STUDY OF BASAL CELL CARCINOMA OVER A 5YR PERIOD WITH HISTOMORPHOLOGICAL FACTORS THAT INFLUENCES ITS PROGNOSIS INCLUDING RECURRENCE
THE TAMIL NADU DR. M.G.R. UNIVERSITY, CHENNAI, TAMIL NADU MAY – 2020
REGISTRATION NUMBER: 201713356
STUDY OF BASAL CELL CARCINOMA OVER A 5YR PERIOD WITH HISTOMORPHOLOGICAL FACTORS THAT INFLUENCES ITS PROGNOSIS INCLUDING RECURRENCE
A dissertation in part fulfillment of the rules and regulations for the M.D. Branch III (Pathology) Degree Examination of the Tamil Nadu Dr. M.G.R Medical University, to
be held in May 2020.
CERTIFICATE
This is to certify that this dissertation entitled “Study of basal cell carcinoma over a 5yr period with histomorphological factors that influences its prognosis including recurrence” is the bonafide work done by Dr Preethi Mary Eapen, in part fulfillment of the rules and regulations for the M.D. Branch III (Pathology) Degree Examination of Tamil Nadu Dr. M.G.R. Medical University, to be held in May 2020.
Dr. Geeta Chacko, MD, PhD.
Professor and Head, Department of Pathology, Christian Medical College, Vellore.
Dr. Anna B Pulimood, MD, PhD.
Principal,
Christian Medical College, Vellore.
CERTIFICATE
This is to certify that this dissertation entitled “Study of basal cell carcinoma over a 5yr period with histomorphological factors that influences its prognosis including recurrence” is the bonafide work done by Dr. Preethi Mary Eapen, in part fulfillment of the rules and regulations for the M.D. Branch III (Pathology) Degree Examination of Tamil Nadu Dr. M.G.R. Medical University, to be held in May 2020.
The candidate has independently reviewed the literature, standardized the data collection methodology and carried out the evaluation towards completion of the thesis.
Dr. Meera Thomas, MD, Professor,
Department of General Pathology, Christian Medical College, Vellore.
CERTIFICATE
This is to certify that this dissertation entitled “Study of basal cell carcinoma over a 5yr period with histomorphological factors that influences its prognosis including recurrence” is a bonafide work done by me, under the guidance of Dr. Meera Thomas, in part fulfillment of the requirements for the M.D Branch III(Pathology) Degree Examination of the Tamil Nadu Dr. M.G.R Medical University, to be held in May 2020.
I have independently reviewed the literature, performed the data collection, analyzed the data and carried out the evaluation towards completion of the thesis.
Dr. Preethi Mary Eapen PG Registrar,
Department of General Pathology, Christian Medical College,
Vellore.
ANTIPLAGIRISM CERTIFICATE
CERTIFICATE
This is to certify that this dissertation work titled “Study of basal cell carcinoma over a 5yr period with histomorphological factors that influences its prognosis including recurrence” of the candidate Dr. Preethi Mary Eapen with registration number 201713356 for the award of Degree of MD Pathology in the branch III. I personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 7 percent of plagiarism in the dissertation.
Guide & Supervisor sign with Seal.
ACKNOWLEDGEMENT
This thesis would not have been possible without the encouragement and support of those closest to me. I take this opportunity to extend my sincere gratitude and appreciation to all those who made this MD thesis possible. First and foremost, I would like to extend my sincere gratitude to my thesis guide Dr. Meera Thomas, for her dedicated help, advice, inspiration, encouragement and continuous support, throughout my thesis.
I am grateful to Dr. Geeta Chacko our Head of Department for her timely advice and support without which this thesis would not have been possible.
I express my heartfelt thanks to all the teaching faculties and non-teaching staffs, for their support during the study, especially our lab staff who have put in a lot of their time and effort to help me.
I am thankful to Mrs.Grace Rebekah, for her statistical advice during data analysis which was pivotal in the making of my study.
I would like to acknowledge my parents, husband and family for their moral support and inspiration. A special thanks to my postgraduate colleagues for going out of their way to be there for me in my time of need.
ABBREVIATIONS
BCC- Basal cell carcinoma Bcl-2 -B-cell lymphoma 2 CYP- Cytochrome 450 DOI- Depth of invasion
EMA- Epithelial membrane antigen 5FL-5-fluorouracil
GST- glutathione S-transferase MC1R- melanocortin 1 receptor
NCCN- National comprehensive cancer network P53- Tumor protein (EC :2.7.1.37)
PNI- Perineural inflammation UV-Ultraviolet
XP- Xeroderma Pigmentosum
1
Contents
Introduction ……… 2
Aims and objectives ………....4
Review of literature ………....6
Materials and methods………38
Results and analysis………....43
Discussion………...74
Summary……… 86
Conclusion………...90
Limitation………93
Bibliography………....95
Annexure………107
2
INTRODUCTION
3
Introduction
Basal cell carcinoma(BCC) is the most common skin cancer worldwide. Basal cell carcinoma accounts for 75% of cases of all non-melanoma skin cancer worldwide.
(2)The incidence of BCC in the European population was 98.6 per 100,000 people per year(68) Comparatively the incidence is reduced in Asians and Africans due to increase in melanin pigment in the skin. (2) Many risk factors have been postulated in basal cell carcinoma like increased exposure to sunlight, immunodeficiency, exposure to arsenic, lighter skin, scars, etc.(3) Pathogenesis of basal cell carcinoma is said to be due to UV rays which induce production of pyrimidine dimers and loss of heterozygosity of both tumor-suppressive genes-P53 and PTCH, resulting in BCC. The mutations in the p53 tumor suppressor gene prevent apoptosis of UV- damaged cells. The tumor-suppressor gene P53 and melanocortin-1 receptor gene are also important for the development of the neoplastic process.(2,3)
The average occurrence is 66 years with a male-to-female ratio of 2.1:1. (30)Basal cell carcinomas generally occur in adults, although they may be seen in children.(2) However, the basal cell carcinoma with early-onset is associated with
syndromes.(2) They include Gorlin syndrome, Xeroderma Pigmentosum and Bazex syndrome.(2,12,13). Basal cell carcinomas are seen almost exclusively on the head, neck, back and chest.(37).
4
AIMS AND OBJECTIVES
5
Aims and objectives
1. Identify the predisposing factors that cause basal cell carcinoma and are involved in its recurrence.
2. To study and describe histomorphological parameters that influence the recurrence in BCC over a 5yr period from January 2013 to December 2017 3. To identify the incidence of p53 positivity in BCC.
6
REVIEW OF LITERATURE
7
Review of literature
Non-melanoma skin cancers are the commonest in the world. Basal cell carcinoma has a 75% predominance over squamous cell carcinoma. (2). Basal cell carcinoma commonly affects Caucasian with fairer skin working in sunnier climates.(1,2,3) .Higher UVR exposure is associated with a higher incidence of BCC. (3) The percentage of skin cancer varies in the Asians (2–4%) and Blacks (1-2%) as compared to the Caucasians (35–40%). (1). Jacob Arthur in 1827 first described basal cell carcinoma as “rodent ulcer”.(1) Basal cell carcinoma is a cancer that begins in the lower part of the epidermis i.e the basal layer of skin. It may appear as a small white pearly papule(2) that grows slowly and may bleed. They are usually found on areas of the body exposed to the sun. About 80% of basal cell carcinomas are seen in the head and neck region, followed by 25% in the trunk. (37). Males have an increased incidence of BCC with a male to female ratio of 2.1:1 (31) at a mean age of 66yrs (30). Basal cell carcinoma occurs between 50-80 yrs.(30,32) BCCs may also develop in scars or sebaceous naevi and are associated with several genetic syndromes. (3).
