Metastatic Skin Cancer Presenting as Ptosis and Diplopia
Gary D. Monheit, M.D.
Associate Professor
Department of Dermatology
University of Alabama at Birmingham
Birmingham, Alabama

Abstract

The keratoacanthoma (KA) can cause a therapeutic conundrum due to its relationship and at times difficult distinction from squamous cell carcinoma both clinically and histopathologically. Some have described this entity as a benign squamous neoplasm advocating watching and monitoring the lesion until regression has occurred while others have described their metastatic potential. We present a case of an aggressive metastatic keratoacanthoma in a healthy Caucasian male with no prior history of skin cancer or trauma to the area of the primary lesion.

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The keratoacanthoma (KA) is a tumor that is characterized by a rapid proliferative stage followed by a stable mature stage leading to spontaneous involution leaving in its wake a scar. It is a relatively common tumor occurring mainly on sun-exposed areas in actinically damaged skin. The following case report involves an atypical aggressive keratoacanthomatous exhibiting behavior worthy of this report. Its peak incidence is between the ages of 50 and 69 and the lesions typically occur as a solitary tumor. While there is a strong suggestion of UV light playing an inciting role in their development, other related factors such as genetics, immunosuppression, chemical carcinogens, viruses, and trauma have also been postulated.1,2 Multiple cases of keratoacanthomas associated with previous trauma have been reported.3

Typically KAs are solitary, however multiple KAs have been characterized. Multiple keratoacanthomas occurring at a young age occurs in the inherited disorder of the Ferguson-Smith type. Generalized eruptive KAs of Grzybowski is characterized by thousands of small, disseminated KAs. KAs also occur more commonly in patients with Muir-Torre syndrome and xeroderma pigmentosum.

Conservative yet complete excision is advocated as the treatment of choice by the majority due to the potential for aggressive, yet typical non-aggressive behavior of the keratoacanthoma. The authors agree with this treatment of choice, however, the treatment of each KA should be individualized based on its clinical behavior and the patient’s general health.

Case Report

A 58-year-old Caucasian male presented with an asymptomatic erythematous papule on his nasal tip beginning as an erythematous macule two weeks earlier. Physical examination revealed a firm red dome-shaped papule 0.6 cm in size. The patient was a healthy individual with no prior history of trauma to this area. The lesion was diagnosed as folliculitis and the patient was begun on an antibiotic regimen. The lesion continued to grow and the patient was seen two weeks later at which time the lesion was 2.0 cm in size and had a keratinacious core. The lesion was treated with shave electrodessication and curettage and the specimen sent to pathology.(Fig 1) The histopathology was consistent with well-differentiated squamous cell carcinoma-keratoacanthomatous type.

Two weeks later the patient presented to our clinic. On physical examination, the patient was found to have a 4.0 X 4.0 X 3.0 cm red firm exophytic tumor with keratinacious ulcerated center extending from his nasal tip onto the nasal dorsum.(Fig 2) No lymphadenopathy, pain, or neurological deficits were noted and the patient was feeling well. The Mohs procedure was preformed on this patient, and the tumor was cleared in three Mohs layers. The end defect resulted in loss of full thickness soft tissue with some collagen loss of the nasal tip, supratip, and dorsum, extending to but not encompassing the ala. There was partial loss of both lateral cartilages and nasal mucosa of the nasal tip with reconstruction.(Fig 3)

Histologic review of the tumor revealed large pink epithelial cells with few mitoses. A tendency for maturation of the keratinocytes occurred at the sides and base of the lesion. A large central keratin plug was noted in the center with whirls of keratin appearing throughout the lesion.(Fig 4)

Within two weeks of the Mohs procedure, the patient presented to our office with a 1.3 cm recurrent lesion on the columella which was cleared in two Mohs layers.(Fig 5, Fig 6) The histology showed an exophytic mass of large well-differentiated keratinocytes with horn pearl formation.(Fig 7) The patient had no lymphadenopathy, no neurological deficits, and was feeling well.

