Adnexal Carcinoma
Adnexal carcinomas are a diverse
group of malignant skin tumors that are derived from the various
components of the skin appendageal structures. These tumors are
extremely rare and comprise well less than 1% of all skin cancers
diagnosed annually. They are difficult to diagnosis clinically because
they can all mimic the more common types of skin cancer, particularly
basal cell carcinoma and squamous cell carcinoma. They can be diagnosed
with certainty only after histological examination. These tumors are
believed to be derived from hair follicle, sebaceous gland, apocrine
gland, or eccrine gland epithelium. They are thought to arise de novo
and can also arise from a preexisting benign precursor. An example is an
eccrine porocarcinoma developing within an eccrine poroma.
Clinical Findings:
These tumors are very rare, and one is unlikely
to consider them in the differential diagnosis when evaluating an
individual with an undiagnosed skin growth. There are few clues to their
origin, which makes diagnosis of these cancerous tumors almost
impossible based on clinical findings alone. Most manifest as a solitary
papule, plaque, or dermal nodule. Most are asymptomatic, but pruritus,
bleeding, and pain may be present.
The diagnosis of these tumors requires
tissue sampling. A punch or excisional biopsy is the best method to
biopsy these lesions, because it allows the pathologist to get a large
enough piece of tissue to evaluate. A punch biopsy is especially
important to help differentiate microcystic adnexal carcinoma from a
benign syringoma. The latter is very superficial in nature, whereas the
microcystic adnexal carcinoma displays a deep infiltrative growth
pattern that will not be appreciated with a superficial shave biopsy.
Pathogenesis:
The pathogenesis of these tumors is poorly
understood. In contrast to basal and squamous cell carcinomas, they are
unlikely to be caused by ultraviolet light exposure. The rarity of the
tumors makes them difficult to study. There appears to be no genetic
inheritance to these malignant tumors, with the lone exception of the
sebaceous carcinoma. Sebaceous carcinoma can be seen in the Muir-Torre
syndrome, which is inherited in an autosomal dominant pattern.
Histology:
Each tumor is unique histologically. The tumors
can be subdivided according to the type of epithelium from which they
are derived: sebaceous, hair follicle, eccrine, or apocrine. The
pathologist is able to differentiate these tumors based on certain
criteria. The tumors show varying amounts of cellular atypia and an
invasive growth pattern. They are usually poorly circumscribed with
varying amounts of mitotic figures, necrosis, and abnormal-appearing
cells. Various gland-like structures can be seen in some tumors, which
can be helpful in making the diagnosis. Often, special
immunohistochemical stains are used to help differentiate the subtypes
of these tumors.
Treatment:
These tumors should all be surgically excised
with clear surgical margins. The Mohs surgical technique has been used
successfully to treat these tumors, as has a standard wide local
excision. Sentinel node removal and evaluation is not routinely
performed, but some clinicians advocate its use, especially in some of
the more aggressive subtypes such as the eccrine porocarcinoma. Sentinel
node removal and evaluation has not shown any survival benefit to date.
Mohs surgery may lead to a decrease in recurrence rate and is tissue
sparing. Because of the rare nature of these tumors and the lack of
prospective randomized studies, it is difficult to determine the best
removal method. For the same reasons, the ultimate prognosis and the
recurrence rate of these tumors are unknown. After diagnosis and removal
of these tumors, the patient should have long-term follow-up to
evaluate for recurrence.
Adnexal tumors that have
metastasized are treated with chemotherapy with or without radiotherapy.
The prognosis is poor for patients who develop metastatic adnexal
carcinoma.
Angiosarcoma is a rare,
aggressive, malignant tumor of vascular or lymphatic vessels. These
tumors can be seen as a solitary finding or secondary to long-standing
lymphedema, such as after radiation therapy or an axillary or inguinal
lymph node dissection. This latter form tends to occur years after the
radiation or surgical procedure. Soft tissue sarcomas are very rare and
make up a small percentage of all malignancies reported.
Clinical Findings:
Angiosarcomas are most common in the older male
population. They have no race predilection. The tumors most commonly
arise in the head and neck region and can manifest in many fashions.
They often appear as a red to purple plaque with ill-defined borders.
They can often look like a bruise, and the diagnosis can be delayed. The
tumor continues to expand, forms satellite foci of involvement, and
eventually ulcerates and bleeds. For some reason, the scalp and face of
older men are most commonly involved. The tumor has a propensity to
involve sun-exposed areas of the face and scalp. The tumors typically
show an aggressive growth pattern and have a tendency to metastasize
early in the course of disease.
Angiosarcomas can also arise in regions of
previous long-standing lymphedema caused by radiation exposure or
surgical procedures. Any procedure that can result in abnormal lymphatic
drainage can lead to chronic lymphedema. It is believed that
long-standing lymphedema can result in the development of angiosarcoma.
Common surgical procedures that cause chronic lymphedema are radical
mastectomies and lymph node dissections of the axilla or groin after a
diagnosis of lymph node involvement by breast cancer or melanoma.
Angiosarcomas arising in areas of chronic lymphedema were first
described by Stewart and Treves and have been given the eponym
Stewart-Treves syndrome
. This type of angiosarcoma is highly aggressive
and portends a poor outcome. The Stewart-Treves type of angiosarcoma
has been reported most commonly in women who have undergone radical
mastectomy or lymph node dissection for treatment of breast cancer.
After years of chronic lymphedema in the ipsilateral limb, the patient
may develop a reddish, bruise-like area on the limb. This area slowly
enlarges and develops plaque-like areas or nodules within the affected
region. At this point, the diagnosis is often entertained, and the
diagnosis is made with a skin biopsy. These tumors tend to be large at
diagnosis, which most likely accounts for the poor prognosis.
Radiation-induced angiosarcomas
may occur at the site of the radiation therapy or as a result of
long-standing chronic lymphedema if the radiation therapy interrupts the
lymphatic drainage. These tumors also tend to be diagnosed after they
have become quite large, and this portends a poor prognosis. These
tumors tend to occur 4 to 10 years after the initial radiation therapy.
Pathogenesis:
Angiosarcomas are soft tissue tumors that are
derived from the endothelial lining of small blood or lymphatic vessels.
Some tumors are found to have elevated levels of vascular endothelial
growth factor (VEGF), which is critical in the regulation of vessel
growth. Other potential players in the pathogenesis of this tumor are
mast cells, which cause an increase in stem cell factor; Fas and Fas
ligand expression; and lack of the vascular endothelial cadherin
protein. All of these factors may interact in an unknown way to induce
tumorigenesis. The exact mechanism of formation of angiosarcoma is
unknown. Radiation-induced angiosarcoma may result from a direct
mutagenic effect of the radiation on the endothelial DNA. No relation
with human herpesvirus-8 infection has been proven.
Histology:
All angiosarcomas share the same pathological
features. The tumor lobules are poorly circumscribed and have an
infiltrative growth pattern. They contain large amounts of vascular
tissue in a disorganized arrangement. The lining of the vascular spaces
contains atypical-appearing endothelial cells. Mitoses are frequently
encountered, as are intracytoplasmic lumina. The same tumor can contain
well and poorly differentiated regions.
Treatment:
The standard treatment is wide local excision
with the goal of obtaining clear margins. This is usually followed by
postoperative radiation therapy. The 5-year survival rate is low
(15%-20%). Tumors that are metastatic or nonoperable can be treated
palliatively with various chemotherapeutic regimens. The median survival
time in these cases is 3 to 6 months.
Basal cell carcinoma (BCC) is
the most common malignancy in humans. Its true incidence is unknown, but
the number of BCCs diagnosed each year easily surpasses the number of
all other malignancies combined. It is estimated to affect approximately
25% to 33% of the U.S. Caucasian population over their lifetimes. The
yearly number of BCCs diagnosed is quickly approaching 1 million. BCC
rarely metastasizes or causes mortality. The real crisis it presents is
in the significant morbidity and cost to the health care system. The
vast majority of these lesions are located on the head and neck region
and are of considerable cosmetic concern. The major morbidity involved
is the significant disfigurement that these locally invading tumors can
inflict.
Clinical Findings:
The prototypical BCC is described as a pearly
red papule with telangiectasias that has a rolled border and a central
dell or ulceration. They occur with highest frequency in sun-exposed
areas of the skin. Most BCCs start as a small red macule or papule and
slowly enlarge over months to years. Once this occurs, the tumor may be
friable and may bleed easily with superficial trauma. The tumors most
commonly range in size from 1 mm to 1 cm. However, neglected tumors can
be enormous and have been reported to cover areas up to 60 cm
2
or more. They affect males and females with equal frequency. BCCs
are more common in individuals with Fitzpatrick type I skin and decrease
in frequency as one moves across the skin type spectrum. Fitzpatrick
type VI skin has the lowest incidence of BCC, but these individuals
still can develop these tumors. BCCs occur with an increasing frequency
with age. They are uncommon in childhood, with the exception of the
association of childhood BCCs with the nevoid BCC syndrome (also called
basal cell nevus syndrome or Gorlin's syndrome).