Dermoscopy may be helpful to identify arborizing blood vessels, ulceration, maple-leaf-like areas etc. In BCCs computer tomography or magnetic resonance imaging is performed for bony, vascular, or major nerve invasion. (3)Skin biopsy aids in confirming the diagnosis. (3)
8
Basal cell carcinomas are usually seen as single lesions. Presence of multiple lesions is often related to hereditary conditions like nevoid BCC syndrome, Rombo syndrome, Bazex syndrome and unilateral basal cell nevus syndrome. Non-
syndromic basal cell carcinomas are rare. (52). In a study by Kiiski V(62) et al 31.1% of basal cell carcinomas in their cohort had shown multiplicity which was commonly affecting the face then scalp (62)
Basal cell carcinomas rarely metastasize to other parts of the body. Squamous cell carcinoma has a significant rate of metastasis 3.7%, compared to BCC which is locally invasive with a metastatic rate of <0.1%. (2) Basal cell carcinoma if
untreated can cause extensive tissue destruction, disfigurement, infiltrate cartilage, muscle or bone with even intracranial extension. (3) The sites of metastasis are primarily to the bone and lungs. (3)Risk factors for metastasis are neglect over many years, perineural invasion, size over 10 cm2, basosquamous and sclerosing subtypes. (3)
Although there is a higher percentage of pigmentation in Indians(1), the incidence of skin cancers in India is low but the absolute number of cases may be significant due to the large population. The existing literature on BCC in India is scant. There have been few publications in which as quoted by Kumar S et al(1), the mean duration of disease was 4.7 years. As described by Kumar S et al(1), though there was higher sun exposure in males compared to females, BCC was commoner in females(63.9%). This has to be explained by intermittent sun exposure in women.
The majority of patients had a single lesion(88.9%). The head and neck region was
9
involved in the majority of cases, with nose being the commonest site (50%).
Nodular and nodulocystic (77.8%) morphology was seen in majority of cases. The mean duration of disease was 4.7 years. Though there was statistically significant higher sun exposure in males compared to females, BCC was commoner in
females. Pigmentation was evident in 22.2% of cases clinically. In another study by Purnima Malhotra et al (60), the most common location was the medial/lateral canthus of the eye. The three lesions on non-sun-exposed sites included thigh, vulva, and trunk.
Basal cell carcinoma in Asians:
In Asian studies by Dr. Moore MG et al(4), equal numbers of males and females in the Asian population developed BCC, whereas in Black Africans, there appears to be a predominance of women and in Caucasians, there appears to be a
predominance of men. These differences may be related to cultural patterns of sun exposure. (4)Asian patients were found to develop their first BCC at a later age and were less likely to develop additional lesions in their lifetime compared to
Caucasians, despite having similar levels of sun, chemical, smoking, and X-ray exposure. These findings help theorize that skin pigmentation is more protective of the carcinogenic effect of ultraviolet light in Asians compared to Caucasians. (4)
10
Types of Basal cell carcinoma:
Nodular BCC is the commonest subtype accounting for over 60% of cases of BCC.
Superficial BCCs account for up to 20% of cases. (2).Most nodular and morphoeic subtypes are found on the head and neck, in contrast to superficial BCC which occurs over truncal sites .(3) 1.5% is micronodular(42), 10.5% is infiltrating(42) 5% are sclerosing(6) and 6% are pigmented (43) in the western population. In an Indian study by Sumir Kumar et al(1) and Khullar G et al(66), the most common variant was nodular(77.8%) followed by pigmented (16.7%). Other subtypes including basosquamous (8.3%), micronodular (19.4%), morpheaform (2.8%), keratotic (2.8%), adenoid (2.8%) infiltrative(14.7%)(66)and BCC with adnexal differentiation (2.8%) were also observed in an Indian population. Associated amyloid may be present in all subtypes of BCC in the advancing edge. They may be due to apoptosis of keratin. Rarely metaplastic bone formation can also be seen.
(20)
The level of invasion may be graded using Breslow's thickness and Clark levels which is most commonly used in malignant melanoma(29).
Clarks levels are:
Level I- Lesions involving only the epidermis
Level II-Invasion of the papillary dermis; does not reach the papillary -reticular dermal interface.
11
Level III-Invasion fills and expands the papillary dermis but does not penetrate the reticular dermis.
Level IV-Invasion into the reticular dermis but not into the subcutaneous tissue.
Level V-Invasion through the reticular dermis into the subcutaneous tissue.
Subtypes:
Superficial BCC(3,4)
These lesions are described as pink flat or slightly elevated lesions with a tendency for peripheral expansion. Histologically they have multiple small nests of basaloid cells located in the superficial dermis, with a clear connection with the basal layer of the epidermis confined to the papillary dermis and no infiltration of tumor cells in the reticular dermis. They are mostly unicentric in origin. Recurrence is said to be very common as the lateral limits of this tumor cannot be determined(20).
Nodular BCC:
It is also called the solid variant. They are usually found on the head and neck region. Clinically they present as round, pearly, flesh-colored papule with telangiectasia that often ulcerates in the center; therefore called rodent ulcers.
(6).Histologically they are characterized by islands of cells with peripheral palisading of nuclei and a haphazard arrangement of the more central cells.
Retraction spaces sometimes form between the tumor islands and the surrounding stroma. Ulceration may be present in larger lesions. (3)
12
Nodulocystic:
Histologically they are characterized by one or more cystic spaces present towards the center of tumor islands. This is due to the degeneration of tumor cells centrally.
This may be associated with an increase in mucin between the tumor cells adjacent to the cyst. Fixation results in mucin shrinkage resulting in separation of tumor lobules from the stroma. Retraction can also be because of reduced
hemidesmosomes and anchoring fibrils. (6)
Pigmented BCC:
Pigmentation in BCC can be present both as dendritic melanocytes and stromal macrophages. It is sometimes misinterpreted as melanoma. Hemosiderin may also be evident. This is due to increased endothelin 1 expression. (20)
Sclerosing(6):
It is also called fibrosing, scirrhous, desmoplastic and morpheic. Clinically it appears as a pale plaque with a shiny surface. Histologically there are narrow, elongated strands and islands of tumor cells embedded in a desmoplastic stroma.
Sclerosing variant, especially in the eyelid, have an increased chance of recurrence.
(45)
Infiltrative:
Clinically they are a thick plaque with poorly defined borders. The overlying skin ulcerates much later. (6) Histologically there is more atypia than in most basal cell
13
carcinomas. The infiltrating cords of basaloid cells are slender and widely
infiltrative, consistent with the so-called morpheic variant of basal cell carcinoma.
