English Refarat

MALIGNANT TUMOURS WITH FOLLICULAR

DIFFERENTIATION

By:

Septina Indriani Saragih

Supervisor:

Dr. dr. T. Ibnu Alferally, M. Ked (PA), Sp.PA, D.Bioeth

DEPARTMENT ANATOMICAL PATHOLOGY

FACULTY OF MEDICINE
UNIVERSITAS SUMATERA UTARA
MEDAN
2022
 MALIGNANT TUMOURS WITH
FOLLICULAR DIFFERENTIATION
Septina Indriani Saragih, T.Ibnu Alferraly
Departement of Pathology Anatomy, Faculty of Medicine
Universitas Sumatera Utara

INTRODUCTION
Cutaneous adnexal tumours are a wide and heterogeneous group of

neoplasms that differentiate towards one or more of the skin appendages or

recapitulate events occurring during embryo development. They include tumours

with predominant apocrine, eccrine, follicular, sebaceous, and multilineage

differentiation. Benign tumours are far more common than their malignant

counterparts, and can occur at any age. Adnexal carcinomas are rare, but their

incidence is increasing, in part in association with ageing populations. They are

more frequent in men than in women, and in non-Hispanic White population than

in other racial groups. Among the adnexal tumours, the most frequent line of

differentiation encountered was sweat gland differentiation (56%), followed by

hair follicle differentiation (28%) and the least frequent being sebaceous gland

differentiation (16%).1,2

1
LITERATURE REVIEW

Anatomy and Histology

The hair is a long keratinized structure originating from epithelial

invaginations of the epidermis called hair follicles. Hair color, size, and texture

vary according to age, genetic background and body part. The face has about 600

hairs/cm2, while the rest of the body has about 60 hairs/cm2. Hair does not grow

continuosly and has a period of growth followed by a period of rest. This growth

does not occur synchronously in all parts of the body or even in the same area. On

the scalp, the growth period (anagen) may last several years, while the period of

follicle regression and inactivation together may last only 3 to 4 months.3

During the anagen period, the hair follicle has a distal dilation called the

hair bulb. A dermal papilla inserts into the base of the hair bulb and contains the

capillary network necessary for the survival of the hair follicle. Loss of blood flow

leads to follicular death. Epidermal cells lining the papillary dermis form hair

roots that produce and communicate directly with the shaft, which protrudes

above the skin. The epithelial cells (keratinocytes) that make up the bulb are

similar to the epithelial cells in the basal and spinous layers of the epidermis.

These cells divide continuously and then undergo keratinization, which

differentiates into specific cell types. In certain types of thick hair, the cells of the

center of the hair root at the top of the papillary dermis produce large, vacuolated

cells with sufficient keratin which will form the hair medulla.3

2
 Other cells differentiate into dense, highly keratinized fusiform cells that

form the hair cortex. The most peripheral cells produce the hair cuticle, a thin

layer of keratinized cells that lines the cortex. Melanocytes in the hair bulb

transfer melanin granules into epithelial cells which then differentiate to form

hair.3

Figure 1. A. Hair schematic drawing, showing hair follicles, including m. arrector pili and
sebaceous glands. B. Micrograph showing the medulla and the cortex at the root of the cut
hair longitudinal and hair root sheath.3

Malignant Tumours with Follicular Differentiation

Cutaneous adnexal tumours with follicular differentiation are uncommon

neoplasms, most of which are benign. The histopathological identification of

malignant follicular tumours is often difficult as these tumours are extremely rare,

and histopathological classifications of follicular tumours are non-uniform.

Moreover, histological features believed to be helpful in identifying malignant

follicular tumours, including nuclear hyperchromasia and pleomorphism, atypical

and or abundant mitoses and an infiltrative pattern of growth, may be absent or

only present focally in tumours with clear-cut malignant behavior.4

3
 Based on WHO Classification of Skin Tumours 4th edition in 2017,

malignant tumours with follicular differentiation divided into pilomatrical

carcinoma, proliferating trichilemmal tumour, trichoblastic

carcinoma/carcinosarcoma, and trichilemmal carcinoma.1

Table 1. Classification malignant tumours with follicular differentiation based on

WHO 4th ed in 2017.1
Malignant tumours with follicular differentiation ICD-O
Pilomatrical carcinoma 8110/3
Proliferating trichilemmal tumour 8103/1
Trichoblastic carcinoma/carcinosarcoma 8100/3
Trichilemmal carcinoma 8102/3

A. Pilomatrical Carcinoma
Pilomatrical carcinoma is a rare malignant tumor that originates from hair

matrix cells. The locally aggressive malignant equivalent of pilomatricoma, which

was first reported by Lopansri and Mihm in 1980, has been referred to as

„pilomatrix carcinoma‟, „malignant pilomatricoma‟, „trichomatrical carcinoma‟, or

„calcifying epitheliocarcinoma of Malherbe‟. Pilomatrical carcinomas are more

predominant in men with a 3:1 ratio and more often middle aged or elderly adults.