The tumors are most likely to
occur (>80%) on the head and neck region. The trunk is the next most
common area. The vermilion border, the palms and soles, and the glans
theoretically should not develop BCCs because these areas are devoid of
hair; however, they can be affected by direct extension from a
neighboring tumor. These tumors rarely metastasize, and those that do
are most often neglected large tumors or tumors in immunosuppressed
patients. BCC most commonly metastasizes to regional lymph nodes and the
lung.
Many clinical variants of BCC
exist, including superficial, pigmented, nodular, and sclerotic or
morpheaform variants. There are many other histological variants.
Clinically, a superficial BCC manifests as a very slowly enlarging, pink
or red patch without elevation or ulceration. If left alone for a long
enough period, it will develop areas of nodularity or ulceration.
Nodular BCCs are probably the most common variant; they manifest as the
classic pearly papule with telangiectasias and central ulceration. The
pigmented variant can mimic melanoma and is often described as a brown
or black papule or plaque with or without ulceration. Early on, these
types of BCCs can appear as pearly papules or plaques with minute flecks
of brown or black pigmentation. Patients with the sclerotic or
morpheaform version often have larger tumors at presentation because of
their slow, inconspicuous growth pattern. These slow-growing tumors are
almost skin colored and have ill-defined borders. They tend not to
ulcerate until they have become large, and this often delays the seeking
of medical advice. These tumors can mimic the appearance of scar
tissue, which can also hinder making the diagnosis. Eventually, the
tumor enlarges enough to cause ulceration or superficial erosions, and
the diagnosis is made. The sclerotic BCC is often much larger than the
other variant types at the time of diagnosis.
The most important genetic syndrome associated with
the development of BCCs is the nevoid BCC syndrome. This syndrome is
inherited in an autosomal dominant fashion and is caused by a defect in
the patched 1 gene, PTCH1
. This gene is located on chromosome 9q22. It
encodes a tumor suppressor protein that plays a role in inhibition of
the sonic hedgehog signaling pathway. A defect in the patched protein
allows for uncontrolled signaling of the smoothened protein and an
increase in various cell signaling pathways,
ultimately culminating in the development of BCCs. Patients with nevoid
BCC syndrome also may have odontogenic cysts of the jaw, palmar and
plantar pitting, various bony abnormalities, and calcification of the
falx cerebri. Frontal bossing, mental delay, and ovarian fibromas are
only a few of the associated findings that can be seen in this syndrome.
Other rare syndromes in which
BCCs can be seen include xeroderma pigmentosa, Bazek's syndrome, and
Rombo syndrome.
Pathogenesis:
Risk factors associated with the development of
BCC include cumulative exposure to ultraviolet radiation and ionizing
radiation. In the past, arsenic exposure was a well-recognized cause of
BCCs, and arsenic pollution is still a concern in some areas of the
world. Since the advent of organ transplantation, there has been an
increase in the development of skin cancers in immunosuppressed organ
recipients. The incidences of BCC, squamous cell carcinoma, and melanoma
are all increased in these chronically immunosuppressed patients.
Mutations of various genes have also been implicated in the pathogenesis
of BCCs, including PTCH1, p53 (TP53), sonic hedgehog (SHH), smoothened (SMO), and the glioma-associated oncogene homolog 1 (GLI1)
. However, it is still believed that most BCCs
are sporadic in nature.
The greatest amount of
information is known about the pathogenesis of BCC in the nevoid BCC
syndrome. The genetic defect in the PTCH1
gene allows for uncontrolled signaling of the
smoothened signaling pathway. This pathway initiates uncontrolled
signaling of the GLI1
transcription factors, which ultimately leads to
uncontrolled cell proliferation.
Histology:
Many histological subtypes have been described,
and a tumor can show evidence of more than one subtype. The most common
subtypes are the nodular and superficial types. These tumors arise from
the basaloid cells of the follicular epithelium. The tumor always shows
an attachment to the overlying epidermis. The tumor extends off the
epidermis as tumor lobules. These lobules are basophilic in nature and
show clefting between the basophilic cells and the surrounding stroma.
The cells have a characteristic peripheral palisading appearance. The
cells in the center of the tumor lobules are disorganized. The ratio of
nuclear to cytoplasmic volume in the tumor cells is greatly increased.
Mitoses are present, and larger tumors usually have some evidence of
overlying epidermal ulceration. The tumor is contiguous and does not
show skip areas. The nodular form of this tumor extends into the dermis
to varying degrees, and its depth of penetration is dependent on the
length of time it has been present.
The superficial type is also quite common.
The tumor does not extend into the underlying dermis but appears to be
hanging off the bottom edge of the epidermis. It has not yet penetrated
the dermal-epidermal barrier. There are numerous other histological
subtypes of BCC including micronodular, adenoid, cystic, pigmented,
infiltrative, and sclerosing varieties.
Treatment:
Various surgical and medical options are
available, and the therapy should be based on the location and size of
the tumor and the wishes of the patient. Tumors on the face are most
often treated with Mohs micrographic surgery. This surgical technique
allows for the highest cure rate and is tissue sparing, resulting in the
smallest possible scar. It is more labor intensive than a routine
elliptical excision. Most BCCs can be treated with an elliptical
excision or electrodessication and curettage.
Medical therapy with imiquimod or
5-fluorouracil has also been shown to be useful in selected BCCs,
usually the small, superficial type. One of the newest treatments is
photodynamic therapy. It is performed by applying aminolevulinic acid to
the skin tumor and then exposing the area to visible blue light. An
oral inhibitor of the smoothened protein, called GDC-0449, has shown
excellent results in patients with the nevoid BCC syndrome.
Bowen's disease is a variant of
cutaneous squamous cell carcinoma (SCC) in situ that occurs on
non–sun-exposed regions of the body. That strict definition is not
always followed, and the term Bowen's disease is often used interchangeably with squamous cell carcinoma in situ
. SCC in situ is often derived from its
precursor lesion, the actinic keratosis. Actinic keratosis is
differentiated from SCC in situ and Bowen's disease by its lack of
full-thickness keratinocyte atypia, which is the hallmark of Bowen's
disease and SCC in situ.
Clinical Findings:
Bowen's disease can occur on hair-bearing and
non–hair-bearing skin, and the clinical appearance in various locations
can be entirely different. Bowen's disease on hair-bearing skin often
starts as a pink to red, well-demarcated patch with adherent scale.
Women are most commonly affected, and it occurs later in life. Multiple
lesions can occur, but it is far more common to see this as a solitary
finding. Erythroplasia of Queyrat is a regional variant of Bowen's
disease that occurs on the glans penis. These lesions tend to be
glistening red with crusting. The area is often well circumscribed. The
diagnosis is often delayed because the lesion is easily confused with
dermatitis, psoriasis, and cutaneous fungal infections. A biopsy should
be performed on any nonhealing lesion or rash in the genital region. It
has been estimated that up to 5% of untreated Bowen's disease lesions
will eventually develop an invasive component.
The relationship between Bowen's
disease and internal malignancy has come under scrutiny; if it exists
at all, it is likely a consequence of the use of arsenic in the past.
Patients with a history of arsenic ingestion are at a higher risk of
developing Bowen's disease and internal malignancy. Now that arsenic
exposure is limited in most developed countries, the association between
Bowen's disease and internal malignancy is thought to be unlikely.
Most SCCs in situ are found on
sun-exposed areas of the skin and develop directly from an adjacent
actinic keratosis. Some SCCs in situ eventually develop into an invasive
form of SCC. This is clinically evident by increased thickness,
bleeding, and pain associated with the lesion.
Pathogenesis:
Exposure to arsenic and other carcinogens has
been implicated in the development of Bowen's disease. Certainly,
ultraviolet radiation and other forms of radiation play a role in the
its pathogenesis. Human papillomavirus (HPV) has been implicated in
causing many forms of SCC. The oncogenic viral types 16, 18, 31, and 33
are notorious for causing mutagenesis and malignancy in cervical and
some other genital SCCs. HPV vaccines may decrease the incidence of
these tumors dramatically in the future. HPV can cause cellular
transformations to occur and is directly responsible for tumorigenesis.
Histology:
Bowen's disease shows full-thickness atypia of
the keratinocytes within the epidermis. No dermal invasion is present.
