Cutaneous carcinoma with mixed histology: a potential etiology for skin cancer recurrence and an indication for Mohs microscopically controlled surgical excision.Abstract: Cutaneous cutaneous /cu·ta·ne·ous/ (ku-ta´ne-us) pertaining to the skin. cu·ta·ne·ous adj. Of, relating to, or affecting the skin. Cutaneous Pertaining to the skin. carcinomas with mixed histology describe nonmelanoma skin cancers which have more than one histologic subtype (programming) subtype - If S is a subtype of T then an expression of type S may be used anywhere that one of type T can and an implicit type conversion will be applied to convert it to type T. . These include basal cell carcinomas with concurrent aggressive growth patterns (such as sclerosing, infiltrating, micronodular, keratinizing, and tumors with perineural involvement) and nonaggressive growth patterns (such as superficial, nodular nodular marked with, or resembling, nodules. nodular dermatofibrosis see dermatofibrosis. nodular episcleritis see nodular fasciitis (below). nodular fasciitis a firm painless nodular swelling, 0. , and follicular fol·lic·u·lar adj. 1. Relating to, having, or resembling a follicle or follicles. 2. Affecting or growing out of a follicle or follicles. ) and squamous cell carcinomas with concurrent poorly differentiated poorly differentiated Oncology adjective Referring to a malignancy in which the malignant cells bear minimal resemblance to the cell from which they arose. Cf Well-differentiated. and well-differentiated components. One mechanism of recurrence of nonmelanoma skin cancer may very well result from the inadequate initial treatment of cutaneous tumors with mixed histology. If the aggressive histologic subtype of the original tumor is initially not suspected based upon the pathology observed from a superficial biopsy specimen, the clinician may initiate therapy that would be appropriate for the less aggressive variant that was diagnosed. Subsequently, the more aggressive tumor may persist and eventually manifest as a clinical recurrence of the cancer. This is particularly important when there is perineural tumor involvement. We describe two patients whose skin cancers had more than one histologic subtype to demonstrate the histologic features of cutaneous malignancies with more than one pathologic pattern and to emphasize how inaccurate a single diagnostic biopsy can be. We also suggest that clinicians consider Mohs surgical excision of nonmelanoma skin cancers since this technique incorporates microscopically controlled removal of the tumor with complete pathologic evaluation of all surgical margins for any residual cancer residual cancer Oncology Any CA that remains after definitive management has been attempted. Cf Recurrent cancer. . Key Words: basal cell carcinoma, cutaneous carcinoma, mixed histology, Mohs, Mohs micrographic mi·cro·graph n. 1. A drawing or photographic reproduction of an object as viewed through a microscope. 2. An instrument used to make tiny writing or engraving. surgery. Mohs microscopically controlled surgery, recurrence, skin cancer, squamous cell carcinoma ********** Nonmelanoma skin cancer is the most common form of malignancy. There are several treatment modalities for basal cell carcinoma and squamous cell carcinoma. (1-10) They include cryotherapy Cryotherapy Definition Cryotherapy is a technique that uses an extremely cold liquid or instrument to freeze and destroy abnormal skin cells that require removal. , (11-13) curettage curettage /cu·ret·tage/ (ku?re-tahzh´) [Fr.] the cleansing of a diseased surface, as with a curet. medical curettage and electrodesiccation, (14,15) intralesional immunomodulator (alpha interferon), (3,16-19) photodynamic therapy photodynamic therapy n. A type of phototherapy in which a nontoxic light-sensitive compound that has been injected into a patient is exposed selectively to light, whereupon it becomes toxic to targeted malignant and other diseased cells. , (3,20-22) radiotherapy (23-25) surgical excision, (26-28) topical chemotherapy topical chemotherapy Treatment with anticancer drugs in a lotion or cream (5-fluorouracil cream or solution), (29,30) topical immunomodulator (imiquimod 5% cream), (19,30-32) and Mohs microscopically controlled surgery. (33-38) The tumor's histology, based on the initial biopsy report, may influence the clinician's choice of therapy. For example, topical imiquimod may be used to treat a biopsy-confirmed basal cell carcinoma of the superficial type. In addition, the clinician may treat this same suspected superficial basal cell carcinoma with liquid nitrogen cryotherapy or curettage and electrodesiccation. However, the classic morphologic appearance of a superficial basal cell carcinoma does not eliminate the possibility that a more aggressive histologic tumor subtype is present in the deeper dermis dermis: see skin. . Also, if the diagnosis of superficial basal cell carcinoma was based upon a shave biopsy shave biopsy n. A biopsy technique