Histologic changes of basal cell carcinomas during vismodegib treatment

Abstract

We report a case of a 63-year-old man with a history of numerous basal cell carcinomas (BCCs) on vismodegib who developed a pink subcutaneous nodule that was thought to be either a BCC or an epidermal inclusion cyst. Sections displayed a dome-shaped lesion composed of large dermal nodules of epithelioid cells with variable cytology. Some of the dermal nodules demonstrated squamatization of the epithelioid cells while others had a predominantly basaloid phenotype. Central necrosis was present in the majority of the large dermal nodules, but the lesion did not stain with CK7 or CK20, helping to rule out internal metastases. The epithelial nodules stained strongly with pancytokeratin (AE1/AE3), p40, and stained lightly with BCL-2, supporting the diagnosis of BCC. However, Ber-EP4 being negative and the presence of significant squamatization suggest vismodegib can alter both the histological and immunophenotype of BCCs. This phenomenon has rarely been reported in literature.

KEY POINTS

• The histology and immunophenotype of basal cell carcinomas can be altered by vismodegib.

• Squamous differentiation and the keratinizing phenomena can be observed in basal cell carcinomas being treated with vismodegib.

• Due to these alterations, patients on vismodegib should maintain regular skin checks and have any suspicious lesions biopsied.

CME

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CASE SUMMARY

A 63-year-old man with a history of numerous basal cell carcinomas (BCC) on vismodegib due to having locally advanced tumors at other sites presented to the clinic with a 1.2 × 1.1 cm pink subcutaneous nodule on the left upper middle chest (Figure 1). There was no previous BCC at the site of the lesion, and it was thought to be either a ruptured cyst or other neoplasm and was biopsied because of its unusual presentation. To confirm the nature of the lesion, a shave biopsy was performed.

Figure 1.

Pink subcutaneous nodule, 1.2 × 1.1 cm, on the left upper middle chest.

On histology, the lesion was squamatized with loss of peripheral palisading and marked central necrosis of many islands of tumor cells. Pleomorphic cells and atypical mitoses were present. Clefting was focally present but always in areas with a brisk surrounding inflammatory infiltrate. The squamatization consisted of hypereosinophilia of the lesional cells. Individual cell hyperkeratinization was also present, and a focal, ruptured keratinous cyst was present in a portion of the lesion. Degenerative changes suggestive of duct formation, some of which contained mucin, were noted in numerous foci within the lesion. Lichenoid inflammation was noted in several foci surrounding tumor nodules. Deeper sections showed the presence of adnexal structures (not shown). Figure 2a displays a dome-shaped lesion composed of large dermal nodules of epithelioid cells with variable cytology. Some of the nodules demonstrated squamatization of epithelial cells (Figure 2b), while others had a predominantly basaloid phenotype (Figure 2c). The epithelial nodules stained strongly with pancytokeratin (AE1/AE3) and p40, indicating a primary cutaneous keratinocytic neoplasm (Figure 3a,b). The nodules stained lightly with BCL-2, supporting the diagnosis of BCC (Figure 3c). The lesion did not stain with CK7 or CK20, evidence against a metastatic origin. Ber-EP4 stain was negative (Figure 3d). Appropriate controls were performed.

Figure 2.

Nodule that demonstrated squamatized phenotype: (a) 10× magnification, hematoxylin and eosin; (b) 20× magnification. (c) Nodule that has a basaloid phenotype. 20× magnification.

Figure 3.

Immunohistochemistry with (a) pancytokeratin (AE1/AE3), (b) p40, (c) BCL-2, and (d) Ber-EP4. (a, b, c) 20× magnification; (d) 10× magnification.

CLINICAL QUESTIONS

1. A 63-year-old man presents to the office for a subcutaneous nodule on his chest that has been present for a few months. Upon questioning, he reports that the lesion has grown in size but remains otherwise asymptomatic. On physical exam, the lesion is a 1 cm pink subcutaneous nodule. Telangiectasias are noted on dermoscopy. The lesion is biopsied and results reveal BCC. What histological markers are expected to be found?

   •   a.BerEP4, BCL2, CD10, pancytokeratin (AE1/AE3)
   •   b.S100, SOX10, MelanA/MART1
   •   c.EMA, BerEP4, adipophilin (membranous vesicular pattern)
   •   d.CK20, CD56, chromogranin, synaptophysin

2. What is vismodegib’s mechanism of action?

   •   a.Inhibits thymidylate synthase
   •   b.Hedgehog pathway inhibitor
   •   c.PD-1 inhibitor
   •   d.Epidermal growth factor inhibitor

Answers are provided at the end of the article.