The mean age of patients with pilomatrical carcinoma is 48 years, ranging from 2

to 88 years. Pilomatrical carcinoma may arise de novo as a solitary lesion, or

through transformation from its benign counterpart, pilomatrixoma. A study

performed by Lazar et al. in 2005 found that pilomatrical carcinoma possible

association with mutations in exon 3 of the β-catenin gene (CTNNB1). Mutations

in the CTNNB1 gene, which allude to a possible common pathogenesis, but

malignant transformation has not been proven.5,6,7,8

4
 Clinically, the tumor is typically present as a solitary, painless,

asymptomatic, slow growing dermal or subcutaneous mass, occasionally

accompanied by bluish skin discoloration or and ulceration. The majority of the

lesion are located in the head and neck, particularly in the preauricular area, scalp,

posterior neck and upper back. Pilomatrical carcinomas have been reported to

range in size from 0.5 cm to 20 cm, with a mean of 3.95 cm, which is slightly

larger than its benign counterpart, pilomatrixoma. The consistency of the tumors

may vary from soft and friable to firm. They may have red, yellow, white, and tan

skin changes. Lesions cannot reliably be distinguished based solely on clinical

appearance, and frequently are mistaken for epidermal cysts.5,7

Figure 2. Pilomatrical carcinoma presenting as ulcerated

nodule on the left temple of an elderly man

Pilomatrical carcinoma appears as a poorly circumscribed and

asymmetrical neoplasm involving the deep dermis, subcutaneous tissue, and even

skeletal muscle and fascia. The lesion is composed of aggregates of neoplastic

cells that vary greatly in shape and size and a tendency for confluence. Extensive

necrosis en masse is often present within these aggregations. The aggregates are

composed of two populations of cells, namely, the basaloid cells and the

5
“shadow” or “ghost” cells. The basaloid cells usually predominate over the

shadow cells. The basaloid cells are neoplastic, matrical cells that have

pleomorphic and hyperchromatic nuclei and prominent nucleoli, scant cytoplasm,

and numerous mitotic figures, including many atypical ones. They give rise to the

second population of shadow cells gradually or in a more abrupt fashion. The

shadow cells have pale, eosinophilic cytoplasm and discrete ghost nuclei.

Although shadow cells are less abundant in pilomatrical carcinoma than in

pilomatricoma, they are very characteristic of the diagnosis. More frequently, the

neoplasm shows cystic spaces containing keratin and detritus material between the

aggregates of matrical cells, resulting from necrosis en masse. Uncommon

histopathological findings in pilomatrical carcinoma include desmoplastic stroma

and vascular, lymphatic, and perineural involvement by neoplastic cell. The

histopathology report must include the depth of infiltration, presence of necrosis

and atypical mitotic figures along with evidence of perineural or vascular

invasion.1,10,11,12

A B

Figure 3. A. Biphasic tumor composed of small darkly staining basaloid cells (solid arrow)
and eosinophilic shadow “ghost” cells (hollow arrow), H&E 4x. B. Higher magnification
shows the 2 cell types : Basaloid () and shadow cells .10,12

6
 A B
Figure 4. A. High-power view of atypical basaloid cells with pleomorphism and frequent
mitoses (arrows) with transition to eosinophilic cells showing matrical keratinization.
(Hematoxylin-eosin stain; original magnification: x200.) B. Extensive necrosis en masse is
present.10,11

Immunohistochemistry is not able to reliably distinguish between benign

and malignant hair matrical tumors. Immunohistochemically, pilomatrical

carcinomas show both nuclear and cytoplasmic staining for β-catenin in the

basaloid matrical cells.1

Figure 7. Strong cytoplasmic and nuclear staining for β-catenin (IHC, x400).

