The applicability of Sonic hedgehog in mixed type basal cell carcinoma Zahra Ayu Lukita Sari, Yulia Farida Yahya, Theresia Lumban Toruan

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Journal of General - Procedural Dermatology & Venereology Journal of General - Procedural Dermatology & Venereology Indonesia

Indonesia

Volume 4

Number 2 Vol. 4, No. 2 (June 2020) Article 6

6-30-2020

The applicability of Sonic hedgehog in mixed type basal cell The applicability of Sonic hedgehog in mixed type basal cell carcinoma

carcinoma

Zahra Ayu Lukita Sari

Department of Dermatovenereology, Faculty of Medicine, Universitas Sriwijaya, dr. Moh. Hoesin General Hospital, Palembang, South Sumatera

Yulia Farida Yahya

Theresia Lumban Toruan

Follow this and additional works at: https://scholarhub.ui.ac.id/jdvi

Part of the Dermatology Commons, Integumentary System Commons, and the Skin and Connective Tissue Diseases Commons

Recommended Citation Recommended Citation

Sari, Zahra Ayu Lukita; Yahya, Yulia Farida; and Toruan, Theresia Lumban (2020) "The applicability of Sonic hedgehog in mixed type basal cell carcinoma," Journal of General - Procedural Dermatology &

Venereology Indonesia: Vol. 4: No. 2, Article 6.

DOI: 10.19100/jdvi.v4i2.128

Available at: https://scholarhub.ui.ac.id/jdvi/vol4/iss2/6

This Article is brought to you for free and open access by UI Scholars Hub. It has been accepted for inclusion in Journal of General - Procedural Dermatology & Venereology Indonesia by an authorized editor of UI Scholars Hub.

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Case Report

The applicability of Sonic hedgehog in mixed type basal cell carcinoma Zahra Ayu Lukita Sari, Yulia Farida Yahya, Theresia Lumban Toruan

Email: zahraayu07@gmail.com

Abstract

Background: Basal cell carcinoma (BCC) is the most common skin malignancy found in nonmelanoma skin cancer. There are multiple factors contribute to risks for BCC but the underlying mechanism is genetic alteration. The Sonic hedgehog (SHH) pathway is implicated in the etiology of the most common BCC. We reported BCC nodular type in the tip of nasal region with increase SHH.

Case Illustration: 50 years old man, presented with hyperpigmented tumor on the nasal tip which easily bleed since 6 months ago. Dermatological examination: the tip of nasal region: a solitaire irregular immobile hyperpigmented tumor, with the size of 2x1x0,3 cm, pearly border with rubbery consistency. Dermoscopy examination found multiple blue-gray globule and telangiectasia feature. Histopathology examination found nodule and micronodule with palisade feature in the periphery and “slit like retraction” in central.

Immunohistochemistry examination found more than 50% cell show SHH expression. Wide surgical excision was done with tumor margin 3 mm.

Discussion: The hedgehog (Hh) pathway known have important role in embryonic development, that responsible for patterning development organ and tisuue. SHH is one protein ligand that most study and well known in Hh pathways.

Conclusion: Activating SHH pathway can resulting in unrestricted SMO activity that causes uncontrollable cell proliferation and eventually carcinogenesis. Increased expression of SHH can be used as a marker in aggresivity of BCC.

Keywords: clinical manifestation, histopathology, immunohistochemistry, Sonic hedgehog pathway

Background

Basal cell carcinoma (BCC) also called Jacob’s ulcer, rodent ulcer, basal cell epithelioma or basalioma, is malignant neoplasm arising from the basal membrane of epidermis.^1,2 BCC was first identified in 1824, and commonly found among Caucasians. BCC accounts for as many as 75%

of all non-melanoma skin malignancies, and there is a trend towards higher incidence rate.^1,3

Complete data regarding the incidence of basal cell carcinoma in Indonesia is not yet established.