The underlying dermis may show a lymphocytic perivascular infiltrate.
The atypia of the keratinocytes extends down to involve the hair
follicle epithelium, and care must be taken when evaluating these
lesions histologically not to mistake this finding for dermal invasion.
Various amounts of cellular atypia are present.
Treatment:
Treatments can be divided into surgical and
nonsurgical forms. The choice depends on various factors, most
importantly the location and size of the lesion. Some tumors are best
treated surgically, whereas others are best treated medically.
Simple excision or
electrodessication and curettage are highly effective treatments.
Cryotherapy is another destructive method that can be selectively used
with good success. Medical therapies include the application of
5-fluorouracil, imiquimod, or 5-aminolevulinic acid followed by exposure
to blue light. These all have been reported to be successful. The risk
of recurrence is between 3% and 10% depending on the type of therapy
used.
Bowenoid papulosis is considered
to be a special variant of squamous cell carcinoma (SCC) in situ that
is caused by the human papillomavirus (HPV) and is located predominantly
in the genital region, particularly on the penile shaft. As with other
HPV-induced genital skin cancers, HPV 16, 18, 31, and 33 are the more
common viral types, although many other subtypes have been found in
these lesions. Bowenoid papulosis is considered by some to be a
precancerous lesion with a low risk of developing invasive properties
and by others as a true SCC in situ. This lesion does have a low risk of
invasive transformation; if it is treated, the prognosis is excellent.
It is believed that approximately 1% of all bowenoid papulosis lesions
will develop into invasive SCC.
Clinical Findings:
Bowenoid papulosis is most commonly found in men
in the third through sixth decades of life. There is no racial
preference. It is believed to be more common in patients who have had
multiple sexual partners because of their increased risk for exposure to
HPV. It is too soon to determine whether vaccination against HPV has
resulted in any changes in the incidence of bowenoid papulosis. The
lesions are most common in males on the shaft of the penis and in
females on the vulva. They are typically well-circumscribed, slightly
hyperpigmented macules and papules that occasionally coalesce into
larger plaques. Minimal surface change is noted. They are often found in
association with genital warts and can be difficult to distinguish from
small genital warts. The cause of bowenoid papulosis is thought to be
transformation of the keratinocyte caused by HPV, and therefore lesions
of bowenoid shed HPV and are contagious.
The lesions are rarely symptomatic and
are usually brought to a physician's attention because of the patient's
concern for genital warts. For undefined reasons, circumcision appears
to help prevent penile cancer. It has been theorized that the
uncircumcised male is at higher risk for penile carcinoma because of
retention of smegma and chronic maceration, which can provide a portal
for HPV infection, in conjunction with chronic low-grade inflammation.
Pathogenesis:
Almost all lesions of bowenoid papulosis have
evidence of HPV. HPV subtype 16 is by far the most predominant HPV type
found in bowenoid papulosis. Cells of the genital region that are
chronically infected with HPV express various proteins that are critical
in the transformation into cancer. The best-studied HPV oncoproteins,
the E6 and E7 proteins, can disrupt normal cell signaling in the p16
(TP16) and retinoblastoma (RB) pathways. This disruption can lead to a
loss of control of cell signaling and loss of normal apoptosis. These
alterations eventually result in loss of the normal cell processes and
the development of cancer.
Histology:
The histology is almost the same as that of SCC
in situ. There is full-thickness atypia of the epidermis with
involvement of the adnexal structures and a well-intact basement
membrane zone. Varying amounts of epidermal acanthosis and
hyperkeratosis are seen. The cells are often enlarged and pleomorphic
with visible mitoses. Evidence of HPV infection is almost universally
seen as cells mimicking vacuolated koilocyte cells. Special techniques
such as polymerase chain reaction (PCR) can be used to look for HPV
subtyping.
Treatment:
After biopsy has ruled out an invasive component
to this tumor, the main treatment of bowenoid papulosis is to
clinically remove the areas of involvement. The importance of decreasing
HPV transmission to the patient's sexual partners must be addressed.
Condoms should be used at all times to help decrease the risk of
transmission. Topical therapy with 5-fluorouracil or imiquimod has been
advocated as the first-line therapy. Surgical treatment with
electrocautery, cryotherapy, or laser ablation has also been reported to
be successful. Both patients and their sexual partners should be seen
for routine follow-up examinations.
Metastasis to the skin is an
uncommon presentation of internal malignancy. Cutaneous metastases are
far more likely to be seen in a patient with a diagnosis of previously
metastatic disease. The frequency of cutaneous metastasis is dependent
on the primary tumor. Almost all types of internal malignancy have been
reported to metastasize to the skin; however, a few types of cancers
account for the bulk of cutaneous metastases. The distribution of the
metastases is also dependent on the original tumor. The most common form
of skin metastasis is from an underlying, previously metastatic
melanoma.
Clinical Findings:
Most cutaneous metastases manifest as slowly
enlarging, dermal nodules. They are almost always firm and have been
shown to vary in coloration. Some nodules eventually develop necrosis,
ulcerate, and spontaneously bleed. Skin metastasis can occur as a direct
extension from an underlying malignancy or as a remote focus of tumor
deposition. Although skin metastasis often arises in the vicinity of the
underlying primary malignancy, the location of tumor metastases is not a
reliable means of predicting the primary source. The scalp is a common
site, probably because of its rich vascular flow.
Sister Mary Joseph nodule
is a name given to a periumbilical skin
metastasis from an underlying abdominal malignancy. This is a rare
presentation that was first described by an astute nun at St. Mary's
Hospital at the Mayo Clinic. This has been described to occur most
commonly with ovarian carcinoma, gastric carcinoma, and colonic
carcinoma.
Melanoma metastases are usually
pigmented and tend to occur in groups. Cutaneous metastasis from
melanoma can manifest with the rapid onset of multiple black papules and
macules that continue to erupt. As the tumors progress, patients can
develop a generalized melanosis. This is a universally fatal sign that
occurs late in the course of disease. It is believed to be caused by the
systemic production of melanin with deposition in the skin.
Breast carcinoma is another form of
malignancy that frequently metastasizes to the skin. Breast carcinoma
tends to affect the skin within the local region of the breast by direct
extension.
Pathogenesis:
The exact reason why some tumors metastasize to
the skin is unknown. This is a complex biological process that is
dependent on many variables. Metastases are likely to be dependent on
size, ability to invade surrounding tissues (including blood and
lymphatic vessels), and ability to grow at distant sites far removed
from the original tumor. This is an intricate process that depends on
the production of multiple growth factors and evasion of the patient's
immune system.
Histology:
The diagnosis of cutaneous metastasis is almost
always made by the pathologist after histological review. Each tumor is
unique, and the histological picture depends on the primary tumor.
Treatment:
Solitary cutaneous metastases can be surgically
excised. The risk of recurrence is high, and adjunctive chemotherapy and
radiotherapy should be considered. Palliative surgical excision can be
undertaken for any cutaneous metastases that are painful, ulcerated, or
inhibiting the patient's ability to function. The prognosis for patients
with cutaneous metastasis is poor. The overall survival rate for
multiple cutaneous metastases has been reported to be 3 to 6 months. The
length of survival is increasing now because of improved treatments.
Dermatofibrosarcoma protuberans
is a rare cutaneous malignancy that is locally aggressive. The tumor is
derived from the dermal fibroblast, and it is not believed to arise from
previously existing dermatofibromas. Dermatofibrosarcoma protuberans
rarely metastasizes, but it has a distinctive tendency to recur locally.
Clinical Findings:
Dermatofibrosarcoma protuberans is a
slow-growing, locally aggressive malignancy of the skin. These tumors
are low-grade sarcomas and make up approximately 1% of all soft tissue
sarcomas. The tumor is found equally in all races and affects males
slightly more often than females. Most tumors grow so slowly that the
patient is not aware of their presence for many years. The tumor starts
off as a slight, flesh-colored thickness to the skin. Over time, the
tumor enlarges and has a pink to slightly red coloration. It slowly
infiltrates the surrounding tissue, particularly the subcutaneous
tissue. If the tumor is allowed to grow long enough, the malignancy will
grow into the fat and then back upward in the skin to develop satellite
nodules surrounding the original plaque. This is often the reason a
patient seeks medical care. The tumor tends to grow slowly for years,
but it can hit a phase of rapid growth. This rapid growth phase allows
the tumor to grow in a vertical direction, and hence the term
protuberans
is applied. If medical care is not undertaken, the tumor will
to continue to invade the deeper structures, eventually invading
underlying tissue, including fascia, muscle, and bone.