The histopathological differential diagnosis of pilomatrical carcinoma

includes pilomatricoma and basal cell carcinoma with matrical differentiation.

Pilomatricoma is a benign cystic neoplasm that appears as a symmetrical, well-

circumscribed lesion with regular and smooth borders; it usually does not show

any areas of necrosis en masse or the cytological atypia seen in pilomatrical

7
carcinoma. Pilomatricoma often exhibits numerous mitotic figures, but this is not

a discriminating feature. Basal cell carcinoma with matrical differentiation is a

neoplasm with all the architectural and cytological features of a basal cell

carcinoma, featuring of shadow cells in some areas, rarely, areas with matrical

differentiation dominate and show certain cytological atypia.1

Although no standard management guidelines for pilomatrix carcinoma

exist, surgical removal is ideal, but reported margins vary from 5 mm to 3 cm.

The recurrence rate for wide local excision (WLE) has been reported as 23%

compared with 83% for simple excisions, and is not dependent on anatomic

location. Local recurrence happened within 2 months after WLE (5 mm margins)

with clear margins on standard histologic sectioning, suggesting Mohs

micrographic surgery (MMS) may be advantageous over standard WLE in

ensuring complete margin control.5 Regarding other treatments, radiation has been

used as an adjuvant or monotherapy with varying results. Chemotherapy, such as

intravenous paclitaxel, has not shown much success.11

The metastatic rate ranges between 13% and 16%, with the most common

site being regional lymph nodes, followed by lung, bone, brain, and other

viscera.1,3 Metastatic risk increases with local recurrence but does not appear to

depend on excision margins or tumor location. 1 After initial diagnosis, a

metastatic workup with imaging is commonly performed along with ongoing

follow-up, although standard guidelines do not exist on the frequency or type of

imaging and follow-up.11

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B. Proliferating Trichilemmal Tumour
Proliferating trichilemmal tumour (PTT) is also known as proliferating

pilar tumor are rare neoplasm of external root of hair sheath that are largely

benign, and characterized as containing trichilemmal keratin. This entity

encompasses a morphological spectrum including benign, atypical (intermediate),

and rare malignant lesions. This neoplasm was first recognized by Wilson-Jones

in 1966 as an entity that had the histologic capacity to simulate squamous cell

carcinoma. Different terminologies have been used to describe this tumor, namely

epidermoid cyst, pilar tumor of the scalp, proliferating trichilemmal cyst,

proliferating epidermoid cyst, giant hair matrix tumor, hydatidiform keratinous

cyst, trichochlamydocarcinoma, and invasive hair matrix tumor.13,14,15

This neoplasm most commonly occurs in women aged > 40 years. The

neoplasm is located on the scalp in > 90% of cases. PTT is thought to originate

from the trichilemmal cyst (TC) and have the potential for malignant

transformation, at which point it is termed a malignant proliferating trichilemmal

tumor (MPTT). PTT is thought to be complication of trauma, irritation, or

inflammation and maybe inherited in an autosomal-dominant mode linked to

chromosome 3. TP53 mutation and loss of heterozygosity at 17p have been found

in the malignant areas of malignant PTT, whereas the benign areas were found to

have retained chromosome arm 17p.1,13,14

In perhaps the most comprehensive study to date, Ye et al stratified these

tumors into three groups within a seris of 76 cases with regard to histologic

criteria and correlated these criteria with malignant potential. Group 1 included

those patients who showed circumscribed silhouettes with “pushing” margins,

mild nuclear atypia, and an absence of pathologic mitoses, necrosis, and invasion

9
of nerves or vessels. Group 2 similar to group 1 but manifested irregular, locally

invasive silhouettes with involvement of the deep dermis and sub cutis. Group 3

showed the invasive growth patterns, prominent nuclear atypia, pathologic mitotic

form, and geographic necrosis with or without involvement of nerves or vascular

structures. PTT usually appears as a solitary, slow growing, exophytic lesion, 2–

25 cm in size. Some lesions show rapid growth.1,13

Figure 8. Proliferating trichilemmal tumor. A large tumor on

the scalp of an elderly woman.1

PTT spans a morphological continuum. At one end of the spectrum, it

appears as a well-circumscribed solid and cystic neoplasm that involves the

dermis and sometimes extends to the subcutaneous tissue. The epithelium shows

smaller basaloid cells are seen palisading at the periphery, these cells enlarge and

become more squamoid as they progress toward the center. Some cells may have

clear or vacuolated cytoplasm, these cells rarely. The periphery of the epithelial

bands generally exhibits a thick, hyaline, eosinophilic, and PAS-reactive basement

membrane that may be focally disrupted. PTT exhibit well-circumscribed borders

without infiltration of adjacent tissue. Intraepithelial keratinization may be present