They infiltrate into collagen bundles. Sometimes there is focal squamous differentiation within the infiltrating cords of basaloid cells, consistent with the metatypical variant of basal cell carcinoma.
Micronodular BCC(6):
Micronodular variant resembles the solid type, but histologically the nests are smaller(1nest<20cell) and the peripheral palisading is not well developed. There is increased chance of recurrence in this variant. Histologically they can also resemble small rounded nodules of basaloid cells with approximately the size of the hair bulb. This variant shows an increased chance of recurrence. (3)
Keratotic(6):
Histologically it is similar to the solid type with keratinization at the center presenting in the form of horn cyst(20). There is very little stroma and no lobar arrangement or follicular differentiation. They are almost indistinguishable from trichoepithelioma.
Infundibulocystic(6):
This variant is commonly seen on the face especially in the elderly. It was first referred to as BCC with follicular differentiation. (20). Histologically there are nests of cells arranged in anastomosing fashion with little stroma containing cyst-
14
like structures in the center. Sometimes melanin may also be present. The stroma may show amyloid or melanin incontinence. In HIV patients multiple lesions are seen.
Metatypical/Basosquamous(6):
Rare variant whose incidence is 1.2 .to2.7% (63). In this subtype mixed basaloid and squamous features are seen. There are three types of cells Basaloid, squamoid and intermediate cells. This variant is predominantly seen in recurrent lesions and in patients who have had radiotherapy. This subtype has a higher metastatic potential and is more aggressive and infiltrative.
Adenoid BCC(6):
Histologically it is characterized by the formation of tubular, gland-like structures and intertwining strands, radially arranged around islands of connective tissue, resulting in a tumor with a lace-like pattern. In rare instances, lumina may be surrounded by cells that have the appearance of secretory cells. The lumina may be filled with a colloidal substance or with amorphous granular material. Adenoid variant is an indolent tumor (46,47)
Fibroepithelioma of Pinkus (fibroepithelial basal cell carcinoma) (6):
A rare variant of BCC(0.2 to 1.4%)(64) and is thought to be derived from follicular epithelial stem cells in the bulge area of the hair follicle. Clinically it is similar to fibroma or papilloma. The lesions are solitary, the most common location being the skin of the back and affect especially women. Radiotherapy is considered a
15
predisposing factor for tumor formation. (3). Histologically, they are characterized by an abundance of stroma bound by fenestrated columns of epithelium with basaloid or squamoid cells. Immunohistochemistry is needed to differentiate
Fibroepithelioma of Pinkus from other variants of BCC (androgen receptor-positive and Merkel cells negative) and trichoepithelioma/trichoblastoma (androgen
receptor-/ Merkel cell +).
Giant cell or pleomorphic variant:
Histologically characterized by cellular pleomorphism, giant cells, apoptosis and mitosis. They may be associated with intracytoplasmic and intranuclear inclusions.
Pleomorphism does not seem to influence the behavior of the tumor. This variant is not more aggressive clinically compared to other variants.(70)
Clear cell BCC:
This subtype histologically shows focal clear cell change with cell showing clear to granular cytoplasm due to the accumulation of lysosomes as a part of degenerative changes. This is a rare variant of basal cell carcinoma.(6)
Matrical BCC:
This variant histologically shows differentiation towards matriarchal cells of hair follicles displaying shadow cells.(6)
16
Metaplastic BCC:
Metaplastic or sarcomatoid BCC is an extremely rare histological subtype of BCC featuring stromal malignant metaplastic features similar to carcinosarcoma. The sarcomatoid component can express diffuse immunopositivity for pan-CK AE1/AE3, CK5/6, CAM 5.2, p63 and D2-40. (26)
BCC with differentiation towards adnexal structures:
It is a rare variant, the incidence of which is not known(65)Histologically there is differentiation towards sebaceous, follicular, eccrine or apocrine structures. In a study by Sushrut Save et al, the basal cell carcinoma with sebaceous differentiation had no recurrence within a 2yr follow up.(48)
Signet ring cell type BCC:
Histologically in this subtype, the cells have laterally displaced nuclei with intracytoplasmic hyaline inclusions composed of intermediate filaments representing aberrant keratinization. It has also been referred to as BCC with
myoepithelial differentiation or rhabdoid basal cell carcinoma as they stain positive for SMA, GFAP and S100.
Granular BCC:
In this subtype histologically the neoplastic cells contains abundant eosinophilic granular cytoplasm due to lysosome like granules.
17
BCC with neuroid type nuclear palisading/Schwannoid:
In this subtype histo logically there is central nuclear palisading reminiscent of schwannoma, however staining for S100 is negative.
Adamantinoid:
Histologically this is characterized by islands of cells with peripheral palisading at the periphery with a loose centre with stellate reticulum like appearance. There are retraction artefacts and high levels of glycogen, hyaluronic acid, and chondroitin sulfate in the vicinity of the tumor.(21). Electron microscopy demonstrates
abundant cellular debris in intercellular spaces and several types of cells, including one with a worm-eaten, degenerative appearance and another with abundant rough endoplasmic reticulum. In a study by Berk DR(49), Adamantinoid BCC has an aggressive course(49).
Risk factors of BCC:
1. UV radiation:
Sunlight is the most frequent association with the development of BCC. There has been a 1.4 times increase in basal cell carcinoma with increased sun exposure(8).
The risk correlates with the amount and nature of accumulated exposure, especially during childhood. Intermittent sun exposure and childhood sun exposure is
considered to be more important than cumulative sun exposure according to Lomas A. et al (3). There was a high incidence of BCC in areas closer to the equator. (3)A
18
latency period of 20–50 years is typical between the time of ultraviolet (UV) damage and the clinical onset of BCC(3). It has been postulated that UVA produces toxic reactive oxygen species. (3) and UVB damages DNA and RNA causing covalent bonding between adjacent pyrimidines with the formation of mutagenic products. (3,8)Indoor tanning, X-ray and Grenz ray exposure are also linked with the development of BCC(1). 93% of basal cell carcinomas were associated with solar elastosis. (33)
2. Age:
BCC’s are most common in people over the age of 40. (3). Basal cell carcinoma (BCC) seen in children, is usually associated with a genetic defect, such as basal cell nevus syndrome, xeroderma pigmentosum, nevus sebaceous,
epidermodysplasia verruciformis, Rombo syndrome or Bazex syndrome. (1) However, the high frequency of local recurrence and multiplicity indicates that careful follow‐up is prudent in young patients with this tumor.(7)
3. Phototherapy and radiotherapy have an increased incidence of BCC. (3).
Absorption of ionizing radiation leads to a direct breaking of chemical bonds or to the production of radicals that produce massive damage in cellular molecules, including lipids and nucleic acids. Exposure to ionizing radiation often leads to exogenous damage, especially to single or double-stranded bonds. This DNA alteration leads to cellular death. (28). According to studies by Omid Zargari et al
19
and Michael D Lichter.et al, 50% of the patients in the former and 13% of the patients in the latter gave a history of BCC associated with irradiation. (50,51).
