Low-grade malignant proliferating pilar tumor simulating a squamous-cell carcinoma in an elderly female: a case report and immunohistochemical study.

A 65-year-old lady presented with an ulcerated lesion over the occipital region of nine-year duration, an incisional biopsy of which was reported as squamous-cell carcinoma. A wide local excision was performed and the tissue was sent for histopathological examination which revealed a low-grade malignant pilar tumor. Focal invasion and atypia were noted. Immunohistochemical (IHC) analysis revealed positivity for CD34 and calretinin immunomarkers favoring outer root sheath origin. Ki67 immunostains revealed a relatively low immunoreactivity indicating the low-grade nature of the tumor; however, p53 immunostain showed strong diffuse nuclear staining confirming the malignant nature of the tumor. Proliferating pilartumors (PPT) are rare tumors and less than 100 well-documented cases of malignant PPT have been reported so far in the literature. These tumors have been recently classified into benign, low- and high-grade malignant tumors and statistically significant difference was found in their biological behavior. However, we propose that IHC can be of immense value in assisting the subtyping of the tumor, so that the behavior and role of adjuvant therapy can be validated in future studies.

INTRODUCTION

Proliferating pilar tumor (PPT) was first described by Wilson-Jones in 1966 as “proliferating epidermoid cyst” and since then, a number of terms have been used to describe this lesion.[1] Some of them are proliferating trichilemmal cyst; giant hair matrix tumor; hydatidiform keratinous cyst; trichochlamydocarcinoma; and invasive hair matrix tumor, reflecting the disparity of interpretation about the nature and biological behavior of this entity.[2] These are rare tumors and less than 100 well-documented cases of malignant PPT have been reported so far in the literature.[3] We report here a case of low-grade malignant PPT which presented to us with an ulcerated scalp lesion with immunohistochemistry marker observation.

CASE REPORT

A 65-year-old lady presented to our hospital with an ulcerated lesion over the occipital region. The swelling was present for the past nine years and was gradually increasing in size; however, it ulcerated after a trivial trauma one month back. On further probing, she gave a history of occasional itching and pain on the swelling over the past six months. An incisional biopsy done outside was reported as squamous-cell carcinoma. Local examination of the lesion revealed an ulceroproliferative lesion on the scalp measuring 2.5×1.5×1.0 cm. The swelling was fluctuant and was not fixed to the underlying bone. No lymph nodes were palpable in the neck. A wide local excision was performed and the tissue was sent for histopathological examination.

Grossly, the specimen measured 3.0×2.0×1.0 cm with a tumor measuring 2.0×1.5×1.0 cm. The skin over the swelling showed a small ulceration measuring 0.4 cm in diameter. On cut surface, the tumor was gray-white solid with areas of chalky white calcifications [Figure 1]. Section examined from the representative areas revealed epidermis showing focal ulceration with an underlying unencapsulated tumor. The tumor was composed of lobulated expansile masses of squamous cells with non-lamellated trichilemmal keratinization and patchy calcification [Figure 2a]. The squamous cells showed focal atypia in the form of nuclear enlargement, irregular nuclear membrane, hyperchromasia, and presence of few atypical mitoses [Figure 2b]. Periphery of the lobules showed invasion into the surrounding stroma with tongues and cords of malignant well-differentiated squamous cells. The interlobular and peripheral stroma showed mononuclear inflammatory infiltrate and foreign body giant cell reaction to keratin. No lymphovascular or perineural invasion was noted. The margins were free from tumor. With the above findings, a diagnosis of low-grade malignant pilar tumor was offered. Immunohistochemical (IHC) analysis revealed definite membrane positivity for CD34 in more than 70% of tumor cells, with normal vascular endothelial cells acting as internal control [Figure 3a]. CD34 along with calretinin [Figure 3b] immunopositivity favored outer root sheath origin of this pilar tumor over squamous-cell carcinoma. Furthermore, IHC staining was done for proliferation markers including Ki67 and p53. Ki67 immunostaining revealed a relatively low immunoreactivity showing staining of about 20% of the nuclei which was focal and present more toward the periphery of the lobules [Figure 3c]. However, p53 immunostain showed strong diffuse nuclear staining, confirming the malignant nature of the tumor [Figure 3d]. The patient was symptom free without any evidence of recurrence or metastasis after six months of follow-up after the surgery.