10
in PTTs, forming small keratin globules that may compress adjacent cells,

squamous eddies, with whorling of epithelial cells, may be observed in more solid

cellular areas. Areas of calcification are often present within the stroma or in

keratinized foci in the epithelium. Inflammatory infiltrate may be present,

composed largely of lymphocytes, histiocytes, and plasma cells; neutrophils and

eosinophils are only occasionally present.

Degree of cellularity and atypia in PTTs varies, with the majority showing

mild to moderate proliferation of the epithelial cyst wall. Characteristic findings

of moderate epithelial proliferation include anastomosing bands and trabeculae

with cystic areas. Some PTTs show prominent epithelial proliferation, exhibiting

solid areas of epithelium and focal cystic areas. Tumors with mild to moderate

cellularity generally demonstrate mild to no atypia approximately 0–4 mitoses/10

high-power field (HPF). Highly cellular tumors generally exhibit moderate to

severe atypia (10 or greater mitoses/10 HPF). Histologic findings in moderate

atypia include large, hyperchromatic nuclei, irregular nuclear membranes,

abundant eosinophilic cytoplasm surrounding the nuclei, and occasionally foci of

single cell necrosis. Invasion of the surrounding tissue may be present. A

desmoplastic stromal response is often seen. Tumors with severe atypia may

additionally exhibit nuclear pleomorphism, dyskeratotic cells, numerous atypical

mitoses, necrotic debris within the keratinous areas, tumor invasion of

surrounding tissue, and metastatic lesions. As tumor invasion occurs, areas of

disruption and loss of basement membrane are evident along with loss of well-

circumscribed, lobulated margins.

11
 Mehregan and Lee propose that truly malignant PTTs exhibit both severe

cellular atypia and invasion of the surrounding connective tissue. The proposed

histologic criteria for diagnosis of MPTT are the presence of abnormal mitoses

and high mitotic rate, marked cellular pleomorphism, cytologic and architectural

atypia, infiltrating margins, necrosis, and aneuploidy. Areas of atypia may be

found adjacent to well-differentiated areas.14

A B

Figure 9. A. Proliferating trichilemmal tumor. H&E; x20. B. Malignant proliferating

trichilemmal tumor. There are cellular atypia and abnormal mitoses throughout this
specimen. H&E; original magnification, x400.14

The histopathological differential diagnosis of PTT includes ruptured

trichilemmal cyst, giant trichilemmal horn, SCC, and the proliferating variant of

epidermal (infundibular) cyst. Ruptured trichilemmal cysts may show irregular

aggregates of keratinocytes with trichilemmal keratinization, but they lack the

solid multilobular structure that characterizes PTT. Giant cutaneous trichilemmal

horns consist of a mixture of squamous epithelial cells and trichilemmal

keratinized debris. In some cases, the base of the horn is directly connected with

an underlying trichilemmal cyst of the scalp. Mitoses are common, but atypical

mitoses are not observed. The nuclei of the squamous cells is monomorphous,

without hyperchromasia or atypia. Uncommonly, SCC may show a cystic

12
configuration, but the nuclear atypia of the neoplastic cells of SCC is more

marked. There is no authentic trichilemmal differentiation in the neoplastic

aggregates of SCC. The so-called proliferating variant of epidermal (infundibular)

cyst consists of cystic structures lined by the infundibular epithelium and

containing basket-weave, basophilic, and orthokeratotic keratin. It has been

reported that there is degeneration into SCC in 20% of cases.1

Immunohistochemical studies may provide a useful tool in detecting

malignancy and in distinguishing PTT from SCC. Staining against proliferating

cell nuclear antigen in benign PTTs is positive in only the basal layers of these

lesions, while PTTs with either focal areas of malignant change or overt

carcinoma both exhibit increased staining in the malignant areas. Malignant

tumors show little to no immunoreactivity to CD34, a marker of outer root sheath

differentiation, suggesting poor differentiation of cells in these lesions. Ki-67