4. Arsenic exposure.
Arsenic is a well water contaminant used in industrial, mining, agricultural and medicinal substances (3,9). There have been studies that have proven arsenic poisoning in the northeastern states, especially West Bengal and
Bangladesh(35,36). Few studies have proved that multiple basal cell carcinoma occur when associated with arsenic keratosis. (36)Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin causing cell cycle and DNA aneuploidy related to the p53 dysfunction induced by arsenic. (22). Both arsenic and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling leading to anti-proliferative and pro-apoptotic effects leading to BCC. (22).
Another hypothesis is that multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4 positive cells is seen. This may cause a change in the interaction between CD4+
cells and epidermal keratinocytes thus resulting in arsenic-induced skin cancer.(22)
5. Immunosuppression. (3): It has been postulated that the heterogeneous expression of class I HLA proteins increases the risk of BCC risk 10-folds.(28)
20
6. Fair skin types have an increased risk of developing BCC.
There is 19 times reduced risk in darker skin. (3). An increase in skin pigmentation results in reduced penetration of photons into the deeper layers of the epidermis as reported by Moore MG et al. (4)
7. Scars:
Presence of scars and previous trauma at the site of formation of BCC is a well- documented risk factor (3)
8. Nevus :
The presence of an extremity nevus was associated with an increased risk of
melanoma and basal cell carcinoma but no significant association was observed for squamous cell carcinoma. (34)
9. Genetic:
PTCH mutations: PTCH mutations are located on chromosome 9q22.(3) It is a tumor suppressor gene. The inactivation of the gene develops a tumor resistant to apoptosis. Basal cell naevus syndrome is due to a mutation in the PTCH gene.
PTCH helps in the production of protein product “Patched1” which inhibits
smoothened (SMO), a G-protein-coupled receptor. In basal cell carcinoma, there is a mutation in PTCH resulting in cessation of SMO inhibition by patched 1. This results in uncontrolled expression of SMO initiating a signal cascade that leads to the activation of transcription factor Gli1. (2)
21
Other polymorphisms associated with BCC are melanocortin 1 receptor (MC1R) polymorphisms and polymorphisms in tyrosinase. (3) Specific polymorphisms associated to Cytochrome 450 and glutathione S-transferase are also risk factors.
CYP2D6 is postulated to be associated with the development of multiple BCCs.
CYP and GST are known to detoxify mutagens, whilst p53 has an important function as a tumor suppressor gene regulating the cell cycle. (2)
Associated syndrome:
1. Gorlin’s syndrome or naevoid basal cell carcinoma (BCC) syndrome (2) It is due to mutations in the genes PTCH1(commonest), PTCH2 and SUFU involved in the hedgehog pathway. In this syndrome, all types of BCC are seen, superficial and solid being the commonest subtypes.
Features of Gorlin syndrome include macrocephaly, frontal bossing, hypertelorism, coarse facial features, keratocystic odontogenic tumors, ectopic calcification, calcification of the falx cerebri, skeletal abnormalities, vertebral or rib anomalies, palmar or plantar pits and multiple large epidermoid cysts. Other features like polydactyly, ocular abnormalities, childhood medulloblastoma and ovarian or cardiac fibromas are also seen (11). They usually begin to appear in the early teens, especially in those treated with radiation for medulloblastoma. It initially develops on the face and the nape of the neck. The median age of onset is about 25 years.
(11)In a study by Elizabeth A. Jones(55) et al by 50 years of age, 76.5% of females
22
and 80% of males had been diagnosed with a BCC (55). They are rarely seen below the waist. (11) The commonest variant of BCC seen in this syndrome is superficial and nodular (53)
2. Bazex Dupre Christol Syndrome
Bazex-Dupré-Christol syndrome is an X-linked dominant pattern with genetic defect localizing to Xq. This mode of inheritance explains the absence of male-to- male transmission. Bazex-Dupré-Christol syndrome is a triad of follicular
atrophoderma, hypotrichosis and basal cell carcinomas. Milia, hypohidrosis,
pinched nose with hypoplastic nasal alae, prominent columella, joint hypermobility and hyperpigmentation of the face, epidermal cysts and trichoepitheliomas are the other reported clinical signs. (12)
3. Xeroderma pigmentosum
Xeroderma pigmentosum. Xeroderma pigmentosum means dry pigmented skin. It is defined by extreme sensitivity to sunlight, resulting in sunburn, pigment changes in the skin and a greatly elevated incidence of skin cancers. (13)
It shows autosomal recessive inheritance, with equal incidence in males and females. Classical XP shows only skin abnormalities. XP patients have an increased risk of non-melanoma skin cancer some with multiple basal cell
carcinoma. XP is an autosomal recessive disorder with 100% penetrance. It results from mutations in any one of eight genes. The products of seven of these genes are
23
involved in the repair of ultraviolet-induced photoproducts in DNA. According to John J.DiGiovanna et al(54), the variant which was seen in his study was nodular and pigmented variants usually aged <20yrs. (54).
4. Rombo syndrome:
Rombo syndrome is an autosomal dominant condition in which basal cell carcinoma is associated with atrophoderma vermiculatum, trichoepitheliomas, hypotrichosis milia, and peripheral vasodilation with cyanosis.(2,23)
5. Oley syndrome.:
Oley syndrome is a variant of Bazex Dupre Christol. Oley syndrome is defined as basal cell carcinoma in association with congenital hypotrichosis and milia. (2,26)
6. Nevus sebaceous:
It is a common congenital hamartoma of the skin, usually on the head and neck. It may undergo malignant transformation to basal cell carcinoma. (38)
7. Albinism:
There is an increased predisposition of patients with albinism for skin cancer, especially squamous cell carcinoma and basal cell carcinoma. (41)Albinism is a congenital disorder by the absence of pigment in the skin, hair and eyes. Albinism
24
results from the absence or defect of tyrosinase, a copper-containing enzyme
involved in the production of melanin. Skin cancers including basal cell carcinomas present at the mean age of 35yrs. The most common variant of basal cell carcinoma seen is the nodular subtype.(61)
Other skin tumors are also seen associated with BCC like trichofolliculoma and squamous cell carcinomas(39,40)
Risk stratification (44):
Basal cell carcinomas were divided into high risk and low risk groups based on their location , size, borders , presence of recurrent tumors, presence of
immunosuppression, prior radiotherapy, histological subtype and evidence of perineural invasion. This was done as the treatment modalities differed in the two groups as described in the table below.
Table 1: “Low” and “High” risk stratification based on various risk factors
25 Table 2: The “L” - low risk, “M” - medium risk and “H” - high risk sites of recurrence.
26
Table 3: Adaptation from NCCN guidelines categorizing the treatment of BCC based on the Low and High grade stratification. (44)
IHC used in BCC p53 expression (16)
p53 is a 53 KD nuclear phosphoprotein encoded by the p53 gene. The gene involved is gene 6 located on chromosome 17. The wild-type of p53 protein
interrupts the progression of cell cycle. The structural abnormalities of the p53 gene include deletions, inactivations, truncations, and point mutations. Mutations of the p53 gene are the most common genetic abnormality in cancer. The p53 gene and its product might be involved in the pathogenesis of human BCC also. (16) Positive nuclear immunoreactivity (1 + or greater) was demonstrated in 83% of BCCs.(16).
