Are You Confident of the Diagnosis?
Characteristic findings on physical examination
Inverted follicular keratosis (IFK) most commonly presents as a keratotic papule or plaque that is usually less than 1.0 cm at its greatest dimension and usually projects no more than 0.5 cm above the skin surface. An inverted component is often detected clinically. The lesion is usually reported to be present for several months prior to presentation.
Ninety percent of these lesions arise on the “head and neck.”, most commonly the face, including the eyelid and lip. However, presentations on the trunk and extremities have been reported. Based on physical examination, most IFK’s are clinically thought to represent verruca vulgares, seborrheic keratoses, or basal cell carcinomas. Only occasionally is the clinical diagnosis an IFK. Some lesions are suspicious for keratoacanthomas or squamous cell carcinomas. Because IFKs cannot be clinically diagnosed with certainty, histologic examination is required.
Expected results of diagnostic studies
Histologic examination reveals a partially exophytic, hyperkeratotic lesion with acanthosis and mild papillomatosis in addition to areas of hypergranulosis (Figure 1). Not surprisingly, the superficial portions of the lesion may be reminiscent of a verruca vulgaris. However, there is also an endophytic component in the form of an inverted, well circumscribed lobule composed of basaloid and squamoid cells.
The basal cells occupy the periphery of the inverted lobule with more squamoid cells occupying more central and superficial portions of the lesion. Squamoid cells with clear cytoplasm may be seen and in these instances, the lesion may be difficult to distinguish from a trichilemmoma (TL) (Figure 2). However, IFK usually lacks a thickened perilesional eosinophilic hyaline basement membrane, a characteristic feature of TL.
A pathognomonic feature of IFK is the presence of tight whorls of bland appearing squamous epithelial cells, commonly known as “squamous eddies” (Figure 3).
Squamous eddies are not a completely specific histologic feature as these may also be seen in irritated seborrheic keratoses. Mild squamous atypia may be seen and occasional mitotic figures may be seen in the basaloid layers. However, overt cytologic atypia or numerous or atypical mitotic figures should raise the suspicion of a squamous cell carcinoma (SCC).
A potential histologic pitfall is the presence of a basophilic stromal response within the confines of the lesion. This finding is similar to what may be seen in a desmoplastic TL (Figure 4), and should not be mistaken for a true desmoplastic stromal response at the advancing border of a SCC.
Because the superficial portions of inverted follicular keratoses can mimick verruca vulgares histologically (Figure 5, Figure 6, Figure 7)and because these two lesions cannot easily be separated clinically, some authors have proposed that inverted follicular keratoses are actually verruca vulgares. However, most studies have not shown any evidence of human papillomavirus within IFK, either by immunohistochemistry or by in situ hybridization or poymerase chain reaction.
IFKs may occasionally show an association with hair follicles or hair follicle-like structures and rarely, sebaceous lobules may be seen at the periphery. Also, IFKs have been shown to express CK17 by immunohistochemistry (Figure 8, Figure 9). This marker highlights the inner layers of the outer root sheath in normal skin and is diffusely expressed in IFK. The expression of this marker in IFK supports the contention that these lesions have a follicular origin and that they reveal outer root sheath differentiation. A report of an IFK arising in association with a trichoblastoma also supports this conclusion.
Lastly, IFK show a different immunohistochemical pattern of staining with bcl-2 antibody compared to seborrheic keratoses. Seborrheic keratoses may show epidermal bcl-2 immunopositivity. In contrast, in IFK the epidermal cells are negative, while there are scattered intraepidermal bcl-2 positive dendritic cells (likely bcl-2 Langerhans cells) (Figure 10).
Bcl-2 functions as an anti-apoptotic protein and its’ expression in Langerhans cells may indicate increased immunogenicity. The lack of bcl-2 immunostaining of epidermal cells in IFK with increased bcl-2 positive dendritic cells may indicate ongoing apoptosis with potential eventual regression of the lesion.
Who is at Risk for Developing this Disease?
Eighty percent of affected individuals are greater than forty years of age and men are more often affected than women. To this point, most cases have been reported in Caucasians.
What is the Cause of the Disease?
Systemic Implications and Complications
There is a report of multiple IFKs as a presenting sign of Cowden’s syndrome. As indicated above, histologically IFK may resemble TL, the classic cutaneous manifestation of Cowden’s syndrome. Therefore, if a patient presents with multiple keratoses that histologically represent IFK, a clinical evaluation for other mucocutaneous manifestations of Cowden’s syndrome, such as TL’s, acral keratoses, and oral and cutaneous fibromas, should be undertaken.
These patients are also susceptible to proliferations and neoplasms of internal organs including breast, thyroid, and endometrium, etc. Therefore, a careful clinical history to investigate for these internal manifestations may also be indicated.
As IFKs are not malignant and rarely recur, shave excision is usually the treatment of choice, but other superficial destructive modalities such as electrosurgery, cryosurgery, or laser ablation may also be appropriate therapies once the diagnosis is secured by histologic analysis. A recurrent lesion is usually treated by conservative excision.
Optimal Therapeutic Approach for this Disease
Only rarely do IFKs recur after biopsy; therefore, additional treatment after histologic diagnosis is not required. There are no reports of malignant transformation. In a clinically suspicious lesion, clinico,pathologic correlation is required as IFKs must be histologically distinguished from squamous cell carcinoma.
As indicated above, patients with solitary lesions are treated conservatively and excision is not required because IFKs are considered benign lesions. However, if the patient presents with multiple IFKs, consideration should be given to the possibility of Cowden’s syndrome.