staining, used in combination with mitotic rate count to measure proliferation

index, was increased in aneuploidy lesions. Regardless of atypia or invasive

properties, most PTT showed positive staining for AE13 and AE14, monoclonal

antibodies directed at pilar-type keratin polypeptides, while SCCs showed no

staining.14

Treatment for benign PTT is simple local excision. PTTs histologically

characterized as lowgrade malignant require wide local excision with a 1-cm

margin of normal tissue to prevent recurrence. Because the margins of PTT may

extend beyond that which is clinically appreciable, the use of Mohs micrographic

surgery may decrease the incidence of recurrence and metastasis after excision

when compared with wide local excision. If the histologic diagnosis of MPTT is

13
made, more aggressive therapeutic measures such as nodal dissection,

radiotherapy, or chemotherapy should be considered in addition to wide local

excision.16,17

PTT is known to recur, especially after conservative local excision; a

meta-analysis of 185 cases showed a local recurrence rate of 3.7%. Reported

recurrences after diagnosis and treatment ranged from within 6 months to more

than 10 years. These lesions may also exhibit aggressive local invasion, across

tissue planes and even intracranially, causing considerable morbidity and even

mortality. Metastases have been reported as early as at the initial presentation and

as late as 10 years.14

C. Trichoblastic carcinoma/carcinosarcoma

This was first described by Regauer et al in 2000 as a malignant

trichoblastoma/trichoblastic carcinoma. Malignant trichoblastoma is a rare

tumour. There are three variants have been described into malignant

trichoblastoma including trichoblastic carcinoma (malignant epithelial

component), trichoblastic sarcoma (malignant stromal component), and

trichoblastic carcinosarcoma (both the epithelial and stromal component).

Trichoblastic carcinoma first describe in the literature in 1962 by

Headington and French as a primary neoplasm of the hair matrix. Trichoblastic

carcinoma is a rare neoplasm thought to arise from malignant degeneration of

benign follicular tumors.1,18 In most cases, trichoblastic carcinoma develop within

pre-existing trichoblastomas, but lesions arising within trichoepitheliomas or de

novo have also been described.19 Both neoplasm appear to affect elderly patients

14
and more common in males, with a 2:1 ratio. The average patient age in the

literature was 65 years, consistent with prior reports describing trichoblastic

carcinoma/carcinosarcoma as a disease of older adults. The most frequent clinical

site for tumors on the head and neck, representing 64.5% of the overall cases. The

pathogenesis of trichoblastic carcinoma is poorly understood, although loss of p53

tumor suppressor function and aberrant PI3-AKT signaling are thought to play a

role.19

Trichoblastic carcinomas are subdivided histologically into low-grade and

high-grade tumours. Whereas morphologically low-grade trichoblastic carcinomas

show indolent behaviour, smaller than high grade lesions, with plaques or nodules

that do not recur if completely excised. Morphologically high-grade trichoblastic

carcinomas are sudden enlargement with inflammation, large size (>3cm),

necrosis, have been associated with a poor prognosis, and potential for systemic

spread. From a histopathological standpoint, trichoblastic carcinoma and basal

cell carcinoma can share many similarities including islands of peripherally

basaloid epithelial cells, follicular papillae, and germinative cells. Because of its

rarity, trichoblastic carcinoma is a difficult diagnosis even for expert

dermatopathologists. It is described as a basaloid enlarged tumor with few

connections to the epidermis. It is often poorly circumscribed and deep infiltration

of the subcutis can be present. The architecture can be trabecular, cribriform or

with nests. The neoplastic cells are often basophilic at the periphery with no

palisading and with an eosinophilic nucleus with hair keratinization. There is a

high mitotic index. Foci of necrosis and calcifications are frequent.19,20,21,22

15
 A B

Figure 10. A. A low-power view reveals a vaguely nodular tumor. The tumor nodules
were composed of variably sized nests of basaloid cells. Some tumor nodules had central
necrosis (white arrow). Deep erosion was noted with loss of the epidermis (H&E, ×40). B.
A high-power view shows atypical round to oval tumor cells. Many mitotic figures are
visible (white arrows). Nuclear pleomorphism is present, with small nucleoli (H&E,
×200).22

Trichoblastic carcinosarcoma is a rare biphasic follicular neoplasm

consisting of a malignant epithelial component resembling follicular germinative

cells closely associated with a malignant stromal component differentiating

towards specific follicular mesenchyme. The term trichoblastic carcinosarcoma

was first used in 2004, the tumour was considered to be a low grade tumour. A

further case report of high grade trichoblastic carcinosarcoma was published in

2008. Grading into low and high grade does not seem to have any prognostic

significance and has not been used in any other publications. The most common

site was head and neck areas. The other sites included extremities, back and

sacrum. The tumour size ranged from 0.9 cm to 20 cm.