27
According to an Indian study by P Malhotra et al 17.6% of basal cell carcinomas showed p53 positivity compared to the Western studies. (60)
According to Reza et al, in basal cell carcinoma there is mutation of p53 causing either two possibilities. The first more popular theory is that p53 becomes a proto- oncogene resulting in the overexpression of p53. The second theory is the deletion of both p53 alleles.(67)
Bcl2 expression: Bcl-2 is a proto-oncogene that has been associated with
programmed cell death. It is seen in self-renewing stem cells. As cells differentiate into mature cells, the expression of Bcl-2 ceases. In the skin, Bcl-2 has been
demonstrated in the basal layer of keratinocytes. Ordinarily, it is not expressed by suprabasal keratinocytes. BCC is composed of basaloid keratinocytes which retain their ability to produce Bcl-2, supporting the hypothesis that BCC is a tumor of undifferentiated keratinocyte stem cells. (17)
BER EP4: All BCCs were diffusely and intensely labelled with BERep4.
Significant differences between the staining of hair follicles and BCC for BERep4, help in distinguishing between BCC and hair follicles.(18)
SOX9: SOX9 is a transcription factor that has multiple functions during development. In the hair follicle, SOX9 is expressed in the outer layer of the epithelial sheath and the hair stem cell compartment. Sox9 acts as a downstream target of the Sonic hedgehog pathway. Activation of this pathway is a major cause of cutaneous basal cell carcinoma.(24)
28
CD10: CD10 is positive in the periphery of basal cell carcinoma. No BCC expressed stromal expression alone(25)
TNM staging (15)
TNM staging for BCC(Non Melanoma skin cancers) was done based on the size, extent of the tumor and structures involved, perineural invasion, presence or absence of nodal involvement including extracapsular extension and metastasis based on the AJCC 8th edition. Other findings relevant to staging or treatment were also included. Staging for tumor of the eyelid were done separately.
Tumor
pT0 - No primary tumour pTis - Carcinoma in situ pT1 Tumour ≤20 mm
pT2 20 mm - ≤40 mm
pT3 Tumour >40 mm or presence of deep invasion, perineural invasion or minor bone erosion.
pT4a Tumour with gross bone invasion
pT4b Tumour with axial skeleton/skull base/foraminal invasion
29
Node
pNX Nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis in a single ipsilateral lymph node ≤30 mm
pN2 Metastasis in a single ipsilateral lymph node 30 mm - 60 mm or in multiple ipsilateral lymph nodes
pN3 Metastasis in a lymph node >60 mm in greatest dimension Skin carcinoma of head and neck (excluding vermillion lip) pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis in a single ipsilateral lymph node ≤30 mm without extranodal extension
pN2a Metastasis in a single ipsilateral lymph node 30 mm-60 mm without extranodal extension
pN2b Metastasis in multiple ipsilateral lymph nodes, <60 mm without extranodal extension
pN2c Metastasis in bilateral or contralateral lymph nodes,< 60 mm, without extranodal extension
30
pN3a Metastasis in a lymph node, > 60 mm, without extranodal extension pN3b Metastasis in a lymph node with extranodal extension
Metastasis
M0-No distant metastasis
M1/pM1- Distant metastatic disease
Table 4: TNM Stage grouping of Basal cell carcinoma.(15)
Eyelid tumour TNM staging Primary tumor (T)(9)
TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ
T1: Tumor 10 mm or less in greatest dimension
31
T2: Tumor more than 10mm, but not more than 20 mm in greatest dimension T3: Tumor more than 20 mm, but not more than 30 mm in greatest dimension Subdivisions:
a no involvement of the tarsal plate or eyelid margin b involvement of the tarsal plate or eyelid margin c involving the full thickness eyelid
T4: Tumor is not resectable due to extensive invasion of ocular, orbital, craniofacial structures or brain
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
pN0: No regional lymph node metastasis, based on lymph node biopsy N1: Regional lymph node metastasis <30mm
N2: Regional lymph node metastasis >30mm
32 Table 5: Differential diagnosis of Basal cell carcinoma(19)
Basaloid Squamous cell carcinoma Exaggerated down-growths of overlying basaloid epithelium is seen in the above entity. These lesions have larger nuclei and greater pleomorphism than typically seen in BCC with absent or only equivocal peripheral palisading and no excess stromal mucin in retraction spaces. Comedo type necrosis is also seen(19)
Table 6: IHC differentiating BCC and Basaloid SCC
33
Desmoplastic trichoepithelioma
In this lesion there are uniform cords of bland basaloid cells generally lacking mitotic activity and inconspicuous apoptotic bodies. The stroma is prominent and formed by laminated collagen bundles around the basaloid cords with relatively uniform cellularity. These should be differentiated from sclerosing/morpheaform basal cell carcinoma.(19)
Table 5: IHC differentiating BCC and Desmoplastic trichoepithelioma
Microcystic adnexal carcinoma
The above lesion has small nests, cord, ductular structures and keratin-filled cysts surrounded by relatively bland basaloid epithelium that lack retraction
artefact. This tumor is seen to extend deep into the stroma. They needs to be differentiated from morpheaform/sclerosing and infiltrative BCC.(19)
34
Table 6: IHC differentiating BCC and Microcystic adnexal tumours.
Trichoepithelioma and trichoblastoma
These are usually large tumors with deep extension and moderate mitotic activity, but with infundibular cysts in trichoepithelioma and a fibrotic stroma surrounding the nests.(19)
Table 7: IHC differentiating BCC and trichepithelioma.
Merkel cell carcinoma
This is characterized by prominent mitotic activity and solid, trabecular and infiltrative cords of small round cells with salt and pepper chromatin and scant cytoplasm. Normally there is no peripheral palisading of nuclei. This should be
35
differentiated from nodular variant of BCC.(19)
Table 8: IHC differentiating BCC and Merkel cell carcinoma
Pilomatricoma, matricoma and pilomatrical carcinoma
Pilomatricomas are composed of peripheral matrical (basaloid) and supramatrical cells, with highly distinctive abrupt keratinization and ‘ghosted nuclei’ (shadow cells) forming cyst-like structures. Pilomatricoma shows a diffuse nuclear b-catenin expression. These needs to be differentiated from matrichial variant of BCC.(19)
Trichilemmoma and trichilemmal carcinoma
They are pale eosinophilic or clear cell tumors with peripheral palisading of nuclei and prominent basement membrane. Columnar cells abuts the basement membrane, may have reversed polarity with the nucleus oriented away from the basement membrane. There is a lack of mitotic activity and apoptotic bodies. A prominent
36
basement membrane is in favour of a diagnosis of trichilemmoma over clear cell BCC.
Table 9: IHC differentiating BCC and Trichilemmoma.
Treatment modalities include the following. Mohs micrographic surgery has a 5- year cure rate of 99% for previously untreated BCC. (2) Standard excision with predetermined margins of normal skin has been shown to provide 5-year cure rates over 98% for BCC. Radiotherapy is an effective treatment modality for patients unable to undergo surgery. It has an overall 5-year cure rate of 91.3% for BCC.