Figure 1

Photomicrograph showing solid gray-white tumor on cut surface, with areas of chalky white calcifications

Figure 2

(a) Photomicrograph showing a tumor composed of lobulated expansile masses of squamous cells with non-lamellated trichilemmal keratinization. Also seen are nests of tumor cells infiltrating the stroma (H and E, ×100) (b) Photomicrograph showing squamous cells with atypia and presence of few atypical mitoses (H and E, ×400)

Figure 3

Photomicrograph showing (a) CD34 membrane positive immunostaining with normal vascular endothelial cells acting as internal control. Also note the absence of the staining in surface epithelial cells (CD34, ×100). (b) Calretinin immunomarker showing positivity in and around the keratin within the squamous lobules highlighting the companion layer of outer root sheath (Calretinin, ×100). (c) Ki67 nuclear immunostaining with focal and peripheral reactivity (Ki67, ×100). (d) Immunostaining with p53 showing strong diffuse nuclear positivity (p53, ×100)

DISCUSSION

Pilar tumors are infrequent comprising only 0.1% of skin biopsies with the malignant counterpart being even rarer.[4] Since its recognition 45 years ago, PPTs were considered pseudoepitheliomatous hyperplasia or at best benign neoplasms which occurred on the scalp of elderly females. However, Saida et al. defined three stages of oncological transformation of trichilemmal tumors – trichilemmal cyst, the adenomatous stage; proliferating trichilemmal cyst, the epitheliomatous stage; and malignant PTT, the carcinomatous stage.[5] Various factors have been implicated in this oncological transformation which include trauma and inflammation.[6] Recently, a clinicopathological study of 76 cases divided PPT into three groups based on the degree of stromal invasion and the level of cytological atypia – benign, low- and high-grade malignant.[2] In this study, 20 cases of low-grade malignant tumors were studied and the mean age of presentation was found to be 64.1 years with a male to female ratio of 1:2. These tumors were present in head and neck region in 80% cases (mostly on the scalp), atypical sites being trunk and arm. Unlike the present case, most cases had a preoperative diagnosis of a benign lesion. However, it must be mentioned that 10% cases had a preoperative diagnosis of squamous-cell carcinoma, as in our case.

Although, the benign PPT exhibits characteristic histologic features, the need to differentiate malignant PPTs (which shows nodular and spindle subtypes) from other malignant tumors cannot be overemphasized. Various IHC markers have been used to highlight the outer sheath differentiation including CD34 and calretinin.[78] CD34 expression strongly supports the outer root sheath origin of the tumor, although one case of CD34 negative malignant PPT has been reported.[7] Our case showed positivity in more than 70% of the cells as compared with only 1% and 20% positivity in one of the case series.[7] This may represent the degree of differentiation of the tumor from CD34 undifferentiated phenotype to CD34 positive differentiated phenotype.[7] Calretinin has recently been found to be the marker of companion layer of the outer root sheath and the positivity in our case confirms the origin.[8] Proliferation markers like Ki67 and p53 can assist in the stratification of these cases into the three-tier classification as suggested by Ye et al.[79] Ki 67 was found to be only focally positive in <5% of the basal cells in trichilemmal cysts and benign PPT as compared with 30 to 40% cells in malignant PPT by one of the investigators,whereas our case showed Ki67 positivity in 20% of the cells.[7] The present case highlights the importance of these markers in the diagnosis and subtyping of this tumor.

All the 20 cases of low-grade malignant PPT in the large clinicopathological study underwent excision with a mean follow-up period of 29.5 years.[2] Three of the 20 cases of low-grade malignant PPT showed recurrence at three months, nine months, and two years, respectively, after the diagnosis and none showed evidence of metastasis. In contrast, the high-grade PPT showed an adverse outcome in 50% cases (25% recurred and 25% metastasized) and none of the benign PPTs showed evidence of recurrence after a mean follow-up period of 96 months.[2] Absence of any adjuvant therapy in previous series has been cited by one of the authors as a reason for adverse outcome in malignant PPTs. They have suggested adjuvant radiation therapy in malignant PPTs to achieve favorable locoregional control.[4] However, their case was a high-grade malignant subtype and the precise role of adjuvant therapy in low-grade tumors like ours needs further validation. The findings in the present case highlight the importance of IHC (especially, CD34, Ki67, and p53) in assisting the subtyping, so that the behavior and role of adjuvant therapy can be validated in future studies on this tumor.