Primary Skin Tumors Research Articles

Signet ring squamous cell carcinoma-the forgotten variant: case report and review of the literature

Squamous cell carcinoma is one of the commonest skin cancers. In most instances, histological diagnosis is straightforward and does not pose any diagnostic challenge to the handling pathologist. We report a rare case of signet ring squamous cell carcinoma (SRSCC) occurring in an 84-year-old woman who presented with a sore on the upper lip. Excision of the lesion showed signet ring carcinoma within a scar and surface ulceration. Deeper sections showed focal area of squamous differentiation. Although rare, consideration of squamous cell carcinoma as a diagnosis of primary skin tumors with signet ring morphology, especially in the absence of history of adenocarcinoma, may prevent missing rare cases of SRSCCs.

A 64 year-old female with scalp metastasis of papillary thyroid cancer

The skin metastasis of papillary thyroid carcinoma (PTC) is a rare condition and the lesions should be differentiated from primary skin tumors. The scalp is the most frequent site which is involved in skin metastasis of PTC. It shows the poor outcome and aggressive nature of disease. In this report, we aim to present a case report of a 64 year-old female with scalp metastasis of PTC in the context of disseminated pulmonary and liver metastasis.

Predisposing Factors and Outcomes of Malignant Skin Tumors in Children

Although benign and metastatic tumors occur in children, primary malignant skin tumors are uncommon in the pediatric population. In this study, the authors aimed to determine the incidence, risk factors, treatment, reconstruction details, and outcome of malignant skin tumors occurring in pediatric patients at the Hospital for Sick Children. The electronic database (CoPath) of the pathology department was searched for all cases of malignant skin tumors treated surgically between January of 2000 and September of 2008. Eighteen patients had been diagnosed and treated surgically for malignant skin tumors. The mean age was 10.4 years. Diagnosis of malignant melanoma was made in 14 patients, diagnosis of basal cell carcinoma was made in four patients, and diagnosis of squamous cell carcinoma was made in one patient. The most common sites of occurrence were lower limbs (33 percent) and face (28 percent). Gorlin syndrome was an underlying predisposing condition in three patients with basal cell carcinoma. All cases of basal cell carcinoma and squamous cell carcinoma underwent surgical resection and primary closure or skin graft. Of the patients with malignant melanoma, seven underwent surgical excision and primary closure and five had excision and skin graft. Eleven patients underwent sentinel node biopsy (Breslow thickness > or = 0.75 mm). Interferon was used as an adjuvant therapy in patients with positive regional lymph nodes. One patient with melanoma suffered a recurrence. Malignant skin tumors are rare in children. In accordance with previously published data, malignant melanoma was the most frequent tumor in our study. Epithelial tumors were less common and were all associated with an underlying predisposing condition.

Burden of Malignancy After a Primary Skin Cancer: Recurrence, Multiple Skin Cancers and Second Primary Cancers

The current paper summarizes relevant recent research on the high risk of recurrence, multiple skin cancers and second primary cancers in the growing number of people with a history of skin cancer; the ultimate purpose is to better assess the burden of malignancy following skin cancer. A number of challenges exist in identifying and tracking both melanoma and non-melanoma skin cancer (NMSC) cases. Most jurisdictions do not routinely track NMSC cases and, even if they do, it is customary to only include the first diagnosis. There are variable rules for counting multiple melanoma cancers, and recurrences are not considered for either major type of skin cancer. Applying insights from recent studies of this issue to Canadian cancer statistics would increase reported diagnoses of NMSC by about 26% and melanoma by 10% in this country. This approach to a fuller assessment of the burden of skin cancers has been called a “diagnosis-based incidence approach” as compared with a “patient-based incidence approach”. A further issue that is not usually taken into account when assessing the burden of skin cancers is the 20% to 30% elevated risk of non-cutaneous second primary cancers following a primary skin tumour. In summary, individuals with skin cancer are subject to a high risk of recurrence, multiple skin cancers and second primary cancers. This burden should be a special concern in the large and growing pool of individuals with a history of skin cancer, as well as among prevention planners.