Dermatofibrosarcoma protuberans
is, for the most part, asymptomatic in the initial phases of the tumor.
As it enlarges, the patient may notice an itching sensation or, less
frequently, a burning sensation or pain. As the tumor enlarges, patients
often notice tightness of the skin or a thickening sensation; however,
this development is so slow that most patients ignore it for many more
months or even years. The differential diagnosis is often between
dermatofibrosarcoma protuberans and a keloid or hypertrophic scar. The
atrophic variant can often be confused with morphea. One clue to the
diagnosis of dermatofibrosarcoma is the loss of hair follicles within
the tumor region. The adnexal structures are crowded out by the
ever-expanding tumor. If the tumor is allowed to enlarge enough, it will
begin to outgrow its blood supply, and ulceration and erosions develop
thereafter. The tumors have ill-defined borders, and determining the
extent of the tumor clinically can be challenging or impossible. A punch
biopsy of the tumor leads to the appropriate pathological diagnosis.
Metastatic disease is uncommon; however, local recurrence after surgical
excision remains an issue.
Pathogenesis:
The exact pathogenesis is unknown. By genetic
chromosomal tissue analysis, these tumors have been found to have a
reciprocal translocation, t(17;22)(q22;q13.1), which is believed to be
pathogenic in causing the tumor. The exact reason for this translocation
is unknown. The translocation causes fusion of the
platelet-derived growth factor B-chain (PDGFB) gene with the collagen type I α1 (COL1A1) gene. This translocation directly causes the PDGFB gene to be under control of the COL1A1
gene. PDGFB is then overexpressed, and it drives
a continuous stimulation of its tyrosine kinase receptor.
Histology:
Dermatofibrosarcoma protuberans shows an
infiltrative growth pattern. It invades the subcutaneous fat tissue. The
tumor cells can be seen encasing adipocytes. The tumor is poorly
circumscribed, and its borders can be difficult to distinguish from
normal dermis. The tumor itself is made up fibroblasts arranged in a
storiform pattern. These tumors stain positively with the CD34
immunohistochemical stain and are negative for factor XIII. These two
stains are often used to differentiate dermatofibrosarcoma protuberans
from the benign dermatofibroma, which has the opposite staining pattern.
The stromolysein-3 stain is also used to help differentiate the two
tumors; it is positive in cases of dermatofibroma and negative in cases
of dermatofibrosarcoma protuberans.
Treatment:
Because of the ill-defined nature of the tumors
and their often large size at diagnosis, wide local excision with 2- to
3-cm margins is often undertaken. Postoperative localized radiotherapy
has been used to help decrease the recurrence rate. Imatinib has shown
promise in dermatofibrosarcoma protuberans as a treatment before surgery
to help shrink large or inoperable tumors. There has also been
anecdotal success with the use of imatinib in metastatic disease.
Extramammary Paget's disease is a
rare malignant tumor that typically occurs in areas with a high density
of apocrine glands. It is most commonly an isolated finding but can
also be a marker for an underlying visceral malignancy of the
gastrointestinal or genitourinary tract. Paget's disease is an
intraepidermal adenocarcinoma confined to the breast; it is commonly
associated with an underlying breast malignancy.
Clinical Findings:
Extramammary Paget's disease is most often found
in the groin or axilla. These two areas have the highest density of
apocrine glands. It is believed that extramammary Paget's disease has an
apocrine origin. There is no race predilection. These tumors most
commonly occur in the fifth to seventh decades of life. Women are more
often affected than men. The diagnosis of this tumor is often delayed
because of its eczematous appearance. It is often misdiagnosed as a
fungal infection or a form of dermatitis. Only after the area has not
responded to therapy is the diagnosis considered and confirmed by skin
biopsy.
The tumor is slow growing and is
typically a red-pink patch with a glistening surface. Itching is the
most common complaint, but patients also complain of pain, burning,
stinging, and bleeding. The area is sore to the touch, and there are
areas of pinpoint bleeding with friction. The red, glistening surface
often has small white patches. This has been described as the
“strawberries and cream” appearance, and it is characteristic of
extramammary Paget's disease. As the cancer progresses, erosions develop
within the tumor, and occasionally ulcerations form. The clinical
differential diagnosis is often among Paget's disease, an eczematous
dermatitis, inverse psoriasis, and a dermatophyte infection. A skin
biopsy is required for any rash in these regions that does not respond
to therapy.
The tumor is often a solitary
finding; however, it can be seen in conjunction with an underlying
carcinoma, most commonly adenocarcinoma of the gastrointestinal or
genitourinary tract. Rectal adenocarcinoma has been the most frequently
reported underlying tumor. The percentage of these tumors that are
associated with an underlying malignancy is not known but is estimated
to be low. Appropriate screening tests must be performed to evaluate for
these associations. Usually, the underlying tumor is diagnosed before
the extramammary Paget's disease or at the same time of diagnosis.
Pathogenesis:
The exact mechanism of malignant transformation
is unknown. Two leading theories exist as to the origin of the tumor.
The first is that the tumor represents an intraepidermal adenocarcinoma
of apocrine gland origin. The second theory is that an underlying
adenocarcinoma spreads to the skin and forms an epidermal component that
manifests as extramammary Paget's disease. Although most believe this
tumor to be of apocrine origin, controversy surrounds this theory, and
the exact cell of origin is still unknown. There are no known
predisposing factors.
Histology:
The histology is diagnostic of the disease;
however, the pathological appearance often mimics that of melanoma in
situ or squamous cell carcinoma. There are a plethora of pale-staining
Paget's cells scattered throughout the entire epidermis. This type of
pagetoid spread of cells is often seen in melanoma. The cells can be
clustered together and can have the appearance of forming glandular
structures. Immunohistochemical staining is often used to differentiate
melanoma and squamous cell carcinoma from extramammary Paget's disease.
Extramammary Paget's disease is unique in that it stains positively with
carcinoembryonic antigen (CEA) and also with some low-molecular-weight
cytokeratins. It does not stain with S100, HMB-45, or melanin A. The
staining pattern with cytokeratins 7 and 20 has been used with some
success to predict an underlying adenocarcinoma; however, the routine
use of these tests is not clinically useful at this time.
Treatment:
The prognosis for extramammary Paget's disease
depends on the stage of the tumor. Disease that is localized to the skin
has an excellent prognosis. The treatment of choice is wide local
excision. The risk of recurrence is high, and lifelong clinical
follow-up is required. The prognosis for disease associated with an
underlying adenocarcinoma is dependent on the stage of the underlying
tumor. Lesions associated with an underlying malignancy have a worse
prognosis. Metastatic disease has a poor prognosis, and various
chemotherapeutic regimens have been tried with and without radiotherapy.
Kaposi's sarcoma is a rare
malignancy of endothelial cells seen in unique settings. The classic
variant is seen in older patients, most commonly individuals living in
the region surrounding the Mediterranean Sea. Kaposi's sarcoma
associated with human immunodeficiency virus (HIV) infection or with
acquired immunodeficiency syndrome (AIDS) is seen predominantly in men,
and the tumor is thought to be caused by human herpesvirus-8 (HHV8).
There is also a variant seen in chronically immunosuppressed patients,
such as those who have undergone solid organ transplantation. The
African cutaneous variant of Kaposi's sarcoma is seen in younger men in
their third or fourth decade of life. Kaposi's sarcoma is a locally
aggressive tumor that rarely has a fatal outcome. The one exception is
the very rare African lymphadenopathic form of Kaposi's sarcoma, which
is distinct from the more common African cutaneous form.
Clinical Findings:
The tumors are very similar in appearance across
the subtypes of clinical settings. They usually appear as pink-red to
purple macules, papules, plaques, or nodules. In the classic form of
Kaposi's sarcoma, the tumors are most often found on the lower
extremities of older men. Some tumors in this setting remain unchanged
for years, and the patient often dies of other causes. Occasionally, the
tumors grow and ulcerate, causing pain and bleeding. The disseminated
form of classic Kaposi's sarcoma can be very aggressive, and patients
require systemic chemotherapy.
AIDS-associated Kaposi's sarcoma is the most
common form of the disease. It is most often seen in younger men. In
comparison with the classic form, this form usually manifests as purple
macules, plaques, and nodules on the head and neck, trunk, and upper
extremities. This is an AIDS-defining illness. Patients with
AIDS-associated Kaposi's sarcoma are at a higher risk for internal organ
involvement. The small bowel has been reported to be the internal organ
most commonly affected by Kaposi's sarcoma, but it can affect any organ
system. Since the advent of multiple-drug therapy for HIV infection,
the incidence of AIDS-associated Kaposi's sarcoma has decreased
dramatically.
