Fibroepithelioma of Pinkus

Are You Confident of the Diagnosis?

Herman Pinkus first described the “premalignant fibroepithelial tumor of the skin” in 1953. This tumor later became known as Fibroepithelioma of Pinkus (FP). FP is an unusual neoplasm. There is significant controversy as to the most appropriate classification for this entity. FP is most commonly classified as a variant of basal cell carcinoma (BCC), which is the authors’ view; however, some dermatologists and dermatopathologists consider FP to be better characterized as a type of trichoblastoma, a benign follicular neoplasm that appears similar to BCC on clinical exam and histopathology.

What you should be alert for in the history

FPs have an indolent nature and are typically asymptomatic. Therefore, patients rarely present with any history other than a slow-growing asymptomatic lesion that sometimes hangs down from the skin. In contrast to other types of BCCs, bleeding and ulceration is uncommon.

Characteristic findings on physical examination

On physical examination, FP characteristically presents as single or multiple slow-growing, flesh-colored or erythematous, broad, dome-shaped, or pedunculated papules. Some present as large pedunculated tumors. Pigment is sometimes present.

Unlike other types of BCCs, most FPs are located on the lower trunk, particularly the lumbosacral area. Cases have also been reported in atypical locations such as the plantar surface, mucosa, perianal area, and genital area. The tumor sometimes presents in association with other lesions, including seborrheic keratoses and basal cell carcinomas. Various FP subtypes have been described, including cystic, pleomorphic, eroded, and giant.

Expected results of diagnostic studies

Dermoscopic features of FP include fine arborizing vessels, sometimes associated with dotted vessels, white streaks, gray-brown pigmentation (in pigmented FP), and gray-blue dots.

Diagnosis confirmation

FP is most commonly mistaken for benign skin lesions. Other entities that may appear clinically similar to FP include an acrochordon (soft fibroma), compound or dermal nevus, neurofibroma, hemangioma, pyoderma gangrenosum, nevus sebaceous of Jadassohn, nevus lipomatosus, and rarely, amelanotic melanoma. In contrast to FPs, acrochordons typically have a narrower base and lack erythema. Compound or dermal nevi lack erythema and pedunculation.

Neurofibromas are usually more compressible and lack erythema. Hemangiomas (angiomas) in adults characteristically present with more prominent erythema, uniform color and shape, and lack pedunculation. Pyoderma gangrenosum may begin as an erythematous papule, but typically rapidly develops into a painful ulcer with surrounding granulation tissue and, in contrast to FP, occurs most commonly on the lower extremities. Fibrous papules are characteristically more white and uniform in shape and color, and occur most commonly on the nose.

Nevus lipomatosus presents as single or multiple flesh-colored or erythematous nodules; however, it usually presents on the buttocks or upper thighs by age twenty. Amelanotic melanomas are not pedunculated.

Who is at Risk for Developing this Disease?

FP is a rare tumor; therefore, most published studies are case reports and case series, and little epidemiologic data is available. Since FP is usually classified as an unusual variant of basal cell carcinoma, most information is derived from BCC epidemiology. Unlike other types of BCC, which are most common on the head and neck, FPs occur most commonly on the lower trunk. This suggests that ultraviolet (UV) exposure may be less important for FP pathogenesis than other BCCs.

FPs usually occur in patients between 40 and 60 years of age. A few cases of FPs in children have been reported. Some reports indicate that FP is more common in women, unlike BCC, which is more common in men. However, other reports indicate an equal gender distribution.

FPs are more common among those with fair skin (Fitzpatrick skin types I and II) and at sites of prior radiation treatment. Other types of basal cell carcinomas are associated with extensive intermittent or cumulative lifetime UV exposure and history of prior nonmelanoma skin cancer, chronic arsenic exposure, treatment with oral methoxsalen (psoralen), and immunosuppression; however, it is unclear if these factors also increase the risk of developing FP.

What is the Cause of the Disease?

Etiology

The understanding of the pathogenesis of FP is incomplete. It is likely that mechanisms are involved that are similar to those involved in other types of BCC. However, unlike other BCCs, most FPs develop on the lower trunk; therefore, chronic UV damage may play a lesser role for FP, although it does occur more commonly in patients with Fitzpatrick skin types I and II.