Adjuvant radiotherapy may be beneficial postoperatively for tumors with perineural invasion. (2). Curettage and cautery involves the removing of epidermis and dermis containing tumor tissue with a sharp ring curette instrument before charring of the base of the wound with electrocautery. It has a cure rate of 91% at 5 years. (2).
Cryosurgery with liquid nitrogen with a single freeze-thaw cycle achieves a cure rate of 95.5%. (2,56). Photodynamic therapy is another effective therapy for low- risk nodular BCC less than 2 mm thickness. The cure rates achieved in these studies were 80–90% for superficial BCC and 52–73% for nodular BCC. (58)
37
Immunotherapy using Imiquimod showed a cure rate of 65.4 %(2,57). 5-
fluorouracil (5FU) a pyrimidine antimetabolite that inhibits DNA synthesis that gives a cure rate of 90% and a clinical cure achieved after10 weeks. (2,59)
38
MATERIALS AND METHODS
39
Materials and methods
All patients diagnosed with BCC over a 5yr period from January 2013 to December 2017 were taken from the pathology electronic retrieval system. Detailed history including demographic variables like age, gender, duration of symptoms, place of residence, exposure to chemicals, history of personal or family history of cancer, history of genetic disorder like xeroderma pigmentosum, albinism and history of previous treatment were taken from CMC electronic clinical data retrieval system.
Clinical data including the recurrence, survival, prognosis and other follow up data were also included in the study.
Slides and blocks from the department archives were reviewed. Only those cases which fulfilled the inclusion and exclusion criteria were included in the study. The minimum sample size was calculated as 61 using “n = 4p (1-p)/ d 2”.The various histological variants were identified. The histomorphological features like depth of invasion, ulceration, perineural or lymphovascular invasion, stromal desmoplasia, tumor-infiltrating lymphocytes margins of excision and other clinical features like syndromic association, site, exposure to UV light and arsenic, etc. that may
influence its prognosis and recurrence were observed. Grading and staging of the lesions were done based on the size into small (< 2 cm in diameter), medium (2 -4 cm in diameter) and large (> 4 cm in diameter) tumors. The minimum population size was calculated for P53 by “n = 4p (1-p)/ d 2”. The minimum population size was 58 with a precision of 10%. P53 immunohistochemistry was done for 107 cases
40
and its relevance to the type and recurrence of basal cell carcinoma were identified.
Based on the clinical and histopathological findings, the results were computed and analyzed using SPSS 16.0 software using Chi square and Fisher exact test.
Inclusion criteria:
1) All patients with basal cell carcinoma with well-stained slides and blocks.
2) Sufficient clinical data Exclusion criteria:
1) Insufficient tissue on slide or block for a definite diagnosis.
2) Adequate clinical details not available
3) Those cases with inconclusive or wrong diagnosis .
41
42
43
RESULTS AND ANALYSIS
44
Results and analysis
Among all the skin tumors that were diagnosed in our institute from January 2013 to December 2017, total number of patients with skin cancers were 2195, of
which 1680(76.5%) were squamous cell carcinoma, 270 were melanomas(12.3%) and 245 (11.2%)basal cell carcinomas.
From January 2013 to December 2017, there were totally 245 patients with basal cell carcinoma. From these we included 168 patients and excluded 77 patients due to lack of slides or blocks, lack of relevant clinical history or misdiagnosis.
The male to female ratio in our study was 1:1. The mean age at which basal cell carcinoma was diagnosed was 54years. (40-70yrs i.e.5th to 8th decade). The youngest patient was 9years and oldest was 87 years of age.
Figure 1: Age distribution of patients with BCC
45
Duration of symptoms prior to diagnosis of basal carcinoma was 3-4years. The mean duration of disease was 4 years. The maximum duration of disease was 30 years and minimum duration of disease was within 1month of presentation.
Figure 2: Duration of symptoms prior to diagnosis in a population with BCC
Distribution in various states
Most patients were from West Bengal, Tamil Nadu, Jharkhand and Bangladesh, probably due to the skewed patient population in our institute.
46 Figure 3: The distribution of patients in various states
Site of involvement:
Most of the basal cell carcinomas only involved a single site (87%), with 4.1%
showing satellitism and 8.3% showing multiple site involvement. 140 patients had BCC over the H area. The commonest subtype being nodular, pigmented
superficial and morpheaform.
When multiple sites were involved the most common site was the cheek and forehead (38%) followed by eyelids (16%), nose (13%), neck, ears and scalp.
Rarely the chest and abdomen were involved. In the face the nasolabial fold, the
47
temporal region of face and the medial canthus were the commonest areas involved accounting for 37.5%, followed by eyelid (17.9%), nose (17.3%), scalp (8.9%) and ear (7.1%). The least common site was the buttock, inguinal region, palm and vulva.
. Figure 4: The involvement of various sites and its multiplicity in BCC Basal cell carcinoma was seen in multiple sites in 14 patients. Of these 5 had
shown syndromic association (35%) which was statistically significant (p value is<0.01).
48 Figure 5: The syndromic association in BCC
Syndromic association: Most BCCs were sporadic in occurrence accounting for 92.8% of the basal cell carcinomas while 8.2% had syndromic association. Of the 12 patients associated with syndromes, 6 had nevus sebaceous. Three of the twelve patients with syndromic association however had recurrences. The risk factors, other than syndromic association in these patients were close margin (<0.4cm) and morpheaform variant which was statistically significant (P<0.05). The site
commonly involved were the limb with nodular, pigmented and superficial being the commonest subtype present. In our study synchronous skin tumours seen with BCC were trichofolliculoma (one patient) and squamous cell carcinoma (2
patients).
49
Figure 6: The distribution of various variants of BCC.
Nodular subtype was the most common (23%) variant. This was followed by Pigmented (15%), Nodulocystic (12.2%), Superficial (11.6%), Morpheaform (10.6%), Micronodular (7.6%), Adenoid (7.6%) and Infiltrative (7.1%). Less
50
common variants like the Basosquamous, Fibroepithelioma of pinkus and adamantinoid variant were also observed on the scalp and the palm respectively.
Table 11: The variants of BCC in the descending order of prevalence
Table12: Perineural invasion seen in the different variants of BCC
Few variants of BCC have an increased chance of perineural inflammation like the Morpheaform, Infiltrative and Micronodular which is statistically significant.
51 Figure 7: Comparison of the various site and variants of BCC
Commonest site seen was on the cheek and forehead (37.3%) mostly involving the nasolabial fold and the medial canthus. Other sites involved included the nose, eyelid, scalp and ear. The nodular variant was commonly seen in the cheek, eyelids, ears and scalp while the pigmented was seen on the face, scalp and the eyelid. Both the aggressive and the indolent BCC subtypes were seen on the H area of the face.(p>0.05) Out of 12 cases of keratotic basal cell carcinoma, 4 were seen in the eyelid. In genital, perianal and inguinal region the common subtype
52
were nodular, pigmented and superficial. +Few variants of BCC have an increased chance of perineural inflammation like the Morpheaform (p value 0.001),
Infiltrative(p value 0.001) and Micronodular (p value 0.01).