In this situation, a detailed skin examination should be performed to exclude any other cutaneous stigmata of Cowden’s syndrome including TLs, acral keratoses, or oral or cutaneous fibromas. Furthermore, a detailed clinical history should be taken to ascertain whether or not the patient is exhibiting other internal signs of Cowden’s syndrome, such as breast, thyroid, or endometrial neoplasms.
Unusual Clinical Scenarios to Consider in Patient Management
As indicated, the most common site of presentation is the “head and neck,” including the lip and eyelid. However, cases do occur on the trunk and extremities and unusual sites of presentation have been reported, such as the conjunctiva and vulva. Furthermore, pigmented variants have been reported that may be clinically mistaken for melanoma.
What is the Evidence?
Spielvogel, RL, Austin, C, Ackerman, AB. “Inverted follicular keratosis is not a specific keratosis but a verruca vulgaris (or seborrheic keratosis) with squamous eddies”. Am J Dermatopathol. vol. 5. 1983. pp. 427-42. (Excellent review of the literature up to 1983, including clinicopathologic presentation of an additional 100 cases seen by the authors. The authors make an argument that inverted follicular keratosis is not a specific keratosis. In addition, there are excerpts from Helwig's original presentation and paper. Helwig is is considered the first to describe inverted follicular keratosis in 1954 at the Proceedings of the 20th Seminar of the American Society of Clinical Pathologists in Washington, DC.)
Mehregan, AH. “Inverted follicular keratosis is a distinct follicular tumor”. Am J Dermatopathol.. vol. 5. 1983. pp. 467-70. (Clinicopathologic description of 100 cases of inverted follicular keratosis. Dr. Mehregan argues that inverted follicular keratosis is a distinct tumor separate from verrucal vulgaris, seborhheic keratosis, or trichilemmoma.)
Mehregan, AH, Nadji, M. “Inverted follicular keratosis and verruca vulgaris”. An investigation for the papillomavirus common antigen. J Cutan Pathol. vol. 11. 1984. pp. 99-102. (An investigation for human papillomavirus antigen using immunohistochemical techniques did not reveal any evidence of viral infection in 20 cases of inverted follicular keratoses, suggesting that inverted follicular keratoses are not verruca vulgares.)
Thom, GA, Quirk, CJ, Heenan, PJ. “Inverted follicular keratosis simulating malignant melanoma”. Australas J Dermatol. vol. 45. 2004. pp. 55-7. (Presentation of a 93-year-old patient with a clinically pigmented lesion on the neck that dermatoscopically also simulated a malignant melanoma. However, histologically the lesion was an inverted follicular keratosis with melanin pigmentation.)
Schweitzer, JG, Yanoff, M. “Inverted follicular keratosis: a report of 2 recurrent cases”. Ophthalmology. vol. 94. 1987. pp. 1465-8. (Describes two patients with inverted follicular keratosis that each recurred approximately one month after excisional biopsy. The lesions were located on the eyebrow and eyelid and after reexcision, the lesions were completely treated without further recurrence.)
Roth, JM, Look, KY. “Inverted follicular keratosis of the vulvar skin”. A lesion that can be confused with squamous cell carcinoma. Int J Gynecol Pathol. vol. 19. 2000. pp. 369-73. (Description of the patient with a labia majora lesion that was initially histologically misdiagnosed as a squamous cell carcinoma.)
Cakmak, SS, Unlu, MK, Bilek, B, Buyukbayram, H, Sakalar, YB. “Conjunctival inverted follicular keratosis: a case report”. Jpn J Ophthalmol. vol. 48. 2004. pp. 497-8. Describes a 21-year-old male with an inverted follicular keratosis of the nasal bulbar conjunctiva that was treated with excisional biopsy with no evidence of recurrence on 9-month follow-up.)
Battistella, M, Peltre, B, Cribier, B. “Composite tumors associating trichoblastoma and benign epidermal/follicular neoplasm: another proof of the follicular nature of inverted follicular keratosis”. J Cutan Pathol. vol. 37. 2010. pp. 1057-63. (Describes trichoblastoma associating with other epidermal/follicular benign neoplasms, including four cases of an associated inverted follicular keratosis. The authors feel this association supports the follicular nature of inverted follicular keratosis. They also show that inverted follicular keratoses diffusely express CK 17. They also performed immunohistochemistry for human papillomavirus in four cases, all of which were negative.)
Ruhoy, SM, Thomas, D, Nuovo, GJ. “Multiple inverted follicular keratoses as a presenting sign of Cowden's syndrome: case report with human papillomavirus studies”. J Am Acad Dermatol. vol. 51. 2004. pp. 411-5. (Describes a patient who meets the clinical criteria for Cowden's syndrome who presented with multiple inverted follicular keratoses.) Human Papillomavirus studies by standard in situ hybridization as well as polymerase chain reaction (PCR) in situ hybridization did not reveal any “specific” or “novel” HPV types within the inverted follicular keratoses.
Ko, CJ, Kim, J, Phan, J, Binder, SW. “Bcl-2 positive epidermal dendritic cells in inverted follicular keratoses but not squamous cell carcinomas or seborrheic keratoses”. J Cutan Pathol. vol. 33. 2006. pp. 498-501. (Describes and contrasts the immunohistochemical pattern of staining between inverted follicular keratoses and seborrheic keratoses and squamous cell carcinomas. The authors speculate that the expression of bcl-2 in some seborrheic keratoses may indicate an antiapoptotic process that is absent in inverted follicular keratoses. Furthermore, the authors speculate that the presence of bcl-2 positive dendritic cells may play an immunologic role in controlling the growth of inverted follicular keratoses.)
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