16
 Histologically, trichoblastic carcinosarcoma can be either well-

circumscribed/pseudo encapsulated or poorly circumscribed and widely invasive.

Surface ulceration may be seen. It is usually a dermal based tumour, but may

extend into subcutis. No epidermal connection is seen. The tumour is biphasic

with malignant epithelial and stromal components. The epithelial component is

composed of basaloid cells with scanty cytoplasm and hyperchromatic nuclei. The

cells may be arranged in a variety of patterns: solid, lobular, delicate strands or

cribriform pattern. A fenestrated growth pattern with slightly myxoid background

has also been described. Peripheral palisading, nuclear atypia, nuclear crowding,

and brisk mitosis are frequent. Large areas of necrosis have also been described.

The stromal component shows sweeping fascicles or sheets of malignant spindle

cells. The cells are pleomorphic with vesicular nuclei, coarse chromatin, and

prominent nucleoli. Multiple typical and atypical mitoses are present. The

epithelial nests are surrounded by one to three layers of stromal cells resembling

trichogenic stroma. These epithelial stromal units sometimes form structures

identical to follicular papillae which are described as „continuous papillae‟ .18

17
 A B

C D

Figure 11. A. Low power showing well circumscribed nodular tumour . B. Biphasic tumour
with basaloid epithelial component and spindle stromal component (H&E 20x). C.
Epithelial component showing nuclear crowding, pleomorphism and mitoses (H&E 40x). D.
Stromal component with nuclear atypia, prominent nucleoli and atypical mitosis (H&E
40x).

Immunohistochemical examination on the epithelial component shows the

expression of PHLDA1, cytokeratin, and AE1/AE3. On mesenchymal component

positive for vimentin.18 Complete surgical excision is the treatment of choice and

is probably sufficient for the majority of tumors excised. Subsequent adjuvant

radiotherapy may be useful in select cases demonstrating local aggressiveness.

Due to the rarity of this tumours, there are no guidelines regarding its treatment.

Information regarding the prognosis of trichoblastic carcinoma is not readily

available as the entity has been only rarely reported. Given the propensity to arise

and expand deeply in the dermis, they may have a more aggressive course than

18
basal cell carcinoma. As in other malignancies, the prognosis can be poor in the

case of metastatic disease, especially in an immunocompromised patient.18,19

D. Trichilemmal carcinoma

Trichilemmal carcinoma is a rare malignant adnexal neoplasm from the

outer root sheath of the hair follicular epithelium characterized by an indolent

clinical course. By this definition, trichilemmal carcinoma is the malignant

counterpart of trichilemmoma. Trichilemmal tumors are a group of tumors

characterized by cells differentiating toward the outer root sheath of hair follicles

witnessed by a variable extent of clear change in the cytoplasm resulting from

accumulation of glycogen. The concept of trichilemmal carcinoma was introduced

by Headington in 1976 which he described as a histologically invasive,

cytologically atypical clear cell neoplasm of adnexal keratinocytes seen in

continuity with the epidermis and/or follicular epithelium. He described the tumor

cells as glycogen rich showing peripheral palisading with a prominent PAS-

reactive, diastase-sensitive basement membrane and trichilemmal type of

keratinization.1,23,24

The histogenesis of this neoplasm remains obscure till date, with many

mechanisms being postulated. A significant number of cases arise de novo.

Factors such as actinic damage like sun exposure, prolonged radiation more than

50–60 diagnostic chest radiographs, immunosuppression following renal

transplantation, postsurgical radiation for other tumors, preexisting burn scars, and

chronic mechanical stimulation play a key role.

19
 Transformation from benign trichilemmoma, occurrence in slightly

damaged skin of elderly people, association with arsenic intake, and xeroderma

pigmentosa have been documented. This is usually encountered between the

seventh and ninth decades of life in the sun-exposed areas with a predilection for

face, scalp, neck, back, and extremities taking the form of plaques, papules, or

solitary nodules with evidence of ulceration, hyperkeratosis, or scabs usually <

3cm in the greatest dimension. Total loss of the tumour suppressor

gene TP53 may contribute to the development of trichilemmal carcinoma.1,23

Gross examination showed an irregular, partly skin-covered soft tissue.