performed with a surgical blade or a razor blade and used for lesions that are elevated above the skin level or confined to the epidermis and upper dermis. for which the tissue specimen only extends into the papillary papillary /pap·il·lary/ (pap´i-lar?e) pertaining to or resembling a papilla, or nipple. papillary, adj similar to a small, nipple-shaped elevation or projection. dermis, a decision regarding the most appropriate treatment may be based on incomplete information, and the tumor may not be adequately treated if a more aggressive histologic variant of the neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. is present in the adjacent or deeper dermis. We report two patients with skin cancers having mixed histologic subtypes and suggest that this phenomenon of cutaneous neoplasms containing pathologic features of more than one variant may represent an unsuspected etiology for nonmelanoma skin cancer recurrence following treatment that was directed toward a tumor subtype considered to have a less aggressive clinical behavior based upon the biopsy tissue specimen available for evaluation. Case Reports Patient 1 A 69-year-old white man developed a recurrent basal cell carcinoma on his nose at the border of the skin graft skin graft Autologous, donated, or surrogate skin removed from one site to cover surfaces on another region with 3rd-degree burns or traumatic tissue loss. See Split-thickness graft. Cf Artificial skin, 'Spray-on' skin. from his previous surgery 4 years earlier. He had recently noted a new pearly papule papule /pap·ule/ (pap´ul) a small, circumscribed, solid, elevated lesion of the skin.pap´ular pap·ule n. pl. on his right nose adjacent to the prior surgical site. A lesional biopsy demonstrated basal cell carcinoma; the histologic subtype was not specified in the initial pathology report. He was referred for excision of the tumor using Mohs microscopically controlled surgery. Cutaneous examination showed a 0.3 X 0.3 cm erythematous erythematous characterized by erythema. papule located at the distal border of a skin graft on the distal right nasal sidewall (Fig. 1). The first stage of Mohs surgery Mohs surgery (mōz), n.pr a surgical technique used primarily in the treatment of skin neoplasms, especially basal cell or squamous cell carcinoma. showed a basal cell carcinoma of mixed histologic subtypes (Fig. 2). There were buds of superficial basal cell carcinoma extending from the basal layer basal layer n. 1. The outermost layer of the endometrium, which undergoes only minimal changes during the menstrual cycle. 2. The inner layer of the choroid in contact with the pigmented layer of the retina. of the epidermis into the papillary dermis and aggregates of nodular basal cell carcinoma in the upper reticular reticular /re·tic·u·lar/ (-lar) resembling a net. re·tic·u·lar or re·tic·u·lat·ed adj. Resembling a net in form; netlike. dermis (Fig. 3). In the deeper reticular dermis, there were morpheaform strands of sclerosing basal cell carcinoma which reached the margin of the specimen (Fig. 4). The tumor was clear after the second stage of Mohs surgery. The postoperative defect extended to cartilage and measured 1.5 X 1.7 cm (Fig. 5). The wound was repaired with a full thickness skin graft (Fig. 6). Patient 2 A 79-year-old white woman developed a new skin lesion on the top of her left ear. The initial clinical differential diagnosis differential diagnosis n. Determination of which one of two or more diseases with similar symptoms is the one from which the patient is suffering. Also called differentiation. included a seborrheic keratosis seborrheic keratosis n. A superficial, benign, verrucose lesion consisting of proliferating epidermal cells enclosing horn cysts, usually appearing on the face, trunk, or extremities in adulthood. , chondrodermatitis nodularis helicis, basal cell carcinoma, and squamous cell carcinoma. A lesional biopsy, consisting of three small pieces of tissue, showed a squamous cell carcinoma extending to the margins of the specimen; the histologic subtype was not specified in the initial pathology report. She was referred for excision of the tumor using Mohs microscopically controlled surgery. Cutaneous examination showed a 1.1 X 0.6 cm erythematous ulcerated Ulcerated Damaged so that the surface tissue is lost and/or necrotic (dead). Mentioned in: Adenoid Hyperplasia nodule nodule: see concretion. nodule In geology, a rounded mineral concretion that is distinct from, and may be separated from, the formation in which it occurs. with surrounding erythema erythema (ĕr'əthē`mə), more or less diffuse redness of the skin due to concentration of an abnormally large amount of blood within the small vessels of the skin (hyperemia), as in burns. on the left superior helix (Fig. 7). The first stage of Mohs surgery demonstrated a squamous cell carcinoma of mixed histologic subtypes in the dermis (Fig. 8). There were aggregates of well-differentiated keratinizing tumor epithelium that extended