However, BCC incidence is increase with age and more common in men than women.⁴ A descriptive observational study conducted at Tumour and Skin Surgery Division, Department of Dermatovenereology, Faculty of Medicine, Sriwijaya University - M Hoesin General Hospital

primary BCC from a total of 15,845 new patients, consisted of 18 (35.4%) cases found in men and 30 (64.6%) cases in women with age ranged from 32-88 years.⁵

To date, the exact mechanism of growth and development of BCC is still controversial.

pathogenesis of basal cell carcinoma is influenced by intrinsic and extrinsic risk factors. Extrinsic factors, particularly UV exposure from sunlight, increases the risk of developing basal cell carcinoma. Recently, it is believed that intrinsic factors play an important role in the pathogenesis of BCC. Several studies that used transgenic murine with smoothened (SMO) mutation showed that cells in BCC originated from interfolicular epidermal layer that is promoted by Sonic hedgehog (SHH). Disturbance in SHH signal pathways affects the development of stem cells.

Elevation of SHH level leads to increased cell

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proliferation.⁶ The objective of this case report is to increase the knowledge and understanding about the role of SHH as a marker for development of BCC.

Case Illustration

A 50-year old man came to Dermatovenereology Clinic of Dr. Mohammad Hussein General Hospital with the chief complaint of having easily bleed, progressively enlarged mass on the tip of nose since around 6 months prior to admission.

According to autoanamnesis, around 5 years ago, he complained of having nodule that started to enlarge. About 6 months ago, the nodule further enlarged reaching the diameter of 2 cm. The mass started to feel itchy and easily bleed. The patient is a driver who is intensely exposed to sunlight approximately 3-4 hours a day without applying any sunscreen cream. There was no history of developing the same complaint in the family. The patient has been smoking around 20 years. There was no history of consuming anticoagulant medication, hypertension, and diabetes mellitus.

Physical examination revealed normal vital signs and good general condition. On the tip of the nasal region, there was a solitary hyperpigmented tumour, 2x1x0.3 cm, irregular border, pearly edge, with erythema and tenderness on the surrounding

tissue. Dermoscopic evaluation revealed multiple blue gray globules with telangiectasis and assessment using ABCD score suspected a malignant lesion. (Figure 1A and 1B). Differential diagnosis included nodular-type BCC and melanoma in situ.

Histopathological investigation revealed that there was tumour mass forming nodular and micronodular structures consisted of proliferation of basaloid cells with oval nucleus, hyperchromatic, limited cytoplasma, basophylic, which formed a palisading structure in the peripheral area and irregularly organized in the center with “slit-like retraction” found between stromal connective tissue and tumour mass in the dermis (Figure 2), suggesting a mixed type basal cell carcinoma. While immunohistochemistry evaluion it was found that more than 50% cells of the tumour expressed SHH (Figure 3).

The definitive diagnosis of this patient was mixed type BCC. The patient underwent wide surgical excision with a three-mm margin from the edge of the lesion followed by full-thickness skin graft with left and lower incision borders were not tumour- free. The patient was followed-up for 3 weeks post full-thickness skin graft and the color of the donor skin graft was similar to surrounding skin, without any signs of infection.

Figure 1. A) Clinical picture of patient B) Dermoscopy show blue gray nest (square) and telangiectasis (arrow)

A B

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Figure 2. Histopathologic findings in 100 times magnification(A) and 200 times magnification(B) shown tumor cell forming solid nodular lesion (red arrow), a palisading structure (black arrow) and “slit-like

retraction” (yellow arrow)

Figure 3. Immunohistochemistry examination with SHH staining in 200 times magnification were positive in the cell membrane, showed by brown colour (black arrow)

Discussion

In this case a 50-year old man with skin type 4 complained of having blackish nodule on the tip of nose. The predilection of BCC usually involves areas with high sun exposure, such as head and neck (52%), trunk (27%), upper extremities (13%) and lower extremities (8%). Approximately, 25- 30% of BCC of the face were found around the nasal area, which is considered as high-risk area due to its anatomic location and an issue in margin identification.³ As described, BCC is associated with sun exposure and 95% of cases were found around areas that intensely exposed to sunlight among the white-skinned population.

