Papillary hidradenoma
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A papillary hidradenoma, also termed hidradenoma papilliferum or mammary-like gland adenoma of the vulva, is a rare, but nonetheless most common benign tumor that occurs in and between anal and genital regions (i.e. anogenital area) of females. These hidradenomas are sharply circumscribed, nodular tumors that usually develop in women's anogenital area (particularly the
vulva The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external sex organ, female sex organs. The vulva includes the mons pubis (or mons veneris), labia majora, labia minora, clitoris, bulb of vestibu ...
) but uncommonly occur in other sites in women and men. Papillary hidradenomas that develop outside of the anogenital region are termed ecctopic papillary hidradenomas or ectopic hidradenoma papilliferums. Anogenital papillary hidradenomas are regarded as tumors that form in anogenital mammary–like glands (MLAGs); MLAGs are a type of
apocrine gland Apocrine () glands are a type of exocrine gland, which are themselves a type of gland, i.e. a group of cells specialized for the release of secretions. Exocrine glands secrete by one of three means: holocrine, merocrine and apocrine. In apocrine ...
. MLAGs were once classified as abnormally located breast tissue glands (see accessory breast tissue@ https://doi.org/10.53347/rID-11125) but are now considered to be normal components of the anogenital region. Microscopically, papillary hidradenomas often resemble certain types of breast tumors. Ectopic papillary hidradenomas are thought to be tumors of apocrine glands which have an as yet unclear relationship to MLAGs. Typically, papillary hidradenomas are solitary, slow-growing, small tumors that may have been present for months to many years before the time of diagnosis. The tumors are usually symptomless but may be intermittently or constantly painful, become ulcerated, and exhibit minor levels of bleeding. The pain resulting from these tumors may be simple tenderness, more or less constant usually mild pain, or, in females,
dyspareunia Dyspareunia ( ) is painful sexual intercourse due to medical or psychological causes. The term ''dyspareunia'' covers both female dyspareunia and male dyspareunia, but many discussions that use the term without further specification concern the f ...
, i.e. pain during and just after sexual intercourse. Rarely, papillary hidradenomas have progressed to what appear to be 1) ''in situ'' malignancies (i.e. malignancies that have neither metastasized nor invaded beyond the layer of tissue where they arose); 2) locally invasive malignancies; or 3) complex tumors intermixed with other malignancies such as extramammary Paget disease,
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
, and
squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
. Furthermore, benign papillary hidradenoma tumors may be confused clinically with cancerous tumorsRobbins and Cotran Pathologic Basis of Disease, 7th edition. ''The Female Genital Tract'' chapter 22, pg. 1067. and recent studies have indicated that other types of tumors have often been mistakenly diagnosed as papillary hidradenomas. Papillary hidradenomas, particularly ectopic papillary hidradenomas, require further study to better define the criteria for their diagnosis.


Presentation

In a review of 264 women diagnosed with anogenital papillary hidradenomas, patients ranged in age from 25 to 82 years (median: 49 years); in 25 cases where the information was available, the tumors had been present for 2–120 months (median: 12 months) with 13 patients reporting their tumor's presence for less than 1 year before diagnosis. All patients had a solitary tumor in the anogenital area except for one patient who presented with four clustered tumors. Most tumors involved the vulva (71.6%) and areas around the
anus The anus (Latin, 'ring' or 'circle') is an opening at the opposite end of an animal's digestive tract from the mouth. Its function is to control the expulsion of feces, the residual semi-solid waste that remains after food digestion, which, d ...
(14%) or space between the anus and vulva, i.e. the perineum (3.8%). Their lesions ranged in size from 0.2 to 2 centimeters (cm.) in largest dimension (median: 0.7 cm.). Smaller studies on one or a few females with anogenital papillary hidradenomas found that the tumors commonly presented as asymptomatic, well-confined, skin-colored, red, or bluish nodules in women of Caucasian origin between the ages of 25–66 years. The nodules were solid or cystic; 0.4 to 2.5 cm. in widest dimension; and usually located in the grooves (termed interlabial sulci or interlabial folds) between the labia majora and labia minora, the
clitoris The clitoris ( or ) is a female sex organ present in mammals, ostriches and a limited number of other animals. In humans, the visible portion – the glans – is at the front junction of the labia minora (inner lips), above the ope ...
, or the region between the vulva and anus (i.e. Frenulum of labia minora). Ectopic papillary hidradenomas in women have been reported to occur on the scalp, eyelid, cheek, forehead, face,
ear canal The ear canal (external acoustic meatus, external auditory meatus, EAM) is a pathway running from the outer ear to the middle ear. The adult human ear canal extends from the pinna to the eardrum and is about in length and in diameter. Struc ...
, and back. Nearly 50% of ectopic papillary hidradenoma have been diagnosed in men; these have occurred on the thigh, arm, armpit, face and eyelid. While usually symptomless, patients may complain that the tumor is ulcerated, bleeds, or is painful. This pain may be simple tenderness, more or less constant but usually mild, or, in females with anogenital lesions, dyspareunia. The rare cases of ectopic papillary hidradenoma in the external auditory canal have presented with unilateral conductive hearing loss sometimes associated with ear pain, drainage of ear fluid, or weakness of a facial muscle(s).