into the reticular dermis (Fig. 9). In addition, in the lateral portion of the specimen, there were thin strands of poorly differentiated tumor cells invading between the collagen bundles and reaching the margin of the specimen (Fig. 10). The tumor was clear after the second stage of Mohs surgery. The postoperative defect extended to cartilage and measured 1.5 X 1.0 cm (Fig. 11). The wound was repaired with a split thickness skin graft, which was harvested from the left forearm (Fig. 12). Discussion Nonmelanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma. The predominant histologic subtypes of basal cell carcinoma include superficial basal cell carcinomas, nodular basal cell carcinomas, basal cell carcinomas with adnexal adnexal /ad·nex·al/ (ad-nek´sal) pertaining to adnexa. adnexal pertaining to, or emanating from, the adnexa. adnexal tumors (sebaceous gland sebaceous gland (səbā`shəs), gland in the skin of mammals that secretes an oily substance called sebum. In humans, sebaceous glands are primarily found in association with hair follicles but also occur in hairless areas of the skin, , eccrine gland eccrine gland: see sweat. , and hair follicle hair follicle n. A deep narrow pit that is formed by the tubular invagination of the epidermis and corium and encloses the root of the hair. Hair follicle ) differentiation, and tumors whose histology is associated with an aggressive growth pattern: infiltrative basal cell carcinomas (consisting of variable-sized aggregates and elongated e·lon·gate tr. & intr.v. e·lon·gat·ed, e·lon·gat·ing, e·lon·gates To make or grow longer. adj. or elongated 1. Made longer; extended. 2. Having more length than width; slender. cords of neoplastic cells that demonstrate irregular invasion of the surrounding stroma stroma /stro·ma/ (stro´mah) pl. stro´mata [Gr.] the matrix or supporting tissue of an organ.stro´malstromat´ic stro·ma n. pl. stro·ma·ta 1. ), keratinizing basal cell carcinoma (consisting of horn cysts and parakeratotic cells [with elongated nuclei and slightly eosinophilic eosinophilic /eo·sin·o·phil·ic/ (-fil´ik) 1. readily stainable with eosin. 2. pertaining to eosinophils. 3. pertaining to or characterized by eosinophilia. cytoplasm cytoplasm: see protoplasm. cytoplasm Portion of a eukaryotic cell outside the nucleus. The cytoplasm contains all the organelles (see eukaryote). ] that lie in strands, in whorls, or around the horn cysts, in addition to the basaloid neoplastic cells with their deeply basophilic basophilic /ba·so·phil·ic/ (-fil´ik) 1. pertaining to basophils. 2. staining readily with basic dyes. basophilic staining readily with basic dyes. cytoplasm), micronodular basal cell carcinomas (consisting of small, rounded aggregates of neoplastic cells), and sclerosing (or morpheaform) basal cell carcinomas (consisting of narrow elongated cords of neoplastic cells with surrounding sclerosis) and basal cell carcinomas with perineural invasion perineural invasion Surgical pathology Extension of epithelial cells around nerves which, while typical of malignancy, may be seen in sclerosing adenosis–breast, and is not per se an indication of malignancy . (39-41) Squamous cell carcinomas are histologically classified based upon their degree of differentiation ranging from well differentiated to poorly differentiated. Since the degree of differentiation may be variable in different fields of the same tumor, a grading system for the histopathology his·to·pa·thol·o·gy n. The science concerned with the cytologic and histologic structure of abnormal or diseased tissue. Histopathology The study of diseased tissues at a minute (microscopic) level. of cutaneous squamous cell squamous cell n. A flat, scalelike epithelial cell. carcinomas-based on the percentage of differentiated cells in that neoplasm--can be used. (42-44) More than 75%, 50%, and 25% of the tumor cells are well differentiated in Grade 1, Grade 2, and Grade 3, respectively. In Grade 4, less than 25% of the tumor cells are well differentiated. (43) Generally, cutaneous squamous cell carcinomas of higher grade, with a greater proportion of poorly differentiated tumor cells, are thought to have a greater tendency toward more aggressive biologic behavior. In addition to the degree of differentiation (which reflects the extent of keratinization keratinization /ker·a·tin·i·za·tion/ (ker?ah-tin?i-za´shun) conversion into keratin. ker·a·tin·i·za·tion n. The conversion of squamous epithelial cells into a horny material, such as nails. of tumor cells), the biologic behavior of cutaneous squamous cell carcinoma is also influenced by the degree of tumor cell atypicality, the depth of tumor penetration, the architectural pattern of invasion, and whether perineural tumor invasion is present. (43-45) [FIGURE 1 OMITTED] [FIGURE 2 OMITTED] [FIGURE 3 OMITTED] [FIGURE 4 OMITTED] Skin cancers occasionally demonstrate pathologic features of more than one tumor or more than one subtype of a single tumor. The pathologic presence of