Burden of malignancy after a primary skin cancer: recurrence, multiple skin cancers and second primary cancers.

The current paper summarizes relevant recent research on the high risk of recurrence, multiple skin cancers and second primary cancers in the growing number of people with a history of skin cancer; the ultimate purpose is to better assess the burden of malignancy following skin cancer. A number of challenges exist in identifying and tracking both melanoma and non-melanoma skin cancer (NMSC) cases. Most jurisdictions do not routinely track NMSC cases and, even if they do, it is customary to only include the first diagnosis. There are variable rules for counting multiple melanoma cancers, and recurrences are not considered for either major type of skin cancer. Applying insights from recent studies of this issue to Canadian cancer statistics would increase reported diagnoses of NMSC by about 26% and melanoma by 10% in this country. This approach to a fuller assessment of the burden of skin cancers has been called a "diagnosis-based incidence approach" as compared with a "patient-based incidence approach". A further issue that is not usually taken into account when assessing the burden of skin cancers is the 20% to 30% elevated risk of noncutaneous second primary cancers following a primary skin tumour. In summary, individuals with skin cancer are subject to a high risk of recurrence, multiple skin cancers and second primary cancers. This burden should be a special concern in the large and growing pool of individuals with a history of skin cancer, as well as among prevention planners.

Neurofibroma like nodules on shoulder: First sign of gastric adenocarcinoma

Cutaneous metastasis is a relatively uncommon manifestation of visceral malignancies. It most often occurs late in the course of a disease but may also be the first presenting sign of advanced visceral cancer. The average incidence of cutaneous metastasis from a visceral neoplasm is 5.3 percent. The incidence of cutaneous metastases from carcinomas of the upper digestive tract has been reported as less than 1 percent. Cutaneous metastases of gastrointestinal tumors are usually nodular and their typical location is in the abdominal wall. A 68-year-old woman presented with a three-month history of painless nodules on the right side of her neck. Skin examination revealed two joined nodules on the right side of her neck. The nodules were skin colored, well-circumscribed, non-motile, soft, and non-tender. Histopathological examination of the skin growth revealed diffuse infiltration of the dermis and subcutaneous tissue by tumoral cells. A diagnosis of metastatic gastric carcinoma was made. However,various cutaneous metastases have been reported as erysipelas-like, zosteriform, and epidermoid cyst-like. Cutaneous metastases must always be distinguished from primary skin tumors. This report emphasizes the need for appropriate investigation of newly appearing, unusual, or persistent skin lesions such as non-healing ulcers, persistent indurated erythemas, and all skin nodules of undetermined causes.

Abstract 341: Effects of immunosuppressive cyclosporin A on epidermal keratinocytes

Abstract Non-melanoma skin cancer, the most common neoplasia after solid organ transplantation, causes serious morbidity and mortality and is related to sun exposure. Cyclosporin A (CsA) has been used widely to prevent rejection in organ transplantation. The mechanism of CsA action in causing cancer was thought to be well understood via immunosuppression. Here, we show that CsA promotes primary skin tumor growth in immune-deficient mice. CsA treatment at therapeutic plasma concentrations promotes growth and survival from removal of extracellular matrix or UVB radiation. CsA treatment enhances AKT activation following serum treatment and UVB radiation. Furthermore we found that PTEN expression, the negative regulator of AKT activation, is reduced significantly upon CsA treatment in human HaCaT and A431 cells and in mouse skin in vivo. Accordingly, the enhanced AKT activation in CsA-treated cells upon UVB radiation is observed in PTEN knockdown keratinocytes. CsA-induced PTEN suppression is critical for increased AKT activation. Inhibition of AKT activation abolishes CsA-promoted growth and survival, indicating that AKT hyperactivation is essential for the enhanced growth and survival of CsA-treated cells. In addition, mTOR signaling as a known AKT downstream target is required for CsA-enhanced growth and survival. Taken together, we have identified PTEN/AKT pathway as new molecular targets of CsA in epidermal keratinocytes, suggesting a previously unknown mechanism in CsA-enhanced skin carcinogenesis. Our findings challenge assumptions about how CsA-associated tumors arise in skin. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 341.

