscribed with infiltrating borders. Neighbouring apocrine glands occasionally show in situ carcinoma. The growth patterns of AC are highly variable, including tubular papillary, cystic, cribriform, micronodular, and solid formations .

MALIGNANT TUMORS

The cells have abundant eosinophilic cytoplasm and large, round to oval, mostly vesicular nuclei that often contain a single prominent eosinophilic nucleolus. Intacytoplasmic PAS-positive diastase- resistant granules are characteristic, and intracytoplasmic iron is sometimes demonstrable . A key diagnostic criterion, decapitation secretion in the form of apical snouts is usually recognizable but may be lacking in poorly differentiated tumours. There is variable mitotic activity, ranging from single mitotic figures in well differentiated tumours and up to 4 mitotic figures per high power field in poorly differentiated carcinomas .

MALIGNANT TUMORS

Immunoprofile The cells of AC express low molecular weight cytokeratin (CAM5.2), epithelial membrane antigen, carcinoembryonic antigen, cytokeratin15, gross cystic disease fluid protein (GCDFP)-15 and occasionally S-100 protein . Myoepithelial cells, detectable by SMA or CK 5/6 immunostaining, are typically absent .

MALIGNANT TUMORS

Differential diagnosis The main differential diagnosis is with (tubular) apocrine adenoma, and the histologic features that distiguish these two conditions are often subtle. Whilst vascular and neural invasion are diagnostic of carcinoma, stromal invasion is less so and may be difficult to ascertain. Tumour silhouette, cellular pleomorphism and mitotic activity may provide clues to malignancy. Prognosis and predictive factors The majority of AC are slow growing tumours with a tendency toward a prolonged course. The overall mortality is low, despite frequent recurrences (30%) and metastases to regional lymph nodes (50%) .

MALIGNANT TUMORS

Extra mammary pagets disease Pagets disease of the breast, and in particular of the nipple, the socalled mammary Pagets disease, was held to derive from neoplastic transformation of the breast ductal system with secondary extension to the skin. In contrast, extramammary Pagets disease was thought to represent a neoplasm arising in the germinative cells of the basal layer of the epidermis. Both processes were held to manifest apocrine differentiation, but both were held to have different paths of lesional development.

MALIGNANT TUMORS

Clinical Features Irrespective of anatomic location, tumors present as erythematous plaques with a scaling or exudative surface. Pagets disease of the breast involves women who most often have an underlying ductal carcinoma and, as one might expect, presentations are typically greater than 40 years of age. Extramammary Pagets disease occurs with an almost equal sex distribution and appears to be concentrated in anatomical sites where apocrine glands manifest greatest density, that is, the vulva, scrotum, perineum, axillae, perineal region, eyelids and the ear canals.

MALIGNANT TUMORS

Histopathologic Features
In Pagets disease, the epidermis manifests a proliferation of single and clustered neoplastic cells showing evidence of glandular differentiation. The nuclei are round to oval with prominent nucleoli and dispersed chromatin; typically, the nuclear diameters are up to double those of adjacent keratinocyte nuclei. The glandular differentiation takes the form of intracytoplastic lumina manifesting a basophilic cytoplasmic hue, sometimes with a sharply demarcated intracytoplasmic cuticle. The glandular epithelia may also cluster together to form common luminal margins . On occasion, the cytoplasm shows fine vacuolation. For reasons not understood, the neoplastic glandular cells in Pagets disease often spare the basal layer of the epidermis and appear to compress it from above . As the neoplastic cells have less well defined intercellular bridges than keratinocytes, they form loosely cohesive groups in a fashion that may mimic an acantholytic process.

MALIGNANT TUMORS

Differential diagnosis
Neoplasms that show pagetoid migration of malignant epithelia include clonal Bowens disease, sebaceous carcinoma and melanomas, particularly of superficial spreading type. With respect to superficial spreading melanoma, the presence of melanin granules in the cytoplasms of the neoplastic cells is an important clue to diagnosis, but we have seen cases of pigmented Pagets disease and pigmented Bowens disease containing melanin granules provided by nurse melanocytes to the neoplastic cells. Thus, one must fall back upon immunohistochemical methods to delineate these lesions. Melanomas express melanocyte lineagespecific markers such as HMB-45 and Melan-A, vs the expression of GCDFP-15, CK 7 and CEA in Pagets disease. Bowens disease, in contrast, will express high-molecular-weight CK but not CK7,

MIXED DIFFERENTIATION

The tumors showing mixed differntiation are 1) Poroma 2) Malignant mixed tumour

REFERNCES

Dermatopathology by lever 10th edition WHO manual of skin tumors Text book of histology wheters .

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