Pathophysiology

Most FPs are sporadic. Other BCCs typically arise from the epidermis and occasionally from the hair follicle outer root sheath. BCCs are thought to arise from pluripotent cells in the basal layer of the epidermis. FP demonstrates a histologic pattern distinct from other BCCs. Some have postulated that tumor invasion of the eccrine duct produces the characteristic histology.

Development of BCCs can result from mutations in a variety of genes. UV exposure causes DNA damage and suppresses local immune response and immune surveillance. Some cases of BCC appear to result from UV-induced mutations in the p53 tumor suppressor gene. Deletion or mutation of the p53 gene prevents apoptosis of UV-damaged cells. Most BCCs over-express p53; however, FP demonstrates a lower level of staining for p53. Trichoblastomas also lack significant p53 staining; therefore, some argue that FPs more closely resemble trichoblastomas than BCCs.

Mutations in the sonic hedgehog (SHH) signaling pathway appear to play an important role in BCC development and possibly FP pathogenesis. Hedgehog is a critical regulator of cell growth and differentiation during embryonic development. In adult tissues, the SHH pathway is mostly inactive; however, activation of the pathway can lead to a variety of tumors, including BCC. Most BCCs have loss-of-function mutations that inactivate patched homologue 1 (PTCH1). Less commonly, BCC may have gain-of-function mutations that constitutively activate smoothened homologue (SMO).

In recent studies, PTCH knock-out mice exposed to ionizing radiation developed BCCs and trichoblastomas that were histologically similar to FP; however, nevoid BCC syndrome patients with PTCH mutations have not been reported to develop FP; therefore, other pathways may be involved.

Systemic Implications and Complications

FPs are not known to be associated with any systemic disorders; however, there are a few reports of FPs associated with other malignancies, including breast carcinoma and Paget’s disease. Unlike BCC, there are no published reports of FP associated with xeroderma pigmentosa, nevoid basal cell carcinoma syndrome (Gorlin syndrome), Rombo syndrome, or Bazex syndrome (also known as Bazex-Dupre-Christol syndrome).

Treatment Options

SURGICAL TREATMENTS

Excision with 4mm margins

Electrodessication and curettage

Mohs micrographic surgery

PHYSICAL MODALITIES

Cryosurgery

Radiation therapy

Photodynamic therapy

MEDICAL TREATMENTS

Topical/Intralesional imiquimod

Topical 5-fluorouracil (5-FU)

Optimal Therapeutic Approach for this Disease

Surgical excision is the first-line treatment for FP. Some FPs may be treated by electrodessication and curettage (ED&C). Under certain circumstances, Mohs micrographic surgery, and physical modalities such as cryosurgery and radiation therapy, may be indicated. Rarely, topical medical treatments may be employed. FPs behave less aggressively than other BCCs. There is one published case of metastases from FP but no reports of death. Selection of the most appropriate treatment requires consideration of tumor size and location, previous treatments, as well as patient factors including patient preference and the patient’s ability to tolerate surgery.

SURGICAL TREATMENTS

Surgical treatments generally have higher cure rates for BCCs than medical therapies. Although there are no published data on the cure rates of surgical modalities for FP, it is likely that FP cure rates are comparable to primary BCC, given the indolent nature of FP. FPs are most commonly treated with surgical excision or electrodessication and curettage.

Surgical Excision

Surgical excision is the first-line treatment for FP and is curative in most cases. As for many BCCs, surgical excision with 4mm margins is advisable and allows pathologic evaluation to confirm clear margins. Surgical excision with at least 4mm margins offers cure rates close to 95% for small (< 1cm) primary nodular BCC.

Electrodessication and Curettage (ED&C)

ED&C is an efficient treatment that offers a cure rate of 90% or higher for superficial BCCs and nodular BCCs less than 2cm on the trunk and extremities. Although no data on cure rates for FP are available, it is likely that cure rates are comparable to such low-risk BCCs.