Trichilemmal carcinoma presents as an erythematous, tan, or flesh-coloured

papule, a keratotic nodule, or an indurated plaque. They are frequently ulcerated.

Cut surface showed a solid, gray-white, and homogeneous area. The deep resected

surgical margin appeared to be involved by the lesion. 23

Figure 12. Ulceroproliferative lesion over the occipital region of the scalp.23

20
 Histopathology trichilemmal carcinoma is characterized by a proliferation

of tumoural lobules composed of large atypical cells with clear cytoplasm with a

sharply defined border and pushing margins continuous with the epidermis or

pilosebaceous structures. The tumour cells give a positive periodic acid–Schiff

(PAS) reaction, and there are prominent nucleoli, frequent mitoses, and foci of

trichilemmal keratinization. At the periphery of the lobules, the keratinocytes

show palisading and are surrounded by a prominent connective tissue sheath. The

tumour is more commonly associated with an invasive component centred on a

pilosebaceous unit and may show pagetoid spread in the overlying epidermis.1,25

For a histologic diagnosis of trichilemmal carcinoma, Headington suggested six

criteria:

1. Continuity with a coexisting benign epithelial tumor, usually a

trichilemmoma.

2. Continuity with the outer sheath epithelium of a coexisting hair follicle.

3. Light microscopy showing glycogen-rich epithelium, peripheral

palisading, and prominent basement membrane zone.

4. Trichilemmal keratinization (absent or minimal granular layer, abrupt

single-cell keratinization, and formation of dense non lamellar keratin).

5. Electron microscopic details similar to normal outer sheath epithelium or

trichilemmoma.

6. Immunocytochemical details similar to normal outer sheath epithelium or

trichilemmoma.

21
 A B

C D

Figure 13. A. Histopathological examination revealed that the nodule exhibited epithelial
tumor islands interspersed with a dense fibrous connective tissue stroma and centrally
located trichilemmal keratinization. B. At higher magnification, the tumor had polygonal
cells, palisade arrangements with focal inversion, a thick hyaline membrane surrounding
each lobule, and atypical cytology. C&D. Tumor cells showing clear cytoplasm, marked
nuclear pleomorphism, and atypical mitoses. H&E, x400.1,23,25

On immunohistochemistry, the tumor cells are strongly positive for p53

and focally positive for CD34 (My10), which is a marker differentiation from the

outer root sheath. They are occasionally positive for epithelial membrane antigen

(EMA). Trichilemmal carcinoma also expresses shows positivity for cytokeratins,

namely CK 1, 10, 14, 17, and 19.1,23 The main differential diagnosis of

trichilemmal carcinoma is clear cell squamous cell carcinoma, although these

tumours are considered by some authors to be the same entity. Squamous cell

carcinoma with clear cells lacks trichilemmal keratinization or lobular

22
proliferation. Trichilemmal carcinoma must be distinguished from other skin

cancers with clear cell changes. The identification of ductal differentiation with

CEA and EMA staining is useful for differentiating hidradenocarcinoma from

trichilemmal carcinoma. Desmoplastic benign trichilemmoma may exhibit an

infiltrative growth pattern but lacks pleomorphism and mitoses. Malignant

proliferating trichilemmal tumour, which is often confused with trichilemmal

carcinoma, demonstrates extensive areas of necrosis, abrupt keratinization,

minimal pleomorphism, low mitotic activity, and foci resembling a trichilemmal

cyst. Proliferating trichilemmal tumour is regarded as a distinct

clinicopathological entity. Sebaceous carcinoma is distinguished by the presence

of multiple intracytoplasmic lipid rich vacuoles indenting the nucleus.23,26

The mainstay of treatment is surgery with wide local excision of the tumor

and active follow-up. Histological clear margins must be documented because of

the potential recurrences, as encountered in a study by Zhuang et al. The other

treatment modalities are Mohs micrographic surgery and immunomodulation with

imiquimod cream. Trichilemmal carcinoma is a carcinoma of low-grade

malignancy with good prognosis that exceptionally can metastasize. Tumour-free

margins are a necessity due to the potential for local invasion and recurrence.

Prognostic factors in trichilemmal carcinoma are limited to lymph node status and

surgical margins.23

23
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