Risk factors involved in genesis of basal cell carcinoma
Sun exposure was histomorphologically measured by solar elastosis. 80.3% of BCCs were associated with solar elastosis.The likelihood of BCC developing when a person has solar elastosis was 1.034 , though this was not statistically significant. Lighter/darker skin was measured by assessment ofbasal cell
pigmentation. Out of 168 patients, 94(56%) had pigmentation of the basal layer and 74(44%) had reduced pigmentation. In our population there was no statistically significant difference in occurrence of BCC in fair or dark skinned individuals.
Other than sunlight exposure, the other risk factors noted were:
Tabe13:Risk factors influencing the occurrence of BCC.
53
BCC caused due to arsenic exposure
The mean age at which arsenic associated BCC was diagnosed was 52years with mean duration of disease being 5years. There were 4 patients with arsenic associated BCC all of whom were from the north east regions of India. Two patients had BCC in single site while two others had BCC in multiple sites. The chances of a person exposed to arsenic developing BCC was 1.473 times compared to the normal population. This was not statistically significant.
Table 14: Comparison of Arsenic keratosis with multiple site involvement.
Though the H area of the face was involved in 2 patients only 1 of them
recurred. The histological subtypes in both the patients with recurrent BCC was a high risk subtype and they had clearance margins<0.4cm. So a multifactorial approach like grading into high risk and low risk category is needed to assess probability of recurrence. (p value is 0.098).
54
Table 15: Other risk factors involved in the genesis of arsenic induced BCC
Histomorphological parameters
Solar elastosis was seen in 80.3% cases of basal cell carcinoma. Solar elastosis is the accumulation of abnormal elastic tissue in the dermis in response to long-term sun exposure. The subtypes commonly seen in BCC associated with solar elastosis was nodular, pigmented and superficial..
Actinic keratosis is a precancerous form of skin damage caused due to exposure to UV rays . Thus UV rays plays a role in the origin of basal cell carcinoma. 44% of basal cell carcinomas in our study were associated with actinic keratosis. 3.5%
of these Basal cell carcinomas were also associated with Bowens disease. Bowen's disease was not a risk factor for developing BCC in our study.
Desmoplasia was seen in 53 cases, i.e. 31.5%. Desmoplasia was most commonly seen in Nodular, Morpheaform, Infiltrative and Pigmented subtypes. The
desmoplasia was statistically significant in Morpheaform (p value<0.01) and infiltrative variants of basal cell carcinoma (p value<0.01).
55
There were no BCCs with Clark's level 1. Superficial and Pigmented BCCs showed the least depth of infiltration i.e. Clarks level 2. The variant which had the
maximum depth of infiltration i.e. Clark's level 5 was Nodular followed by Micronodular and Infiltrative. Most BCCs fell into Clark's level 3. Depth of invasion was associated with an increased chance of recurrence, though this was not statistically significant.
Figure 8: Comparison of the variants of BCC with Clarks levels.
With increase in depth of invasion there was more chance of perineural inflammation.
This was statistically significant.
56
Recurrence in basal cell carcinoma
Among all the basal cell carcinoma 14.2%(24 out of 168 cases) recurred. The variables associated with recurrence included
1. Size
Figure 9: Comparison of Recurrence and size.
Most of the patients had a tumour size less than 2cm.(78%) Recurrence in patients with tumour size <2cm was 15.3%. In patients with tumour size >2cm, recurrence was 11.36%. This was not statistically significant(p value is 0.510)
57
2. Depth of invasion (DOI)
On comparing the depth of invasion to the incidence of recurrence, there was an increase in recurrence with increase in depth of invasion. But there was no statistically significant difference between DOI and recurrence by univariate analysis.(p value is 0.847). Odds ratio was 0.917 (95% CI of
0.3814 to 2.2060.)
Figure 10: Comparison of recurrence and depth of invasion
Figure 11: Comparison of recurrence and depth of invasion.
58
3. Margin of clearance
Seventy one percent of the patients had at least 1 margin<4mm. But recurrence was seen in BCCs in this subset ie margin <0.4cm only in 19% of these patients.
Univariate analysis showed recurrence was more likely when margin were
<4mm{Odds ratio 2.3571 within 95% confidence limits) though this was not statistically significant (p value is 0.6896).
Figure 12: Comparison of recurrence and margin of clearance.
59
4. Syndromic association
Three out of twelve patients with BCC associated with syndromes showed recurrence. There was no statistically significant association of syndromic BCC and recurrence. (The p value was 0.382). The only other risk factor in these cases were close margin <0.4cm. The BCC subtypes with syndromic association which recurred were Nodulocystic, Adenoid, Pigmented and Nodular. There was also a significant association with BCC in multiple sites when BCC was associated with a syndrome(p<0.05).
Table16: Comparison of syndromes with BCC Variants, Site and Margins causing recurrence.
Figure13: Comparison of recurrence and syndromic association.
60
5. Site of involvement
Among the various sites of recurrence, BCCs in the H area of face showed more chance of recurrence cheeks (27%), followed by eyelid(19.2%), nose(15.3%) and scalp(11.5%) though this was not significantly associated(p=0.717).
Table17: 2x2 Chi square table comparing recurrence and involvement of H area.
Figure 14: Comparison of recurrence and site.
The sites that did not have recurrence were the chest, genital region and buttock.
61
6. Desmoplasia
Figure 15: Comparison of recurrence and desmoplasia.
Eight out of 53 cases of BCC with desmoplasia showed recurrence i.e. 15% of desmoplastic cases showed recurrence. This was not statistically significant (p value 0.839)
62
7. Tumor infiltrating lymphocytes
Figure 16: Comparison of recurrence and tumor infiltrating lymphocytes
Among the BCCs which showed recurrence, 12 out of 24 cases had reduced tumour infiltrating lymphocytes. So when a patient with BCC presented with recurrence he or she was more likely to have decreased tumour infiltrating lymphocytes.. But all patients with decreased tumour infiltrating lymphocytes did not show recurrence,(p value = 0.502). Odds ratio is 0.7143 (95% CI: 0.3004 to 1.6982.)
63
8. Ulceration
Figure 17: Comparison of recurrence and ulceration
Of 120 (71.4%) cases of ulcerated basal cell carcinoma, 16 patients showed recurrence. i.e 13.3%. There was no statistically significant association with ulceration and recurrence.(p=0.577)
9. Perineural invasion (PNI)
PNI was seen in 10.7% of basal cell carcinomas. Those with PNI were significantly associated with recurrence using univariate analysis. (p=0.026).
None of the cases of BCC had lymphovascular invasion.
64
10. Type of BCC
The most common subtype of basal cell carcinoma which recurred was
Nodular variant followed by Nodulocystic, Morpheaform and Pigmented. Only two cases of Nodular variant was singularly seen with no association with other variants. The commonest variants that were associated with Nodular variant were Pigmented (30%) and Morpheaform (22%). These nodular variants that had recurred were in the H area with increased depth of invasion.Thus multifactorial risk factors may be the reason that Nodular variant had recurred.
All the recurrent variants of basal cell carcinoma from the eyelid had Nodular variant associated with Morpheaform, Infiltrative or Micronodular variant. The infiltrative variants that did recur were associated with PNI except for 1 aberrant case.