ED&C is generally the least expensive treatment option; however, it is somewhat operator dependent and is a “blind” technique in that it does not allow pathologic evaluation of tissue to confirm clear margins. Electrodessication and curettage may produce cosmetically acceptable scars; however, ED&C often results in hypopigmented, atrophic, or hypertrophic scars that are less aesthetic than the fine linear scars resulting from excision by a skilled surgeon. The technique depends on the contrast between friable tumor tissue and firm normal dermis; therefore, it is suboptimal for FPs that demonstrate small tumor foci on pathology or FPs that have recurred after previous treatment.

Mohs Micrographic Surgery

Mohs micrographic surgery is the only technique that allows evaluation of the entire surgical margin. Mohs surgery offers the highest long-term cure rate of any treatment for BCC, with cure rates of 98%-99% for primary BCC. Mohs surgery allows evaluation of 100% of the tissue margin, whereas traditional excision uses standard vertical “bread-loaf” sectioning, which allows evaluation of less than 1% of margin. Therefore, Mohs surgery allows smaller margins than traditional excision and is thus tissue-sparing.

Given that most FPs are located on the lower trunk and follow a less aggressive course, tissue conservation and complete margin evaluation may not be necessary for most FP tumors. Mohs surgery is most useful for FP tumors that are large (> 2cm), recurrent, or in higher risk locations, such as the head and neck. Mohs surgery is more time and labor intensive than other techniques; however, Mohs surgery is similar in cost to excision with permanent sections, and is less costly than excision with frozen section pathology.

PHYSICAL MODALITIES

Physical modalities, including cryosurgery and radiation therapy, may be used for FP in certain settings. Such modalities are less invasive than surgery but offer no pathologic evaluation to confirm clear margins. There are no published data on cure rates for FP treated by such physical modalities; however, it is likely that cure rates for FPs are comparable to primary BCC.

Cryosurgery

Cryosurgery offers cure rates of 90% or higher for low-risk BCC. Cryosurgery is an efficient treatment but is operator dependent. Some degree of pain or discomfort and postoperative swelling is expected due to the freeze-thaw cycle and necrosis of tumor tissue. Cryosurgery may produce good cosmetic results, particularly in fair-skinned patients; however, hypopigmentation is common and scarring may be less predictable than with other treatments. The best candidates for cryosurgery are patients with low-risk lesions, those with fair skin (Fitzpatrick Type I), and those who are unable or unwilling to tolerate a more invasive surgical procedure.

Radiation Therapy (RT)

RT can offer cure rates of 90% or higher for primary BCCs. This is comparable to cure rates obtained with treatment by excision or electrodessication and curettage. RT may be useful for elderly or debilitated patients who cannot tolerate surgery.

Disadvantages of RT include high cost, patient inconvenience, and adverse effects. Full radiation treatment typically requires 15 to 30 treatment sessions over 2 to 6 weeks. Higher numbers of treatment sessions at lower radiation dose fractions generally provide better cosmesis but involve greater patient inconvenience and higher cost.

Following RT, initial cosmetic results may be good to excellent; however, long-term cosmetic results tend to be suboptimal. In a large retrospective review, the proportion of BCC sites treated by RT with good or excellent long-term cosmetic outcomes was only 63%, which was significantly lower than ED&C or surgical excision. Recurrent BCCs in previously irradiated areas are often very aggressive and difficult to treat. Reconstruction options are also limited in irradiated skin due to fibrosis and compromised vasculature.

Radiation oncologists typically treat BCC with superficial/orthovoltage x-ray radiation or electron beam radiation (EBR). Superficial x-rays have a useful depth of less than or equal to 5mm and are best suited for superficial skin cancers. EBR is more commonly available and may be used for superficial tumors with careful treatment planning. National Comprehensive Cancer Network (NCCN) guidelines recommend 5-10mm RT margins for BCCs less than 2cm, and 15-20mm margins for tumors greater than 2cm. An additional 5mm margin is often added for poorly defined lesions; therefore, irradiated areas can be significantly larger than the clinical tumor.