Two weeks later the patient first noted a blurring of his vision and ptosis of his right upper eyelid.(Fig 8) He stated he was seeing double. No pain was noted although the patient was experiencing occasional headaches. No lymphadenopathy was present. Also at this time a 0.7 cm recurrence of the tumor was noted on his nasal dorsum.(Fig 9) The tumor was cleared in 2 Mohs layers and the histology was similar to the histology of the columella recurrence showing an exophytic mass of large well-differentiated keratinocytes with horn pearl formation.

The patient was referred to a neuroophthalmologist. On physical examination the visual acuity of the right eye was 20/30 and the left eye was 20/20. Both pupils were equal and reactive to light and accommodation. Extraocular movements of the right eye were 10% of normal for all gazes. Extraocular movements of the left eye were normal. Cranial nerves 5 and 7 were intact bilaterally. A diagnosis of unilateral cranial nerves 3, 4, and 6 palsy was made and a mass in the cavernous sinus was suspected. An MRI was obtained to determine the etiology. The MRI revealed an increase in contrast uptake surrounding the carotid flow void in the right cavernous sinus. There was no evidence of parenchymal involvement in the brain.(Fig 10) Due to the acute and unilateral nature of the symptoms and the patient’s previous history of aggressive keratoacanthoma, a diagnosis of metastatic squamous cell carcinoma-keratoacanthomatous type to the apex of the cavernous sinus was made. A PET scan also demonstrated intense hypermetabolic uptake in the right cavernous sinus with an SUV of 11.7. No other uptake was noted in the head, neck, or chest.

A tumor panel was held, and it was decided that the best method of treatment would be palliative chemotherapy and radiation treatment. Fractionated radiotherapy was decided upon due to the proximity of the tumor to the optic nerve. The poor prognosis was discussed with the patient. Interestingly the patient’s eye movement and double vision began to improve before therapy was begun. Even with this improvement in symptoms before treatment, the decision for radiation and chemotherapy was made due to the very poor prognosis of tumor in the cavernous sinus.

The patient underwent chemotherapy utilizing Carbo/Taxol on a weekly bases for a total of 4 weeks and radiotherapy receiving a total of 60 Gy. He currently has no ptosis of the right eye and his extraocular movements are intact bilaterally. Figure 11 He states that his double vision no longer occurs regularly, however he will notice occasional double vision late in the evening when he feels his eyes are fatigued.

A repeat MRI done 6 weeks after finishing therapy (3 ½ month after original MRI) revealed an interval decrease in size of the right cavernous sinus mass with only subtle asymmetrical thickness and more intense enhancement of the right cavernous sinus versus the left. This represents improvement in the metastatic disease.

Discussion

The keratoacanthoma is a tumor that is characterized by three clinical stages: proliferative stage, mature stage, and involutional stage. The proliferative stage is characterized by rapid growth over a two to four week period often achieving a size of 2 cm or more with histology similar to a well-differentiated squamous cell carcinoma with many mitotic cells. The mature stage is typically characterized as a dome-shaped nodule with a keratinous core. The histopathological findings of a mature lesion are typically exoendophytic with an invaginating mass of keratinizing, well-differentiated squamous epithileum at the sides and bottom of the lesion. A central keratin-filled crater is present with lipping of the edges of the lesion which overlap the central crater, giving a symmetrical appearance. The epithelial cells are large with a eosinophilic hue to their cytoplasm. A mixed inflammatory infiltrate is present. The involutional stage tends to take place after a few months with tumor resorption leaving a scar. During the involutional stage the lesion flattens, keratinocytes become shrunken and stain intensely with eosin. Granulation tissue and fibrosis occur at the base of the lesion. Although some lesions may persist for more than a year, the typical course usually takes about 4 to 6 months.1 The mechanism that is responsible for the regression of KAs is poorly understood, but is thought to be an immunologically mediated response.4 Activated CD4-positive T lymphocytes are present in the infiltrate along with an increase in Langerhans cells.5 There is increased apoptosis of the keratinocytes and it has been noted that expression of bcl-2 is lost in regressing KAs.6

It is difficult to distinguish absolutely between keratoacanthoma and squamous cell carcinoma both clinically and histopathologically. Rapid growth and a keratin core help to distinguish the two clinically. However both can grow rapidly and when rapid growth occurs in squamous cell carcinomas, central necrosis of the tumor can lead to ulceration and scabbing which at times can be somewhat similar in appearance to the keratin core. Histological features which favor the diagnosis of KA over SCC include a symmetric exoendophytic lesion with lipping and a central keratin plug, as well as the pattern of cell keratinization with large central cells that have slightly paler eosinophilic cytoplasm.7,8,9 At the current time there is no immunohistologic staining pattern which easily and definitively distinguishes between the two diagnoses.