Histopathology

Microscopic
histopathological Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...
analyses of papillary hidradenoma tumors typically reveal a nodule in the
dermis The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided i ...
, i.e. layer of skin between the
epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...
and
subcutaneous tissue The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and macr ...
. The tumor consists of complex patterns of interconnecting tubular and papillary (i.e. thin finger-like or frond-like) structures. These structures are lined with glandular epithelial and myoepithelial cells. The glandular epithelial cells appear to be excessively proliferating in the ducts leading to the epidermis and show oxyphilic changes, (i.e.
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
filled with large
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
,
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...
, and
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
s) while the myoepithelial cells often appear
clear cell In histology, a clear cell is a cell that shows a clear cytoplasm when stained with hematoxylin and eosin (H&E). Normal histology In the skin, some secretory cells in the epithelium appear as clear cells, and are one of the components of eccri ...
-like, i.e. have uncolored
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
when stained with
hematoxylin and eosin Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin-eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnos ...
. The histopathology of anogenital and ectopic papillary hidradenomas are similar to each other. Image: Papillary hidradenoma - intermed mag.jpg , Intermediate magnification Image: Papillary hidradenoma - very high mag.jpg , Very high magnification


Immunohistochemistry

Immunohistochemical analyses of anogenital papillary hidradenoma tumors have detected the expression of both the
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
and
progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resid ...
s in 18 and the
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
in 4 of 20 cases. In another study of anogenital papillary hidradenomas, expression of the estrogen receptor was restricted to the tumors' glandular epithelial cells while the tumors' myoepithelial cells expressed tumor protein p63 and alpha-smooth muscle actin protein. Presence of the estrogen and progesterone receptors may underlie the female prevalence of anogenital papillary hidradenomas as well as their development in females only after
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
. The anogenital tumor cells may also express
vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a type III intermediate filament (IF) protein that is expressed ...
, various cytokeratin proteins, and in a minority of cases the DNA of
human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
(infection by this virus and the presence of its DNA does not appear involved in the development of papillary hidradenoma). These immunohistochemistry findings have not as yet been reported in atypical papillary hidradenomas.


Gene and signaling pathway abnormalities

Several studies have reported the presence in anogenital papillary hidradenoma tumor cells of mutations in one or multiple genes that lead to the production of proteins that directly or indirectly stimulate the PI3K/AKT/mTOR intracellular signaling pathway. The mutated genes include '' PIK3CA, AKT1, PIK3CA,
MAGI1 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 is an enzyme that in humans is encoded by the ''MAGI1'' gene. Function The protein encoded by this gene is a member of the membrane-associated guanylate kinase homolog ...
,
SYNE1 Enaptin also known as nesprin-1 or synaptic nuclear envelope protein 1 (syne-1) is an actin-binding protein that in humans that is encoded by the SYNE1 gene. Function This gene encodes a spectrin repeat containing protein expressed in skeletal ...
, USP9X, KLNI'' (also termed ''CASC5''), ''
RNF213 Ring finger protein 213 is a protein that in humans is encoded by the ''RNF213'' gene. RNF213 is a 591kDa cytosolic E3 Ubiquitin-ligase with RING finger and AAA+ ATPase domains. Clinical relevance Chromosome-wide linkage analysis found that moya ...
, FLCN, PDGFRB, AR'' (i.e. the androgen receptor gene), '' BTK,
MLL3 Lysine N-methyltransferase 2C (KMT2C) also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) is an enzyme that in humans is encoded by the ''KMT2C'' gene. Function This gene is a member of the myeloid/lymphoid or mixed-linea ...
, KAT6A,
BRD3 Bromodomain-containing protein 3 (BRD3) also known as RING3-like protein (RING3L) is a protein that in humans is encoded by the BRD3 gene. This gene was identified based on its homology to the gene encoding the RING3 (BRD2) protein, a serine/threo ...
,
EP400 E1A-binding protein p400 is a protein that in humans is encoded by the ''EP400'' gene. Interactions EP400 has been shown to interact with Transformation/transcription domain-associated protein, RuvB-like 1 and Myc ''Myc'' is a family of reg ...
,
TET2 Tet methylcytosine dioxygenase 2 (''TET2'') is a human gene. It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Function ' ...
, IL6,'' and ''
IL7R The interleukin-7 receptor is a protein found on the surface of cells. It is made up of two different smaller protein chains - i.e. it is a heterodimer, and consists of two subunits, interleukin-7 receptor-α (CD127) and common-γ chain recep ...
.'' The PI3K/AKT/mTOR pathway promotes the grow (i.e. proliferation) and survival of cells and is abnormally activated in, and appears to contribute to the development and or progression of, a wide range of tumors. While further studies are needed, these findings suggest that the cited mutations lead to stimulation of the PI3K/AKT/mTOR pathway and thereby promote the development and/or progression of anogenital papillary hidradenoma in the majority of cases. These abnormalities have not yet been reported in ectopic papillary hidradenomas.