Early RT adverse effects may include redness, tenderness, warmth, xerosis, pruritus, peeling, oozing, and ulceration. Late adverse effects may include skin atrophy, scarring, telangiectasia, hyperpigmentation, alopecia, non-healing ulcers, and subsequent development of skin cancers in the treated area. Mucosal surfaces tend to tolerate RT well, whereas areas subjected to frequent trauma, such as the hands and feet, are less well suited to RT.

Photodynamic Therapy (PDT)

PDT is a newer modality, is generally well-tolerated, and provides excellent cosmetic results. In studies, PDT cure rates for BCC range from 70% to 80%; however, PDT may be less effective for FP than BCC. Although little data is available, surgical modalities most likely provide higher cure rates than PDT.

PDT involves application of porphyrins, which are photosensitizers, to tumor tissue in the physician’s office. When this porphyrin is activated by specific wavelengths of light, toxic oxygen-free radicals are generated and selectively destroy tumor tissue, while causing minimal damage to surrounding normal skin. The abundant fibrous stroma associated with FP may interfere with PDT efficacy. In addition, pigmented FPs may not respond to PDT due to absorption of photoactivating light by melanin.

In the United States, 5-Aminolevulinic acid (ALA) is the only PDT agent that is FDA approved. PDT is FDA approved for treatment of actinic keratoses, but also has been used to treat BCCs. Superficial BCCs respond better to PDT treatment than deeper tumors or more aggressive histologic subtypes. Patients must be instructed to avoid UV exposure following PDT because such exposure may lead to erythema and rapid development of sunburns.

Other PDT agents are not yet approved in the United States. Methyl aminolevulinic acid (MAL) is approved in Europe for treatment of superficial BCC and appears to be more effective than ALA in treating BCC. MAL has achieved 3-month complete response rates of 85% to 93% for superficial BCC and 75% to 82% for nodular BCC. However, in a recent case study, nine treatments with topical MAL and red light failed to clear a FP. Porfimer, which is administered intravenously, can cause generalized photosensitivity that may last for several months. Other PDT agents remain under investigation.

MEDICAL TREATMENTS (TOPICAL)

Topical medical treatments for FP may be considered in patients who are unwilling or unable to tolerate surgical modalities. There are no published data on cure rates for topical imiquimod and topical fluorouracil for FP. Both agents are FDA approved for treatment of superficial BCCs under 2cm in diameter.

Imiquimod

In studies, imiquimod has achieved cure rates of at least 70% for superficial BCC. Imiquimod is available as a 5% or 3.75% cream, and stimulates a local immune response to the tumor via activation of toll-like receptors 7 and 8. Imiquimod appears to recruit lymphocytes, dendritic cells, and macrophages to the local area. Imiquimod stimulates prominent cytokine release, mediated predominantly by interferon, and leads to apoptosis and tumor regression.

The most common imiquimod treatment regimen for BCC is once daily application on weekdays (five times weekly) for 6 weeks; however, treatment should be continued until clinical clearance of the tumor is achieved or an alternate treatment is selected. In addition, some patients may not tolerate five times weekly application and less frequent application over a longer time period is sometimes necessary. In some cases, topical imiquimod has been used to treat small nodular BCCs in low-risk locations, but cure rates are lower than for superficial BCCs. Adverse effects may include erythema, stinging, burning, pruritus, ulceration, dyspigmentation, and scarring as well as occasional systemic flu-like symptoms.

Imiquimod should be used with caution in patients with autoimmune diseases such as lupus, and in those who are immunosuppressed such as transplant and HIV patients. Flare of autoimmune disease, particularly systemic and subacute cutaneous lupus, is possible with imiquimod use. Imiquimod should only be considered in such patients if other treatment options have failed or are impractical. Patients should be monitored closely for potential autoimmune disease flares. The cost of treatment with imiquimod, including medication and office visits, is similar to the cost of office-based surgical excision and repair.

Topical 5-FU

Topical 5-FU has demonstrated cure rates of approximately 80% for superficial BCC. Topical 5-FU interferes with DNA and RNA synthesis by blocking the methylation reaction of deoxyuridylic acid to thymidylic acid, which impedes cell growth and division and leads to tumor cell apoptosis. Topical 5-FU 5% cream is typically applied twice daily for 6 weeks.