Tropical African cutaneous
Kaposi's sarcoma is most often seen in younger men. The clinical
findings are not much different from those of the classic form of
Kaposi's sarcoma. These patients are much more likely to suffer from
severe lower-extremity edema. The tumor also has a higher incidence of
bone invasion than the other types. The main difference between the
classic and the African forms of Kaposi's sarcoma is the age at onset.
The aggressive form of African Kaposi's sarcoma occurs in childhood and
is often fatal because of its aggressive ability to metastasize. The
lymph nodes are often involved before the skin is. The reason the
African forms act so differently from each other is poorly understood.
Pathogenesis:
The pathogenesis of the classic and African
forms of Kaposi's sarcoma is unknown. The cell of origin of this tumor
is believed to be the endothelial cell. Matrix metalloproteinases 2 and 9
have been shown to increase angiogenesis and increase the tissue
invasion of the affected endothelial cells. Kaposi's sarcoma associated
with AIDS or other immunosuppressive states is believed to be caused by
the action of HHV8 in a genetically predisposed individual. HHV8 is
thought to cause dysregulation of the immune response in the afflicted
endothelial cells, allowing them to proliferate uncontrolled by normal
immune functions.
Histology:
Biopsies of Kaposi's sarcoma show many
characteristic findings. The promontory sign is often seen; it is
represented by plump endothelial cells jutting into the lumen of the
capillary vessel. Many slit-like spaces are also seen. These spaces
represent poorly formed blood vessels, which are thin walled and easily
compressed. They are filled with red blood cells. The tumor in general
is very vascular, with a predominance of vascular spaces and a large
amount of red blood cell extravasation into the dermis.
Treatment:
For classic Kaposi's sarcoma, the mainstay of
therapy has been localized radiation treatment. Many other treatments
have been advocated, including topical alitretinoin, imiquimod,
intralesional vincristine, and interferon. Systemic chemotherapy for
disseminated and aggressive forms is indicated and is usually based on a
regimen of either vinblastine, paclitaxel, bleomycin, or pegylated
liposomal doxorubicin.
The keratoacanthoma is a rapidly
growing malignant tumor of the skin that is derived from the
keratinocyte. The tumor is believed by many to be a subset of squamous
cell carcinoma of the skin, but its natural history and morphology are
distinct enough to merit a separate discussion. Most keratoacanthomas
are solitary, but many rare variants have been well documented. These
variants include the Ferguson-Smith, Witten-Zak, and Grzybowski
syndromes.
Clinical Findings:
The classic solitary keratoacanthoma starts as a
small, flesh-colored papule that rapidly enlarges to form a crateriform
nodule with a central keratin plug. The tumor is unique in that, if
left alone, the keratoacanthoma will spontaneously resolve after a few
weeks to months. The nonclassic form of keratoacanthoma does not
spontaneously resolve, and it is inadvisable to leave these tumors
alone, because a high percentage will continue to enlarge. If left
alone, these tumors can behave aggressively, with local invasion as well
as distant metastasis. The most common area of metastasis is the
regional lymph nodes. The most common variant of keratoacanthoma is the
solitary variant. This almost exclusively occurs in sun-exposed regions
of the body. The peak age at onset is in the fifth to sixth decades of
life. These tumors are more common in the Caucasian population, and
there is slight male preponderance.
Many unique variants of keratoacanthomas
exist. Keratoacanthoma centrifugum marginatum is one such variant that
manifests with an ever-expanding ridge of neoplastic tissue. As the
tumor enlarges, it becomes an enormous-sized plaque with a peculiar
raised border. These tumors can be massive and can encompass a large
portion of a limb. This subtype presents a therapeutic challenge.
Multiple keratoacanthomas occur
rarely and have been divided into three distinct subtypes. The
Gryzbowski syndrome consists of multiple keratoacanthomas erupting in a
generalized distribution, almost always in an adult. The Ferguson-Smith
form consists of multiple keratoacanthomas occurring in an autosomal
dominant fashion. The keratoacanthomas are uniform in appearance and
also form in a generalized pattern. The onset is in childhood, and the
tumors have a higher chance of spontaneously resolving. The Witten-Zak
syndrome also has an autosomal dominant inheritance pattern. The tumors
are more variable in size and configuration than in the Ferguson-Smith
subtype. The onset of this type is also in childhood.
Pathogenesis:
The exact pathogenesis is unknown; however, the
tumor has a keratinocyte cell origin. There is more evidence for the
keratinocytes derived from hair follicle epithelium as the primary cell
responsible for the formation of this tumor. Keratoacanthomas have an
increased incidence in patients with chronic ultraviolet exposure and in
the chronically immunosuppressed. The classic keratoacanthoma is
described as a self-resolving tumor. The reason that some of these
tumors undergo autoinvolution is unknown. There is evidence to suggest
that the tumors, like hair follicles, are under a preset growth and
involution control system. The hair follicle grows to a certain point,
after which a signal stops the growth of the hair, the follicle is shed,
and a new hair shaft is formed. Perhaps the growth and involution of
keratoacanthomas is analogous to the turnover of hair follicles.
Keratoacanthomas are also seen with an increased incidence in Muir-Torre
syndrome. It is possible that the genetic defect in these patients may
play a role in the pathogenesis of keratoacanthomas.
Histology:
The tumor is typically a cup-shaped exophytic
nodule that has a prominent keratin-filled plug. The borders of the
tumor are well circumscribed. The tumor is symmetric. Neutrophilic
abscesses within the outer layers of the involved epidermis are a
characteristic finding in keratoacanthomas. The keratinocytes that make
up the bulk of the tumor have a glassy cytoplasm with large amounts of
glycogen. Other unique findings in this tumor are the presence of plasma
cells and eosinophils and the elimination of elastic fibers through the
overlying epidermis.
Treatment:
After a keratoacanthoma has been biopsied, the
treatment of choice is surgical removal. This can be done with a
standard elliptical excision or with Mohs micrographic surgery.
Intralesional methotrexate and oral retinoids have been used in
refractory cases and in individuals who cannot tolerate surgery. The
familial forms of keratoacanthoma often require long-term retinoid
therapy to keep the tumors at bay.
Malignant melanoma is one of the
few types of cancers that has continued to increase in incidence over
the past century. Currently, the incidence of melanoma in the United
States is 1 in 75 Caucasians; this is projected to continue to increase
over the next few decades. However, the rate of mortality from melanoma
has dropped, probably as a result of early detection and surgical
intervention. According to cancer registries, melanoma ranks sixth in
incidence for men and seventh for women. Melanoma is the most common
cancer in women aged 25 to 30 years. Approximately 700,000 cases of
melanoma were diagnosed in the United States in 2009, and approximately
9000 people died from complications directly related to melanoma.
Clinical Findings:
Melanoma follows a characteristic growth
pattern. The tumor arises de novo from previously normal skin in
approximately 60% of cases and from preexisting melanocytic nevi in the
remaining 40% of cases. Melanoma is uncommon in children, the one
exception being melanoma arising from giant congenital nevi. The
incidence of melanoma peaks in the third decade of life and remains
fairly stable over the next 5 decades. There is no gender predilection.
Melanoma is more common in the Caucasian population. There are regional
variances in distribution of melanoma. The back is more commonly
involved in men and the posterior lower legs in women. However, melanoma
has been described to occur in any area of the skin and mucous
membranes. Melanoma has also been shown to develop within the retinal
melanocytes, causing retinal melanoma. This rare tumor is often found
incidentally on routine ophthalmological examination.
Melanoma has been described using the ABCDE mnemonic: a symmetric, irregular b order, variation in c olor, d iameter greater than 6 mm, and e
volving or changing. These are rough guidelines
and are not meant to be used to diagnose melanoma. They are intended to
be used by the lay public to increase awareness and as a method to
screen for melanoma. Some melanomas have all of the ABCDE
characteristics, and some have only one or two of them. Some variants of
melanoma do not follow the ABCDE rules at all, but these are extremely
rare.
There are four main variants of
melanoma. The most common one is the superficial spreading type,
followed by the nodular type. Lentigo maligna melanoma and acral
lentiginous melanoma make up the remaining types. Rare variants are also
seen, including the amelanotic type and the nevoid type. Superficial
spreading melanoma is the most common variant of melanoma seen in
clinical practice. It usually manifests as a slowly enlarging,
irregularly shaped macule with variegation in color. If not recognized
and removed, the melanoma will continue to enlarge and will eventually
develop a vertical component that clinically represents the nodular form
of melanoma. Some nodular forms of melanoma can develop de novo without
the preceding superficial spreading type of melanoma as a precursor
lesion. Nodular lesions are often relatively large at the time of
diagnosis. This type of melanoma has entered its vertical growth phase,
and it is believed that at this point it has developed the ability to
metastasize.