multiple different neoplasms coexisting in a single cancer lesion can result either from (1) a collision tumor collision tumor, n See tumor, collision. , in which two or more cutaneous malignancies coincidentally collide and clinically appear as one lesion (46) or (2) a metatypical tumor, in which the epidermal Epidermal Referring to the thin outermost layer of the skin, itself made up of several layers, that covers and protects the underlying dermis (skin). Mentioned in: Antiangiogenic Therapy, Histiocytosis X epidermal keratinocytes Keratinocytes Cells found in the epidermis. The keratinocytes at the outer surface of the epidermis are dead and form a tough protective layer. The cells underneath divide to replenish the supply. differentiate into tumor cells of both basal cell carcinoma and squamous cell carcinoma, such as a basosquamous (or basaloid squamous cell) carcinoma. (47-49) Skin cancer with mixed histology refers to basal cell carcinomas that contain a mixed pattern of pathologic subtypes and squamous cell carcinomas that contain more than one subtype of differentiation. [FIGURE 5 OMITTED] [FIGURE 6 OMITTED] [FIGURE 7 OMITTED] [FIGURE 8 OMITTED] Skin cancer recurrence results from persistence of tumor following the initial or subsequent treatment. Several factors may influence whether nonmelanoma cutaneous neoplasms recur. These include the biologic behavior of the tumor, the immunologic status of the patient, and the cancer-directed treatment. The skin cancer's biologic behavior is partially dependent upon the histologic pattern of the cutaneous tumor. (50-56) Basal cell carcinomas with aggressive growth patterns and poorly differentiated squamous cell carcinomas have an increased incidence of recurrence. (42-45,57-60) Also, the majority of recurrent basal cell carcinomas are aggressive from the onset. (57) The patient's degree of immunocompetence immunocompetence /im·mu·no·com·pe·tence/ (-kom´pe-tens) immunoresponsiveness; the capacity to develop an immune response after exposure to antigen. also contributes to the ability of their innate host defenses to limit the recurrence or metastasis metastasis /me·tas·ta·sis/ (me-tas´tah-sis) pl. metas´tases 1. transfer of disease from one organ or part of the body to another not directly connected with it, due either to transfer of pathogenic microorganisms or to of their skin cancers. Basal cell carcinomas in immunosuppressed Immunosuppressed A state in which the immune system is suppressed by medications during the treatment of other disorders, like cancer, or following an organ transplantation. Mentioned in: Fifth Disease individuals demonstrate more aggressive biologic behavior. (52) For example, the recurrence rate of basal cell basal cell n. A type of cell found in the deepest layer of the epithelium. carcinoma--even after treatment with Mohs surgery--is significantly higher in patients with impaired immune function Immune function The state in which the body recognizes foreign materials and is able to neutralize them before they can do any harm. Mentioned in: Herbalism, Traditional Chinese, Stress Reduction (such as patients with chronic myelogenous leukemia Chronic myelogenous leukemia (CML) Also called chronic myelocytic leukemia, malignant disorder that involves abnormal accumulation of white cells in the marrow and bloodstream. Mentioned in: Bone Marrow Transplantation ) as compared with persons with an intact immune system. (61) [FIGURE 9 OMITTED] Finally, the approach to therapy for skin cancer, which is often influenced by the pathologic features observed on the biopsy specimen of the malignancy, also plays a role in the potential recurrence of that tumor. More aggressive tumor subtypes usually require more aggressive treatment. (62) For example, based upon the management of the tumor, variable rates of tumor persistence or recurrence for primary basal cell carcinoma have been observed: 0% to 21% for cryotherapy, (12,13,63-65) 3% to 42% for curettage and electrodesiccation, (66-69) 2% to 30% for intralesional alpha interferon, (16,18,70,71) 0% to 35% for photodynamic therapy, (3,20,21,72) 7% to 16% for radiotherapy, (3,23,48,73) 2% to 10% for surgical excision, (10,74-77) 7% to 21% for topical 5-fluorouracil, (29,30,78) and 0% to 31% for topical imiquimod. (19,30,32,79) Recurrence rates following excision using the Mohs microscopically controlled technique have been reported as 1.0% to 3.3% and 3.4% to 7.3% for the treatment of primary and recurrent basal cell carcinoma, respectively. (80-84) Clinicians often perform a superficial shave biopsy of a lesion that is suspected to be a nonmelanoma skin cancer to establish pathologic confirmation. We suggest that a possible mechanism for the recurrence of nonmelanoma skin cancer may result from the inadequate initial treatment of cutaneous tumors with mixed histology. For example, similar to our first patient, the superficial portion of a skin cancer may only demonstrate a basal cell carcinoma with a