Both topical 5-FU and imiquimod pose a risk of incomplete treatment. A BCC may appear to be clear clinically; however, pathologic evaluation may demonstrate residual areas of tumor that are not clinically apparent. Topical 5-FU is slightly less expensive than imiquimod. Adverse effects may include erythema, stinging, burning, pruritus, and hypopigmentation.

Patient Management

Most dermatologists recommend follow-up for complete skin examinations at least every 6 to 12 months. All previous FP sites should be monitored for signs of recurrence. More frequent follow-up is often recommended if patients have developed multiple tumors in a short time period or continue to develop new suspicious lesions.

The role of UV damage in FP pathogenesis remains unclear; nevertheless, it is prudent to counsel patients regarding UV avoidance and protection. Patients should be encouraged to use broad-spectrum sunscreens with sun protection factors of 30 or higher, wear a broad-brimmed hat during outdoor activities, and engage in outdoor activities before 10 am or after 4 pm. Even among older patients, UV avoidance and protection appears to decrease the risk of developing nonmelanoma skin cancers.

Unusual Clinical Scenarios to Consider in Patient Management

Although characteristically on the trunk, FPs may appear at unsual sites, including the genitalia.

FPs are not known to be associated with any systemic disorders; however, there are a few reports of FPs associated with other malignancies, including breast carcinoma and Paget’s disease.

What is the Evidence?

Ackerman, AB, Gottlieb, GJ. “Fibroepithelial tumor of Pinkus is trichoblastic (basal-cell) carcinoma”. Am J Dermatopathol. vol. 27. 2005. pp. 155-9. (Discussion that goes on to supply evidence that FP is actually a basal cell carcinoma. Well written and compelling.)

Aszterbaum, M, Epstein, J, Oro, A, Douglas, V, LeBoit, PE, Scott, MP, Epstein, EH. “Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice”. Nat Med. vol. 5. 1999. pp. 1285-91. (Well-performed study showing that UV and radiation both increase the risk of BCC development in mice.)

Betti, R, Inselvini, E, Carducci, M, Crosti, C. “Age and site prevalence of histologic subtypes of basal cell carcinomas”. Int J Dermatol. vol. 34. 1995. pp. 174-6. (Large review of subtypes of BCC including FP, with demographic patient population information.)

Bowen, AR, LeBoit, PE. “Fibroepithelioma of Pinkus is a fenestrated trichoblastoma”. Am J Dermatopathol. vol. 27. 2005. pp. 149-54. (Authors' opinion that FP is a form of trichoblastoma.)

Cohen, PR, Tschen, JA. “Fibroepithelioma of Pinkus presenting as a sessile thigh nodule”. Skinmed. vol. 2. 2003. pp. 385-7. (Case report discussing the natural history, clinical findings, and therapy.)

Heymann, WR, Soifer, I, Burk, PG. “Penile premalignant fibroepithelioma of Pinkus”. Cutis. vol. 31. 1983. pp. 519-21. (Unusual location of a FP—seen on the penis.)

McNiff, JM, Eisen, RN, Glusac, EJ. “Immunohistochemical comparison of cutaneous lymphadenoma, trichoblastoma, and basal cell carcinoma: support for classification of lymphadenoma as a variant of trichoblastoma”. J Cutan Pathol. vol. 26. 1999. pp. 119-24. (Discusses the immunohistochemical findings in various forms of BCC and close variants.)

Park, MY, Kim, YC. “Fibroepithelioma of Pinkus: poor response to topical photodynamic therapy”. Eur J Dermatol. vol. 20. 2010. pp. 133-4. (FP treated with PDT with suboptimal results.)

Pinkus, H. “Premalignant fibroepithelial tumors of skin”. AMA Arch Derm Syphilol. vol. 67. 1953. pp. 598-615. (Original article describing FP)

Su, MW, Fromer, E, Fung, MA. “Fibroepithelioma of Pinkus”. Dermatol Online J. vol. 8. 2006. pp. 12-2. (Nice overall review of FP)

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