65
Figure 18: Comparison of recurrence and the different variants and different sites.
66
Table 19: p value of the recurrence vs. variants
10. Risk stratification and recurrence.
According to the National Comprehensive Cancer Network all BCCs were stratified into high risk and low risk category based on location, size, primary or recurrent, immunosuppression, site of prior RT, histological subtype and perineural invasion.
67
Table20: The risk stratification of the recurrent cases of BCC.
The risk stratification was calculated for all 168 cases of BCC and was also done for the 24 cases which recurred. Those patients with score</=3 was categorised as low risk and all patients with score >3 was categorised as high risk.
Morpheaform, Basosquamous, Infiltrative and Micronodular pattern fell into the High Risk category, whereas Adamantinoid, BCC with sebaceous differentiation, Fibroepithelioma of Pinkus, Pigmented and Superficial fell into the low risk category. 72.5% of Nodular, 67.7% of Adenoid, 90%keratotic and 65.2% of
Nodulocystic also fell into the High Risk category. Here 6 out of 24 cases in the low
68
risk category and 18 cases in the high risk category showed recurrence. A few high risk variables were seen in the low risk category like PNI and site which could have been the cause for recurrence.
High risk
Figure 19: High risk stratification of recurrence with the different variants
69 Figure 20: Low risk stratification of recurrence with the different variants
Table 23: 2x2 Chi square table comparing recurrence and risk stratification.
Though 75% of the recurred cases showed high risk stratification this was not statistically significant(p=0.2546). Odds ratio was 1.91 (95%CI: 0.7145 to 5.101.)
70
Table 21: Significance of recurrence in various variants
There was an increased risk of recurrence in Nodular(p value =0.004), Pigmented(p value =0.004), Morpheaform(p value =0.001) and Micronodular(p value <0.001) subtype when they were stratified into low and high risk category.
Table 22: The recurrence compared with various sites.
The sites that have an increased risk of recurrence was the “H area of the face”
including the nose, eyelids, lips and ears{ face(p value <0.001), nose(p value
<0.001), lip(p value =0.006), ear (p value =0.001)and eyelid(p value <0.001)}. The
71
rarer sites like the vagina, trunk and limbs were also significantly at risk of
recurrence, this may be due to less number of cases in these sites creating a bias.(p value <0.001)
11. TNM staging:
Most of the patients (65.6%) were in stage I; 32.7% were in stage II and 1.7% were in stage III. Most of the patients had a tumor size less than 2cm.(78%)Most of the patients had a tumor size less than 2cm.(78%) i.e. stage I. Recurrence in patients with stage I was 15.3%. In patients stage II and III together the recurrence was 11.36%. This was not statistically significant (p value is 0.510). Patients (3 in number) with tumor size>4cm did not recur. So multiple variables are involved in recurrence in BCC.
Figure 21: The TNM staging of BCC
72
12. p53:
Table 23: Comparing variants against the low intensity and high intensity staining of p53.
The p53 score of less than or equal to 4 was seen in aggressive variants of BCC like Micronodular, Infiltrative, Basosquamous and Morpheaform. 68.2% of patients had lowp53 staining.
Table 24: 2x2 Chi square table comparing recurrence and the intensity of P53 staining.
Low p53 score (</=4) was seen in 10/15 recurrent cases of BCC i.e.66.67% of recurrent basal cell carcinoma but this was not statistically significant(p value
=0.978) . Odds ratio is 1.0164 (95%CI: 0.3195 to 3.233.)
73
There was no statistically significant association of low or high p53 with the various BCC variant(p value>0.05), different sites(p value>0.05) , tumour infiltrating
lymphocytes(p=0.58) or perineural invasion(p=0.5).
74
DISCUSSION
75
Discussion
1. Age distribution
The average age at which basal cell carcinoma commonly presents is between 50- 80yrs as described by Robert S Bader et al(32), Yannis Scrivener and Sumir Kumar (1) et al(30). In our study BCC commonly presented between 40-70 years of age which was in concordance with the above authors. The mean age in our study was 54yr. The mean age was slightly lower that the study by Yannis Scrivener et al(30).
Basal cell carcinoma was associated with younger age group only when associated with syndromes like Xeroderma Pigmentosum <30yrs of age(2 cases, one 9yrs and other 28yrs)
2. Gender
In our study the Male to Female ratio was 1:1. This was not in concordance with studies by Robert S Bader et al (31)and Kumar S et al(1) where the M:F ratio was 2.1:1 and ratio for Kumar S et al was 1:1.78(63.9%). Our study was in
concordance with an Asian study by Moore MG et al(4) who postulated that equal numbers of males and females were affected in the Asian population, whereas in Black Africans, there appeared to be a predominance of women and in Caucasians, there appeared to be a predominance of men.
76
3. Duration of disease.
According to Kumar S. et al(1) in a study on South Asians, the mean duration of disease was 4.7yrs. This was in concordance with our study where the mean duration of disease was 4.025yrs.
4. Site distribution
According to Kiiski V et al(62) 31.1% of all BCCs showed multiplicity of sites.
This was not in concordance with our study where only 13% showed multiplicity.
When multiple they were more likely to be associated with syndromes in our study.
According to S Chung et al(37), most BCCs occurred in the head and neck region followed by trunk. In another study by P Malhotra et al (60), the most common location was the medial/lateral canthus of the eye. This was in concordance with our study where most of the BCCs occurred on the face(37.5%) which included the nasolabial fold, the temporal region of face and the medial canthus. This was followed by eyelid (17.9%), nose (17.3%), scalp (8.9%) and ear (7.1%). According to P Malhotra et al (60)the lesions on non sun exposed sites included thighs, vulva and trunk. This was in concordance with our study where BCCs were also seen in the abdomen, back, buttocks, inguinal region and vulva.
77
5. Variants of Basal cell carcinoma
Table 25: Comparing Indian study and our study.
In an Indian study by Sumir Kumar et al (1)the most common variant was Nodular(77.8%) followed by Pigmented (16.7%). Other subtypes included Basosquamous (8.3%), Micronodular (19.4%), Morpheaform (2.8%), Keratotic (2.8%), and Adenoid (2.8%) and BCC with adnexal differentiation (2.8%). This was in concordance with our study. According to Khullar G(66) et al the infiltrating variant constituted 14.7% unlike in our study where this variant constituted only 7.1% .
78
Table 26: Comparing the Indian study and Western study with our study.
According to a study by Samarasinghe V et al(2), the commonest variant in the western population was, Nodular and Nodulocystic which was 60-80% of their
cases followed by Superficial( 20%) subtype. This was in concordance with our study where Nodular variant was the commonest but was much less in number (35.2%=23% of nodular+12.2% of nodulocystic) compared to the above study.
Our study had higher number of Pigmented BCCs( 15%) followed by Superficial subtype(11.6%) like in studies by Samarasinghe V (2)et al and Sumir Kumar et
al(1). According to a study Deepadarshan K et al(43), Caucasian population had only 6% pigmented BCCs. In our study the commonest variant was the pigmented variant(15%) after the Nodular and Nodulocystic subtype.