DISCUSSION

Vismodegib is a small molecule that inhibits the hedgehog pathway by inhibiting Smoothened. Therefore, vismodegib is a helpful treatment for patients with locally advanced BCC who are unsuitable surgical candidates or for those with metastatic BCCs.¹

BCCs that achieve a complete response when treated with vismodegib will regress, presenting clinically with a scar the same size and shape as the original lesion.¹ Among patients treated with vismodegib, two-thirds will have an objective response and one-third will have a complete response.² Since vismodegib’s initial approval by the US Food and Drug Administration in 2012, few articles have been published on the histological appearance of BCCs during vismodegib therapy.¹

The lesion was diagnosed as a BCC with reactive squamous metaplasia. The most likely differential diagnosis would be a basosquamous carcinoma (BSC). However, we typically use the following histologic criteria for the diagnosis of BSC: loss of Ber-EP4 staining in portions of the tumor, loss of palisading, increased nuclear atypia, significant squamous differentiation, and loss of basaloid cytology in portions of the tumor.³ The lesion in our case could not be diagnosed as a BSC due to the complete loss of Ber-EP4 stain in all portions of the tumor. Since multiple biopsies of the lesion were not performed, we acknowledge that a single biopsy may not be fully representative of the tumor.

This case supports the concept that BCC histology and immunophenotype can be significantly altered during vismodegib treatment. Immunophenotypically, the lesions can have decreased or complete absence of critical markers. In this case, the decrease of BCL-2 and lack of Ber-EP4 expression—the markers demonstrating primary keratinocyte origin and histological features demonstrating a combination of basaloid and squamatized histology—agrees with previous literature findings of vismodegib-treated BCCs.^4,5 A possible explanation includes an “in transition” immunophenotype of a resolving or incompletely treated BCC. An alternative explanation is selection for hedgehog pathway–resistant tumor cells by vismodegib that may have altered gene expression that may lead to partial or complete switching of the tumor to an SCC. In one study, Kuonen et al proposed that vismodegib-resistant BCCs had increased RAS/MAPK activity, a well-known oncogenic pathway in the development of SCCs.⁶ In another study, Ransohoff et al demonstrated that vismodegib-resistant BCC switched to an SCC possibly through newly acquired mutations in NOTCH1/2 (important in tumor angiogenesis, immune cell responses, and tumor stem cells maintenance) and KMT2C (potential tumor suppressor).⁴

The lesion was excised, and the patient was advised to maintain regular skin checks and continue to monitor for suspicious lesions while on vismodegib.⁷ It was recommended that he continue vismodegib as tolerated until clinical resolution or treatment failure. Our patient continued treatment with vismodegib for 18 months and was clinically responding to the medication, implying that the patient’s treated lesions had not developed resistance. He stopped treatment at that time due to tolerability issues, including severe muscle cramping. At that point, most of his lesions had either complete clinical resolution or were at least significantly decreased in size. A positron emission tomography scan was not performed, because there was little concern for metastasis. This case highlights the importance of understanding potential histologic alterations that BCCs undergoing treatment with vismodegib may demonstrate. This knowledge can help providers identify BCCs in vismodegib patients and additionally raises awareness of the importance of biopsies to rule out other cutaneous and metastatic carcinomas.

ANSWERS TO CLINICAL QUESTIONS

Question 1, a. Patients with BCC are positive for BerEP4 (80%–100%), BCL2 (100%), CD10 (75.8%), and pancytokeratin (100%), which is useful in differentiating BCCs from other skin cancers.^4,8 S100, SOX10, and MelanA/MART1 (b) are stains commonly used in the diagnosis of melanoma.⁹ EMA, BerEP4, adipophilin (membranous vesicular pattern) (c) are stains commonly used in the diagnosis of sebaceous carcinomas. Adipophilin can be found in basaloid cells present in BCCs, but in a granular pattern.⁹ CK20, CD56, chromogranin, and synaptophysin (d) are stains associated with Merkel cell carcinoma, with the most characteristic being the perinuclear dot staining of CK20.⁹

Question 2, b. Vismodegib inhibits the hedgehog pathway by competitively inhibiting Smoothened. Smoothened is a G-protein-couple transmembrane receptor that works to transduce signals in the Sonic Hedgehog pathway.¹ Thymidylate synthase inhibitors (a) are a type of chemotherapy that blocks the synthesis of thymidine, which is a nucleoside required for DNA replication. This is the mechanism of action of 5-fluorouracil, which is commonly used to treat actinic keratoses, squamous cell carcinoma in situ, and superficial BCCs.¹⁰ PD-1 inhibitors (c) are a type of immunotherapy that blocks immune-suppressing ligands to help T cells better target and destroy cancer cells. Common examples include cemiplimab in the treatment of BCCs and SCCs and pembrolizumab in the treatment of BCCs, SCCs, melanoma, and Merkel cell carcinoma.¹¹ Epidermal growth factor (EGFR) inhibitors bind to the extracellular domain of EGFR to inhibit dimerization, which inhibits tumor growth. Cetuximab is one example that is indicated in the treatment of advanced SCC of the head and neck but is also used to treat cutaneous SCCs.¹¹

Disclosure statement/Funding

The planners and faculty for this activity have no relevant financial relationships to disclose. The patient consented to publication of this case report.