Acral lentiginous melanoma has
long been thought to portend a poor prognosis. This is most likely not
because of the subtype but because this type of melanoma is often
diagnosed later in the course of its development. The lesions are often
located on the soles, toes, or hands. Patients are often unaware of
their presence, and they can mimic a subungual hematoma or bruise.
Notably, this form of melanoma is more commonly seen in the African
American population.
Lentigo maligna melanoma is most
often seen on the face of patients in their fifth to seventh decades of
life, especially in those with a considerable sun exposure history.
This type of melanoma can be difficult to treat and has a propensity for
local recurrence. The borders of the melanoma are ill defined, and it
is difficult to distinguish the background normal sun-damaged
melanocytes from the tumor cells.
Amelanotic melanoma is the most
difficult of all melanomas to diagnosis. These tumors often appear as
slowly enlarging pink patches or plaques with no
pigment. They are commonly misdiagnosed as dermatitis or tinea
infections, and the diagnosis is often delayed. They can also resemble
actinic keratoses. The lack of pigment takes away the clinician's most
important diagnostic clue. These tumors are often biopsied because they
have not gone away after being treated for something entirely different
or after they have developed a papule or nodule. At that point, they are
still most commonly thought to be basal cell carcinomas or squamous
cell carcinomas; rarely does the clinician include amelanotic melanoma
in the differential diagnosis. Patients with albinism or xeroderma
pigmentosum are at a higher risk for development of amelanotic melanoma.
These patients need to be screened routinely, and any suspicious
lesions should be biopsied.
Pathogenesis:
There is no single gene defect that can explain
the development of all melanomas. The most plausible theory is that a
melanocyte within the epidermis is damaged by some external event, such
as chronic ultraviolet exposure, or by some internal event, such as the
spontaneous mutation of a key gene in the regulation of cell
proliferation or apoptosis. After this event has occurred, the abnormal
melanocyte proliferates with the epidermis, starting as an in situ
variant of melanoma. After time, the clonal melanoma cells begin to
coalesce and form nests of melanoma cells. They then continue to
proliferate and enlarge until the clinical features are evident. The
tumor enters a radial growth phase at first and eventually develops a
vertical growth phase with metastatic potential.
Approximately 10% of melanomas
are considered to be an inherited familial form. Although no one gene
explains all of these tumors, the p16 gene (TP16)
is likely the main susceptibility gene. This
gene, when mutated, increases an individual's risk for melanoma as well
as pancreatic carcinoma. TP16
is a tumor suppressor gene that is inherited in
an autosomal dominant fashion. Genetic testing for this gene is
commercially available.
Histology:
The diagnosis by histology of melanoma is based
on multiple criteria, including symmetry, melanocyte atypia, mitosis,
distribution of the melanocytes within the epidermis, lack of maturation
of melanocytes as they extend deeper into the dermis, circumscription,
and architectural disorder. Melanoma is believed to begin with an in
situ portion, followed by an upward spread of single melanocytes within
the epidermis, termed pagetoid spread. If no epidermal component of
melanoma is seen, the possibility of a metastatic focus is entertained.
Treatment:
When a clinician encounters a pigmented skin
lesion that is believed to be a melanoma, the lesion should be biopsied
promptly. The best method for biopsy of a pigmented lesion that is
suspicious for melanoma is with an excisional biopsy method using a
small (1-2 mm) margin of normal surrounding skin. This allows for the
diagnosis and an accurate measurement of the Breslow depth. The Breslow
depth is the distance from the granular cell layer to the base of the
tumor. This depth is considered to be the most important prognostic
indicator for melanoma.
Therapy for melanoma is based on
the Breslow thickness, the presence of ulceration, and the mitotic rate
of the primary tumor. The standard of care is to perform a wide local
excision with varying margins of skin based on the criteria described
previously. Melanoma in situ is treated surgically by wide local
excision with 5-mm margins.
Sentinel lymph node sampling is
becoming routinely performed in the care of these patients and aids in
staging of the disease. If the patient has a positive sentinel lymph
node biopsy for metastatic melanoma, staging is performed based on
positron emission tomography/computed tomography (PET/CT) scanning and
magnetic resonance imaging (MRI) of the brain. Patients with metastatic
disease to local lymph nodes only are offered a localized lymph node
dissection and adjunctive therapy with interferon. Those with widespread
metastatic disease are given various chemotherapeutic regimens or
enrolled into clinical studies. The mortality rate for stage IV melanoma
is very poor. Follow-up for melanoma patients is based on the stage of
disease. The National Comprehensive Cancer Network/National Cancer
Institute (NCCN/NCI) has published standardized guidelines for
clinicians.
Merkel cell carcinoma is an
uncommonly encountered neuroendocrine malignant skin tumor that has an
aggressive behavior. This tumor is derived from specialized nerve
endings within the skin. The tumor promoting Merkel cell polyomavirus
has been implicated in its pathogenesis. The prognosis of Merkel cell
carcinoma is worse than that of melanoma. This tumor has a high rate of
recurrence and often has spread to the regional lymph nodes by the time
of diagnosis.
Clinical Findings:
Merkel cell carcinoma is a rare cutaneous
malignancy with an estimated incidence of 1 in 200,000. Merkel cell
carcinoma is much more common in Caucasian individuals. The tumor has a
slight male predilection. The average age at onset is in the fifth to
seventh decades of life. The lesions occur most often on the head and
neck. This distribution is consistent with the notion that chronic sun
exposure is a predisposing factor in the development of this tumor.
These tumors also occur more commonly in patients taking chronic
immunosuppressive medications. The tumors often appear as red papules or
plaques that quickly increase in size. They can also appear as rapidly
enlarging nodules. On occasion, the tumor ulcerates. The clinical
differential diagnosis is often between Merkel cell carcinoma and basal
cell carcinoma, inflamed cyst, squamous cell carcinoma, or an adnexal
tumor. These tumors are so rare that they are infrequently in the
original differential diagnosis.
It has been estimated that up to 50% of all
patients diagnosed with a Merkel cell carcinoma will develop lymph node
metastasis. Other notable areas of metastasis include the skin, lungs,
and liver. The staging of this tumor is based on its size (<2 cm="" nbsp="" or="">2 cm), the involvement of regional lymph nodes, and the presence of
metastasis. Patients with higher-stage disease have a progressively
worse prognosis. Patients with metastatic disease (stage IV) have a
5-year survival rate of 0%. In contrast, the 5-year survival rate for
local stage I or II disease is 65% to 75% and approximately 50% to 60%
for stage III (lymph node involvement). Grouping all stages together,
one third of the patients diagnosed with Merkel cell carcinoma will die
from their disease.
Pathogenesis:
Merkel cell carcinoma is derived from a
specialized cutaneous nerve ending. The normal Merkel cells function in
mechanoreception of the skin. Merkel cells, like melanocytes, are
embryologically derived from the neural crest tissue. Chronic
immunosuppression is believed to be one of the largest risk factors.
Patients taking immunosuppressive medications after organ
transplantation are at much higher risk than age-matched controls.
Chronic sun exposure and its effect on downregulating local immunity in
the skin have also been theorized to play an etiological role. The
Merkel cell polyomavirus has been studied to assess its role in the
development of Merkel cell carcinoma.
Polyomaviruses are similar in nature and
structure to the better-known papillomaviruses. There are at least five
polyomaviruses that cause human disease. Most of them affect patients
who are chronically immunosuppressed at a higher rate than healthy
matched controls. Researchers have implicated the Merkel cell
polyomavirus as a potential cause of Merkel cell carcinoma. This virus
has been isolated from a high percentage of Merkel cell tumors, but not
from all of them. It is likely to be a player in the pathogenesis of a
subset of patients with Merkel cell carcinoma, but it is unlikely to be
the only explanation. The discovery of this virus may lead to
therapeutic options in the future.
Histology:
Merkel cell carcinoma is a neuroendocrine tumor.
The tumor is composed of small, uniformly shaped, basophilic-staining
cells. The tumor is poorly circumscribed and grows in an infiltrative
pattern between dermal collagen bundles and subcutaneous fat lobules.
The cells have a characteristic nuclear chromatin pattern. These tumors
can be stained with various immunohistochemical stains. The most helpful
one is the cytokeratin 20 stain. It has a characteristic, if not
pathognomonic perinuclear dot, staining pattern.