BCC located on the tip of the nose is common and has the ability to infiltrate and destruct the surrounding tissue.⁷ The risk of recurrence is

increased by 2.5 times in cases occurred around the nasal region.⁸

BCC has several clinical features, with the nodular type as the most common type. Which is commonly found around the head and neck.^2,3 According to the European Guidelines 2014 criteria, clinical diagnosis of BCC in categorized into nodular type which presented as papule or nodule with telangiectasia found around the lesion. Superficial type of BCC appears as a patch or erythematous plaque with scale.

Morphea type appears as a white scar-like plaque with induration and poorly-defined border.

Pigmented and ulcerative type can be found in the three aforementioned types.⁹ Clinical features of micronodular basal cell carcinoma include rising or flat yellow-whitish tumour infiltrate.¹⁰ In this

A B

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with characteristics of nodular type basal cell carcinoma.

According to WHO, diagnosis BCC by means of histopathological examination based on the growth pattern of the tumour cells consists of non- aggressive/low-risk and aggressive/ high-risk basal cell carcinoma. Several subtypes that are classified into aggressive type, include morphea, infiltrative, micronodular, basosquamous/

metatypical/ mixed basal cell carcinoma, whereas those categorized as non-aggressive basal cell carcinoma include nodular and superficial type.

High-risk basal cell carcinoma is correlated with the aggressive type due to its subclinical tumour spread, aggressive nature of tumour cells, and incomplete tumour excision. There are some features that indicate high risk for recurrence and also used for cancer staging, which are tumour that embodies more than 2 mm thickness, tumour invasion to the lower dermis or subcutaneous layer, invasion to adjacent nerves, and tumour occuring around ear or upper lip.^11,12 As in this case, tumour nest comprising of basaloid cells in a palisading arrangement in the peripheral part (micronodular). Surrounded by connective tissue in the dermis and accompanied by slit-like retraction which had thickness of more than two mm and invaded the lower dermis. These features are in accordance with the characteristics of mixed type basal cell carcinoma with a high risk of recurrence. In this case, the clinical and histopathological features showed different characteristics, hence we conducted a more specific test which was SHH molecular test.

The mechanism of a signal pathway in BCC remains uncertain. However, A study stated that the development of BCC is affected by an increase in SHH expression.¹³ In the development of mammals, it is known that SHH plays an important role in cell proliferation through intercellular communication, regulation of cell death and stem/ germinal cells’ survival. SHH also takes part in the self-renewal process of stem cells in integumentary and other systems. In contrast with the embryonic period, SHH pathway is turned off in adult and an increase in SHH leads to suppression of patched (PTCH) and smoothened (SMO) expression, where in a normal state, SMO activates Gli under the influence of PTCH. Increased SHH ligands promote transcription of GLI expression in a cell nucleus that causes uncontrollable cell proliferation and eventually carcinogenesis.^6,8,13 SHH test is a quantitative method for assessing the number of cells expressing SHH by looking at

the dark-brown color intensity per 10 visual fields with 400x magnification where it was observed that more than 50% of tumour cells expressed SHH (+4). In this case, an increase in SHH expression was in accordance with histopathological features as micronodular is considered as a marker of tumour aggressiveness. This was supported by a study conducted by Celebri et al. that concluded SHH signal has a role in the conversion of carcinoma in situ to an invasive type and also another study by Kim that analysed immunohistochemistry features of SHH signal in prostate adenocarcinoma and concluded that SHH expression is associated with aggressive tumour.^6,14

In this case, which conceived non-tumour free margins of incision and high SHH expression, it is highly possible that the patient would develop recurrence, therefore routine observation is highly necessary.

Conclusion

This paper reports a case of BCC that occurred in a 50-year old man. Based on clinical features, the patient was considered to have nodular type BCC which is in contrast with the results form histopathological study showing the characteristics of micronodular type basal cell carcinoma. SHH as biomolecular test support the diagnosis of mixed basal cell carcinoma in accordance to histopathological finding.

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