nonaggressive histologic growth pattern while the deeper portion of that same tumor reveals a sclerosing basal cell carcinoma. The pathology report from that specimen would only document a basal cell carcinoma with a less aggressive clinical behavior and the clinician may be prompted to initiate therapy with a modality that is only appropriate for tumor subtypes with less aggressive histologic features. Unfortunately, it would not be unexpected for the tumor to persist following the insufficient, albeit unintentional, treatment and to recur clinically. [FIGURE 10 OMITTED] [FIGURE 11 OMITTED] Another example, similar to our second patient, concerns a squamous cell carcinoma which contains both well-differentiated and poorly differentiated tumor cells. If the poorly differentiated component is not noted on the initial biopsy specimen, the possible use of adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant) 1. assisting or aiding. 2. a substance that aids another, such as an auxiliary remedy. 3. treatment modalities (such as postoperative radiotherapy, superficial parotidectomy Parotidectomy Definition Parotidectomy is the removal of the parotid gland, a salivary gland near the ear. Purpose The main purpose of parotidectomy is to remove cancerous tumors in the parotid gland. , and/or closer follow-up after surgery)--in addition to margin-controlled excision of the residual tumor--may not be considered for the patient. This is also of particular importance when there is perineural tumor involvement. (85,86) Cutaneous tumors with mixed histology are not rare. A retrospective study of recurrent skin cancer observed that 25% of recurrent sclerosing basal cell carcinomas (9 of 36 tumors) had nodular areas of tumor superficially or peripherally with areas of sclerosis usually at the base where it may have been inapparent inapparent not clearly seen. inapparent infection infection without clinical signs. or not reached by biopsy. (87) Another retrospective study was also performed over a 2-year period to detect the frequency of basal cell carcinomas containing more than one pathologic pattern. An estimated frequency of cancers with a mixed pattern of nodular and infiltrative basal cell carcinoma was 10.5% (42 biopsies from approximately 400 basal cell carcinoma specimens). (39) Hence, a conservative speculation is that possibly between 10 to 25% of basal cell carcinoma recurrences may be secondary to undiagnosed, and therefore insufficiently treated, basal cell carcinomas with mixed histology since the cancers were preliminarily managed as a less aggressive pathologic variant of basal cell carcinoma based on the evaluation of only the superficial portion of the tumor. [FIGURE 12 OMITTED] Conclusion Two patients whose skin cancers had more than one histologic subtype are reported to demonstrate the histologic features of cutaneous malignancies with more than one pathologic pattern and to emphasize the importance of adequate tissue sampling at the time of biopsy. If the aggressive histologic subtype of the original tumor is not suspected based upon the pathology observed from a superficial biopsy specimen, the clinician may initiate treatment that would be appropriate for the less aggressive variant that was diagnosed; however, this therapy would indeed be inadequate for the more aggressive malignancy that may actually be present. Subsequently, the more aggressive histologic subtype in the deeper portion of the tumor may persist and eventually manifest as a clinical recurrence of the cancer. Hence, it may be helpful for suspected tumors to be sampled as completely as possible to have the most accurate histologic microstaging information upon which to base treatment decisions. In addition, clinicians may want to request from their pathologists that histologic subtypes of basal cell carcinomas and squamous cell carcinomas be included in the patient's pathology reports. 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RELATED ARTICLE: Key Points * Cutaneous carcinoma with mixed histology refers to basal cell carcinomas that contain a mixed pattern of pathologic subtypes and squamous cell carcinomas that contain more than one subtype of differentiation. * Recurrence of nonmelanoma skin cancer may very well result from the inadequate initial treatment-based on the presumed histologic subtype--of cutaneous tumors with mixed histology. * Between 10% to 25% of basal cell carcinoma recurrences may be secondary to undiagnosed, and therefore insufficiently treated, basal cell carcinomas with mixed histology. * Mohs surgical excision of nonmelanoma skin cancers incorporates microscopically controlled removal of the tumor with complete pathologic evaluation of all surgical margins for any residual cancer. * Clinicians should consider Mohs surgical excision of nonmelanoma skin cancers in order to ensure adequate treatment of unsuspected cutaneous carcinomas with mixed histology. |
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