Treatment:
Surgical excision with wide (2-3 cm) margins is
still the standard therapeutic treatment. Sentinel node sampling has
been helpful in staging. Those patients with localized disease often
undergo postoperative irradiation of the surgical removal site. Those
with widespread metastatic disease are often treated with
cisplatin-based chemotherapeutic regimens.
Mycosis fungoides is the most
common form of cutaneous T-cell lymphoma. The cutaneous T-cell lymphomas
are an assorted group of cancers with varying genotypes and phenotypes.
Mycosis fungoides is a rare form of cancer, but it is considered to be
the most frequent form of cutaneous lymphoma. Mycosis fungoides is
predominantly a disease of abnormal CD4+ lymphocytes that have become
malignant and have moved into the skin, causing the characteristic
lesions. Advances with immunophenotyping and gene rearrangement studies
have helped to characterize the disease and are used for diagnostic and
prognostic purposes. Altogether, mycosis fungoides is a rare condition
afflicting approximately 1 in 500,000 people.
Clinical Findings:
Mycosis fungoides often manifests as a slowly
progressing rash that occurs in double-covered areas such as the groin
and breast skin. The buttocks are a very common area of involvement.
There is a 2 : 1 male predominance. Mycosis fungoides is seen in all
races, with a predominance in the African American population compared
with the Caucasian or Asian population. It is infrequently encountered
in children. Mycosis fungoides is staged based on its appearance, the
body surface area (BSA) involved, and the involvement of lymph nodes,
blood, and other organ systems. The most common stage of mycosis
fungoides is stage IA.
Stage IA mycosis fungoides
carries an excellent prognosis, with most patients leading a normal life
span and dying from another cause. Stage IA disease is typically
described as patches of involvement totaling less than 10% of the BSA
and no lymph node involvement. The rash of stage IA disease appears as
thin, atrophic patches on the buttocks, breasts, or inner thighs. There
are often areas of poikiloderma (hyperpigmentation and hypopigmentation
as well as telangiectasias and atrophy). The atrophy has been described
as “cigarette paper” atrophy: The skin exhibits a fine crinkling similar
to freshly rolled cigarette paper. The rash is often asymptomatic, but
pruritus can be problematic for some. The diagnosis of mycosis fungoides
is based on the clinical and pathological findings.
Patch-stage mycosis fungoides can go
undiagnosed for years to decades because of its indolent nature and
often bland appearance. It often appears as psoriasis, a nonspecific
form of dermatitis, and initial biopsies are often nonspecific. The
application of topical steroids before a skin biopsy is obtained may
alter the histological picture enough to make the diagnosis of mycosis
fungoides impossible. Often, serial biopsies over years are required
until one shows the characteristic features of mycosis fungoides. It is
best to biopsy a previously untreated area. In addition to being a very
slow-developing cancer, it is possible that mycosis fungoides may start
as a form of dermatitis and over many years transform into a malignant
CD4+ process.
At the other end of the spectrum
is the Sézary syndrome. This is an erythrodermic variant of mycosis
fungoides with peripheral blood involvement. Circulating Sézary cells
are the hallmark of this syndrome. The Sézary cells are enlarged
lymphocytes with cerebriform nuclei. The cerebriform nuclei can best be
appreciated under electron microscopy. It is considered to be a leukemic
phase of mycosis fungoides. Sézary syndrome has a poor prognosis.
There are many varying stages of
disease between these two extremes. The morphology of cutaneous
lymphoma changes from patches to plaques to nodules or tumors. Varying
amounts of ulceration may be present. The natural history of progression
of mycosis fungoides is variable and difficult to predict clinically.
The most accurate way to predict the course is based on the type of
involvement and the BSA involved. The smaller the BSA
of involvement, the better the prognosis. A worse prognosis is seen
with the nodular form as opposed to the plaque type or the patch form of
mycosis fungoides.
Pathogenesis:
The etiology of mycosis fungoides is unknown.
The pathomechanism that causes the responsible lymphocytes to transform
into malignant cells is unknown. Significant work has looked at various
causes including retroviruses, environmental insults, gene deletions,
and chronic antigen stimulation. However, the exact mechanism of
malignant transformation for this disease, which was originally
described in 1806, remains unresolved.
Histology:
Stage IA disease shows the characteristic
histological findings of mycosis fungoides. There is a lichenoid
infiltrate of abnormal lymphocytes with cerebriform nuclei. There are
varying amounts of epidermotropism without spongiosis. The
epidermotropic cells are the abnormal lymphocytes that have entered the
epidermis. Occasionally, collections of the lymphocytes occur within the
epidermis as small groupings called Pautrier's microabscesses.
Immunophenotyping of the cells present reveals the infiltrate to be
predominantly CD4+ lymphocytes with a loss of the CD7 and CD26 surface
molecules. Clonality of the infiltrate can be determined by performing a
Southern blot analysis. The presence or lack of clonality is not
diagnostic, and this test is not routinely performed.
Peripheral blood can be analyzed
by flow cytometry for the presence of circulating lymphoma cells. This
is a rare finding in low-stage disease and a near-universal finding in
Sézary syndrome.
Treatment:
Treatment of mycosis fungoides is based on the
stage of disease. Stage IA disease is often treated with a combination
of topical corticosteroids, nitrogen mustard ointment, narrow-band
ultraviolet B (UVB) phototherapy, or psoralen + ultraviolet A (PUVA)
phototherapy. As the BSA of involvement increases, the use of creams
becomes difficult. Phototherapy is often used for those with widespread
patch disease.
Isolated tumors respond well to
local radiotherapy. Often, systemic treatments are employed as well.
These systemic agents include the retinoids (bexarotene, acitretin, and
isotretinoin) and interferon, both α and γ types. Extracorporeal
photophoresis has been used for all stages of mycosis fungoides,
especially Sézary syndrome. The patient is given intravenous psoralen
and then has peripheral blood removed and separated into its components.
The white blood cells are isolated, exposed to UVA light, and then
returned to the patient. The exposed leukocytes that have been damaged
by the psoralen and UVA are believed to induce a vaccine-like
immunological response.
Total skin electron-beam therapy
can be used in special cases in institutions that have the technical
capability. Denileukin diftitox is an approved therapy for refractory
disease. This drug is created by fusion of the interleukin-2 (IL-2)
molecule and the diphtheria toxin. Cells that express the CD25 molecule
(IL-2 receptor) are selectively killed by this medication. Denileukin
diftitox can cause severe side effects and should be administered only
by specialists adept at its use. Many new medications are being used
with variable success in the treatment of mycosis fungoides, including
an anti-CD52 monoclonal antibody, alemtuzumab, and various
investigational mediations. Bone marrow transplantation is another
option for life-threatening refractory disease.
Despite the many therapies available, no treatment
has been shown to increase survival in patients with mycosis fungoides.
It is therefore inadvisable to treat stage IA disease with a medication
that has acute, potentially life-threatening side effects.
Sebaceous carcinoma is a rare
malignant tumor of the sebaceous gland. These tumors are most frequently
seen on the eyelids. They are most commonly found as solitary tumors
but may be seen as a part of the Muir-Torre syndrome. The Muir-Torre
syndrome is caused by a genetic abnormality in the tumor suppressor
genes MSH2 and MLH1
and is associated with multiple sebaceous
tumors, both benign and malignant. The syndrome is also associated with a
high incidence of internal gastrointestinal and genitourinary
malignancies.
Clinical Findings:
These tumors are most commonly found on the
eyelid skin and the eyelid margin. The reason is that the periocular
skin contains many types of modified sebaceous glands, including the
meibomian glands and the glands of Zeis. Many other, less common
modified sebaceous glands exist, including the caruncle glands and the
multiple sebaceous glands associated with the hairs of the periocular
skin. It is believed that most sebaceous carcinomas arise from the
meibomian glands, with the glands of Zeis the second most common site of
origin. The meibomian glands are modified sebaceous glands that are
located within the tarsal plate of the upper and lower eyelid.
Sebaceous carcinoma has been
reported to occur in all areas of the body, but the vast majority occur
on the eyelids, with the next most common area being the rest of the
head and neck region, probably because the density of sebaceous glands
is higher in these regions. The tumors typically start as small
subcutaneous nodules or thickenings of the skin. They are initially
asymptomatic and can be mistaken for a stye or chalazion. The tumor
almost always has a slight yellowish coloration, which, together with
the characteristic periocular location, can help with the diagnosis. The
major differentiating factor is that these other two inflammatory
processes are very acute in onset, are painful, and resolve within a few
weeks. Sebaceous carcinoma is a slow-growing tumor that persists and
continues to enlarge, eventually causing erosions and ulceration. Once
this occurs, the tumor becomes painful and can easily bleed with
superficial trauma. The clinical differential diagnosis is often between
sebaceous carcinoma and a basal cell carcinoma or squamous cell
carcinoma.