Malignant transformation and metastasis of KAs have been reported in the literature as rare but serious and at times life ending events. These reports lend themselves to the belief that the KA is in actuality an expression of squamous cell carcinoma and should not be considered a benign entity. The most evidential cases, reported by Hodak et al describe 3 cases of metastasizing KAs.10 Each case report includes a clinical and histopathologic diagnosis of primary KA treated with excision and a histologic diagnosis at the site of metastases consistent with metastatic KA. The first case described an immunologically competent 86-year-old female with diagnoses of KA on her cheek and resultant metastatic disease diagnosed in the ipsilateral parotid a few months later. She was treated with radiation therapy with no evidence of recurrence or further metastasis observed over a 2 year period. The second case describes an immunologically competent 86-year-old man with a diagnosis of KA on his left shoulder. Four months later, a left axillary mass was noted and was consistent with metastatic disease. The patient died several months later with the cause of death due to metastatic squamous cell carcinoma. The third case describes an immunologically competent 77-year-old man with a KA on his neck and a subsequent metastatic lymph node 2 cm from the primary lesion. Six months after the node was excised in total, no recurrence or metastatic disease was noted.10 Another example of aggressive KA in the literature is reported by Piscioli et al describing a 9 cm KA in a patient with impairment of cellular immunity which recurred locally and metastasized to regional lymph nodes. No follow up on the patient was given.11

One other case of invasive KA with metastatic disease to the cavernous sinus has been reported. Grossniklaus et al reported 3 patients with a diagnosis of superficially invasive (extending into muscle and with perineural invasion) keratoacanthoma in the periorbital region. One tumor exhibited late perineural extension into the cavernous sinus which was confirmed histologically. No follow up on the patient was given.12

Our patient presented with an aggressive KA which metastasized to the cavernous sinus causing signs and symptoms consistent with cavernous sinus syndrome. The cavernous sinus is a small but complex structure housing a venous plexus, the carotid artery with its periarterial sympathetic plexus, and several cranial nerves. The abducens nerve (CNVI) runs lateral to the internal carotid artery, the oculomotor nerve (CNIII) runs in the most superior and lateral border of the sinus, the trochlear nerve (CNIV) runs just inferiorly to CNIII. More inferior but still within the lateral dural border of the cavernous sinus runs the ophthalmic division of the trigeminal nerve.

Cavernous sinus syndrome is characterized by multiple cranial nerve neuropathies. Deficits in these nerves can lead to impairment of ocular movements, Horner’s syndrome (miosis, ptosis, apparent enophthalmos, and hemianhidrosis), and sensory loss of more commonly the ophthalmic division of the trigeminal nerve and less commonly the maxillary division of the trigeminal nerve. The pupil can be involved or spared and pain associated with this syndrome is variable.

Several disease states other than neoplasms can cause a cavernous sinus syndrome. These include infections, noninfectious inflammatory disorders such as Tolosa-Hunt Syndrome, and vascular lesions.13

The most common neoplastic lesions in the cavernous sinus are caused by direct invasion of intracranial tumors such as pituitary adenoma.13 Less commonly, perineural spread of a head and neck malignancy or hematogenous spread from distant sites can occur. Most metastatic lesions to the cavernous sinus, orbital, or intracranial areas occurring from a primary lesion on the head and neck are thought to be due to perineural spread of squamous cell carcinoma.14,15 However, the diagnosis of an intracranial metastases in patients with head and neck squamous cell carcinoma is rare and carries with it a very poor prognosis.16,17 Zhu et al reported a case in which a 70-year-old male with multiple cutaneous SCCs of the head and neck developed metastatic disease of the cavernous sinus and leptomeninges, and cauda equina during a 5 year period histologically consistent with moderately differentiated SCC. Veness et al advocate adjunctive radiotherapy if perineural involvement is present in aggressive tumors on the forehead or periorbital area to prevent orbital spread.15