Diagnosis

The diagnosis of anogenital papillary hidradenoma lesions, while often suggested based on their clinical presentations, must be differentiated from a wide range of other similarly presenting anogenital lesions such as hemorrhoidal disease,
anorectal abscess Anorectal abscess (also known as an anal/rectal abscess, or perianal/perirectal abscess) is an abscess adjacent to the anus. Most cases of perianal abscesses are sporadic, though there are certain situations which elevate the risk for developin ...
es, virus-related wart-like lesions,
sebaceous cyst A sebaceous cyst is a term commonly used to refer to either: * Epidermoid cysts (also termed epidermal cysts, infundibular cyst) * Pilar cysts (also termed trichelemmal cysts, isthmus-catagen cysts) Both of the above types of cysts contain kera ...
s, mucous cysts, lipomas, neurofibromas, metastatic carcinomas with papillary histopathology, syringocystoadenocarcinoma papilliferum (i.e. malignant syringocystadenoma papilliferum), syringocystadenoma papilliferum,
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
s, eccrine porocarcinomas,
squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
s, nodular lesions in extramammary Paget disease,
dermatofibroma A dermatofibroma, or benign fibrous histiocytomas, is a benign nodule in the skin, typically on the legs, elbows or chest of an adult. It is usually painless. It usually ranges from 0.2cm to 2cm in size but larger examples have been reported. It ...
, focal areas of mucinosis, colloid milium, and
sebaceous adenoma A sebaceous adenoma, a type of adenoma, a cutaneous condition characterized by a slow-growing tumor usually presenting as a pink, flesh-coloured, or yellow papule or nodule. James et al. 2006 Rapini et al. 2007 Significance Sebaceous adenomas, ...
s. This differentiation is made by finding that a lesion has the histopathological features typical of papillary hidradenomas. However, some cases diagnosed as ectopic papillary hidradenomas, particularly those occurring in men, have subsequently been found to be syringocystadenoma papilliferums or
trichoepithelioma Trichoepithelioma is a neoplasm of the adnexa of the skin. Its appearance is similar to basal cell carcinoma. One form has been mapped to chromosome 9p21. Types Trichoepitheliomas may be divided into the following types: :* Multiple familial ...
s. Further studies are required to better define the criteria for ectopic papillary hidradenomas.


Treatment and prognosis

The treatment of choice for anogenital and ectopic papillary hidradenomas, regardless of their locations, is similar: resection of the tumor while preserving the surrounding structures. Recurrence of these tumors is rare and usually due to incomplete removal of the primary lesion. As of 2021, there has been no reported recurrence of ectopic papillary hidradenomas. Prognosis after complete surgical removal of anogenital and ectopic papillary hidradenomas is excellent.


Malignant transformation of papillary hidradenomas

Transformations of papillary hidradenomas into malignant forms are extremely rare. Two cases progressed to ''in situ'' (malignant cells present in the tumor but have neither
metastasized Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
, i.e. spread to distant tissues nor invaded beyond the layer of tissue from where they arose) cancers; two cases appeared to have infiltrated locally but not metastasized; and one case was a rapidly fatal lesion that appeared to be an
adenosquamous carcinoma Adenosquamous carcinoma is a type of cancer that contains two types of cells: squamous cells (thin, flat cells that line certain organs) and gland-like cells. It has been associated with more aggressive characteristics when compared to adenocarcino ...
that arose in a papillary hidradenoma. It is not clear that these cases actually represent true progression of papillary hidradenoma into a
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.


See also

* Hidroacanthoma simplex *
List of cutaneous conditions Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the body and composed of skin, hair, nails, and related muscle and glands. The major function of this system is as a barrier against t ...


References


External links

{{DEFAULTSORT:Papillary Hidradenoma Gynaecologic disorders Epidermal nevi, neoplasms, and cysts