Sebaceous carcinomas occur with a
higher incidence in the older female population. There is a
predilection for Caucasians and for patients receiving chronic
immunosuppressive therapy. Patients with the Muir-Torre syndrome are at
dramatically higher risk for sebaceous carcinoma compared with
age-matched controls. Previous radiation therapy for the treatment of
facial or ocular tumors has also been shown to be a predisposing factor
for the development of sebaceous carcinoma.
As the tumors enlarge, they
exhibit an aggressive local growth pattern. They can rapidly enlarge and
metastasize to regional lymph node basins.
Pathogenesis:
Solitary sebaceous carcinomas arise from
sebaceous glands, but the exact pathomechanism is not understood. Many
risk factors have been determined, but how these translate into tumor
development is still being studied. More is known about the sebaceous
tumors associated with the Muir-Torre syndrome. This syndrome is caused
by a genetic defect in the mismatch repair genes. The syndrome is
inherited in an autosomal dominant fashion. The genes that are abnormal
in this syndrome are responsible for microsatellite instability within
the cells of the sebaceous carcinomas and may lead directly to malignant
transformation of the benign sebaceous gland.
Histology:
These tumors are derived from sebaceous glands
and show a high degree of infiltrative growth. The tumor deeply invades
the subcutaneous tissue; in the periocular area, it often invades the
underlying muscle tissue. The lesions are poorly circumscribed, and
mitoses are frequently seen. The tumor cells are large basaloid cells
that show areas of mature sebocyte differentiation and areas that are
poorly differentiated.
Treatment:
The tumors are locally aggressive and have a
high rate of regional lymph node metastasis. The treatment of choice is
surgical removal, either with Mohs micrographic surgery or with a wide
local excision, making sure to get clear tumor margins. These tumors
have a high risk of recurrence, and clinical follow-up is required. The
use of postoperative radiotherapy is warranted in specific cases.
Patients with metastatic disease may benefit from a combination of
radiotherapy and systemic chemotherapy.
Squamous cell carcinoma (SCC) of
the skin is the second most common skin cancer after basal cell
carcinoma. Together, these two types of carcinoma are known as
non-melanoma skin cancer. SCC accounts for approximately 20% of all skin
cancers diagnosed in the United States. SCC can come in many variants,
including in situ and invasive types. Bowen's disease, bowenoid
papulosis, and erythroplasia of Queyrat are all forms of SCC in situ. A
unique subtype of SCC is the keratoacanthoma. Invasive SCC is defined by
invasion through the basement membrane zone into the dermis. SCC has
the ability to metastasize; the most common area of metastasis is the
local draining lymph nodes. Most forms of cutaneous SCC occur in
chronically sun-damaged skin, and they are often preceded by the
extremely common premalignant actinic keratosis.
Clinical Findings:
SCC of the skin is most commonly located on the
head and neck region and on the dorsal hands and forearms. These are the
areas that obtain the most ultraviolet sun exposure over a lifetime.
This type of skin cancer is more common in the Caucasian population and
in older individuals. It is more prevalent in the fifth to eighth
decades of life. The incidence of SCC increases with each decade of
life. This form of non-melanoma skin cancer is definitely linked to the
amount of sun exposure one has had over one's lifetime. Fair-skinned
individuals are most commonly affected. There is a slight male
predilection. Other risk factors include arsenic exposure, human
papillomavirus (HPV) infection, psoralen + ultraviolet A light (PUVA)
therapy, chronic scarring, chronic immunosuppression, and radiation
exposure. Transplant recipients who are taking chronic immunosuppressive
medications often develop SCCs. Their skin cancers also tend to occur
on the head and neck and on the arms, but in addition they have a higher
percentage of tumors developing on the trunk and other non–sun-exposed
regions.
SCCs of the skin can occur with
various morphologies. They can start as thin patches or plaques. There
is usually a thickened, adherent scale on the surface of the tumor.
Variable amounts of ulceration are seen. As the tumors enlarge, they can
take on a nodular configuration. The nodules are firm and can be deeply
seated within the dermis. Most SCCs are derived from a preexisting
actinic keratosis. Patients often have chronically sun-damaged skin with
poikilodermatous changes and multiple lentigines and actinic keratoses.
Approximately 1% of actinic keratoses per year develop into SCC.
Subungual SCC is a difficult
diagnosis to make without a biopsy. It is often preceded by an HPV
infection, and the area has often been treated for long periods as a
wart. HPV is a predisposing factor, and with time a small percentage of
these warts transform into SCC. This development is usually associated
with a subtle change in morphology. There tends to be more nail
destruction and a slow enlargement over time in the face of standard
wart therapy. Prompt biopsy and diagnosis can be critical in sparing the
patient an amputation of the affected digit.
A few chronic dermatoses can predispose to the
development of SCC, including lichen sclerosis et atrophicus,
disseminated and superficial actinic porokeratosis, warts, discoid
lupus, long-standing ulcers, and scars. Many genetic diseases can
predispose to the development of SCC; two of the best recognized ones
are epidermodysplasia verruciformis and xeroderma pigmentosum.
Pathogenesis:
SCC is related to cumulative ultraviolet
exposure. Ultraviolet B (UVB) light appears to be the most important
action spectrum in the development of SCC. UVB is much more potent than
ultraviolet A light. UVB can damage keratinocyte DNA by causing
pyrimidine dimers and other DNA mutations. The damaged
DNA leads to errors in translation and transcription and ultimately can
lead to cancer. The p53 gene (TP53)
is one of the most frequently mutated genes.
This gene encodes a protein that is important in cell cycle arrest,
which allows for DNA damage repair and apoptosis of those cells that
have been damaged. If the p53
gene is dysfunctional, this critical cell cycle
arrest period is bypassed, and the cell is allowed to replicate without
the normal DNA repair mechanisms acting on the damaged DNA. This
ultimately leads to unregulated cell division and cancer.
Histology:
Actinic keratosis shows partial-thickness atypia
of the lower portions of the epidermis. The adnexal structures are
spared. SCC in situ shows full-thickness atypia of the epidermis that
also affects the adnexal epithelium.
SCC is derived from the keratinocytes. The
pathological findings are characterized by full-thickness atypia of the
epidermis and invasion of the abnormal squamous epithelium into the
dermis. Variable numbers of mitoses are seen, as well as invasion into
the underlying subcutaneous tissue. Horn pearls are often seen
throughout the tumor. The tumors are often described as being well,
moderately, or poorly differentiated. Many histological subtypes of SCC
have been reported, including clear cell, spindle cell, verrucous,
basosquamous, and adenosquamous cell carcinomas.
Treatment:
Actinic keratoses can be treated in myriad ways.
Cryotherapy with liquid nitrogen is very effective and can be used
repeatedly. If this fails to clear the area, or if the actinic keratoses
are numerous, medical therapy is often given with 5-fluorouracil (5-FU)
or imiquimod. These creams work, respectively, by directly killing the
affected cells or by causing the immune system to attack and kill the
affected cells. They are both highly effective. The disadvantage is that
they cause an inflammatory response that can be severe and cause
erythema, crusting, and weeping during the period of application,
usually 1 month or longer.
The treatment for SCC in situ is often
electrodessication and curettage or simple elliptical excision. 5-FU
cream is also effective but leads to a higher rate of recurrence than
the traditional surgical methods. 5-FU is appropriate as a first-line
agent for bowenoid papulosis. If in follow-up any residual areas are
left, surgical removal is indicated. Occasionally, large areas of SCC in
situ on the face are treated by the Mohs surgical technique.
Invasive SCC should be treated
surgically, with Mohs surgery for lesions on the face or recurrent
lesions; standard elliptical excision is adequate for most invasive
SCCs. Some small, well-differentiated SCCs have been treated
successfully with electrodessication and curettage. The metastatic rate
for cutaneous SCC is low, but certain locations have a higher rate of
metastasis. These areas include the lip, the ear, and areas of chronic
scarring or ulceration in which the tumors develop. Recurrent SCCs,
those larger than 2 cm in diameter, and those developing in patients
taking chronic immunosuppressive medications pose a higher risk for the
development of metastatic disease. Patients with chronic lymphocytic
leukemia (CLL) are at much higher risk for metastases; the reason is
unknown but is thought to be related to the immunosuppression resulting
from their CLL. The most common areas for metastasis are the local lymph
nodes and lung.
Metastatic SCC of the skin
should be treated with adjunctive radiotherapy and chemotherapy.
However, these therapies have not shown a clear survival benefit, and
the key to treatment ultimately lies in the prevention of metastasis.
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