Our patient revealed an acute onset of diplopia due to a limited range of motion of the right eye as well as ptosis of the right eyelid. Due to the patient’s recent history of aggressive KA with two recurrent lesions on his nose, the acute nature of the deficits, and the unilaterality of the findings, a metastatic lesion was diagnosed and the need for a biopsy to verify diagnosis was not felt to be necessary. The MRI visually localized the lesion, however due to the patient’s findings of multiple CN deficits, the location of the lesion without MRI could be deduced. Our patient’s findings were consistent with a right sided CN III, IV, and VI palsy, with sparing of the pupil, vision, and sensation to the upper face. The cavernous sinus is the location where these three cranial nerves are in the closest proximity. CN III acts on the levator palpebrae muscle allowing elevation of the eyelid. Therefore a palsy of CN III can cause ptosis of the upper eyelid, however, if CNIII were the only nerve affected, the patient would have a fixed “down and out” gaze due to the unopposed action of the superior oblique and lateral rectus muscles. The patient had only 10% of normal ocular movement and double vision of all gazes. Therefore palsy of the CN IV and VI were also suspected. The sparing of the pupil is consistent with sparing of the papasympathetic fibers which run with CN III innervating the sphincter muscles of the iris and the ciliary muscle. Normal sensation to the V1 distribution of the face is consistent with sparing of the ophthalmic branch of CN V. Therefore localization of the metastatic lesion to a position just lateral and superior to the carotid artery in the cavernous sinus is possible without MRI.

We do believe that the two lesions occurring 2 weeks and 4 weeks after the initial Mohs procedure were recurrences of the original KA and stand by the diagnosis of KA as opposed to SCC. Rook and Champion reported that excision of KAs in the growth phase can be followed by “recurrence”.18 The authors agree with Haws et al and Griffiths that such recurrences are likely to represent a reactive process in the phase of proliferation rather than a neoplastic change of a KA to a SCC.19,20 This is further supported by the fact that trauma can induce KA lesions.3 It is possible that both the trauma from the excision and the fact that the KA excised was in the proliferative phase contributed to the recurrence or reactive proliferation of the primary lesion. This is further supported by the observation that local recurrence of invasive SCC after complete excision is extremely rare and when recurrence does occur, it occurs either months to years later within the scar of the excision site or as a regional lymph node metastases. It typically does not occur as a metastatic lesion to the skin somewhat near the primary lesion.

It is interesting to note that our patient was beginning to have improvement in his ocular symptoms and headaches before therapy was begun. The beginning of the regression in symptoms occurred 2 ½ months after the original red macule was noted on his nose. Even with this improvement in symptoms before treatment, the decision for radiation and chemotherapy was made due to the very poor prognosis of tumor in the cavernous sinus. Typically, squamous cell carcinoma metastatic to the cavernous sinus holds a survival time of under 6 months. It has currently been 3 ½ months since the patient first noted symptoms of cavernous sinus syndrome and his symptoms continue to improve.

The patient has since undergone chemotherapy and radiation treatment with recovery of his eye movement and resolution of his diplopia. Could it be that the keratoacanthoma had reached the involutional stage even before therapy was begun which could explain this improvement in symptoms with out therapy? A repeat MRI is scheduled in 6 months. The patient will continue to be followed closely.

Conclusion

The difficulty in definitive diagnosis and at times rare but aggressive behavior of this tumor can result in difficulty in treatment decision as well as patient counseling. Due to this difficulty most people advocate conservative excision, although many treatment plans have been tried for KAs. It is important that each lesion and patient is evaluated individually to ascertain the best treatment. KAs behaving aggressively must be respected and treated with early intervention and possibly adjunctive therapy.