Long‐term results after reconstruction of full thickness scalp defects with a dermal regeneration template

Large scalp defects in which the pericranium has to be resected can be reliably reconstructed using Integra. In the present study, we retrospectively analysed the long-term outcome of our patients. Nineteen patients were included who had received Integra dermal regeneration template for treatment of full thickness scalp defects after resection of various malignant tumours. All patients were followed up with a mean follow-up time of 31 months (14-72). All transplants were on almost equal levels with the surrounding skin. Cosmetic results were acceptable and scars were stable. Nodal ultrasound status was negative in all patients. During the follow-up period of up to 72 months, no local recurrences were observed. One patient with a leiomyosarcoma received radiotherapy after transplantation. In the irradiated area, multiple small regular-shaped round ulcerations and later on partial necrosis of the transplant occurred when the patient developed renal failure 29 months after the initial operation. Five patients died of disease not related to the primary skin tumour. All other patients are alive and free of disease without any complications. After reconstruction of full thickness scalp defects with Integra, the cosmetic results are appealing and we observed no local recurrences during the follow-up period.

Immunosuppressive Cyclosporin A Activates AKT in Keratinocytes through PTEN Suppression: IMPLICATIONS IN SKIN CARCINOGENESIS

Non-melanoma skin cancer, the most common neoplasia after solid organ transplantation, causes serious morbidity and mortality and is related to sun exposure. Cyclosporin A (CsA) has been used widely to prevent rejection in organ transplantation. The mechanism of CsA action in causing cancer was thought to be well understood via immunosuppression. Here, we show that CsA promotes primary skin tumor growth in immune-deficient mice and keratinocyte growth in vitro. In addition, CsA enhances keratinocyte survival from removal of extracellular matrix or UVB radiation. At the molecular level, CsA increases AKT activation after serum treatment and UVB irradiation. Furthermore we found that expression of PTEN, the negative regulator of AKT activation, is significantly reduced post-CsA in human HaCaT and A431 cells and in mouse skin in vivo. CsA-induced PTEN down-regulation occurs at the transcription level and is epidermal growth factor receptor-dependent. Such PTEN suppression is required for increased AKT activation. Inhibition of AKT activation abolishes CsA-promoted growth and survival, indicating that AKT hyperactivation is essential for both growth and survival of CsA-treated cells. In addition, mTOR signaling as a known AKT downstream pathway is required for CsA-enhanced growth and survival. Taken together, we have identified the PTEN/AKT pathway as new molecular targets of CsA in epidermal keratinocytes, suggesting a previously unknown mechanism in CsA-enhanced skin carcinogenesis. Our findings challenge assumptions about how CsA-associated tumors arise in skin.

The Immunosuppressive Surface Ligand CD200 Augments the Metastatic Capacity of Squamous Cell Carcinoma

CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in well-differentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200(+) SCC cells may depend on their ability to interact with CD200R(+) immune cells. The predominant population of CD200R(+) stromal cells was CD11b(+)Gr-1(+) myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200(+) SCC keratinocytes to directly engage and modulate CD200R(+) myeloid-derived suppressor cells is essential to metastatic survival.

Adnexal tumours of the skin as markers of cancer‐prone syndromes

Adnexal tumours of the skin are benign, more rarely malignant, primary skin tumours that originate from, or differentiate towards, hair follicles, sebaceous and sweat glands. Although they are usually encountered as single, sporadic tumours, they may occasionally be multiple, hereditary; in that case, they may herald complex genetic syndromes that comprise visceral cancers. Dermatologists should be aware of these adnexal skin tumours, the diagnosis of which may contribute to an early detection of a cancer-prone syndrome with a potentially lethal outcome. The main tumours falling into this category and their associated syndromes are reviewed here.

Value of p63 and podoplanin (D2‐40) immunoreactivity in the distinction between primary cutaneous tumors and adenocarcinomas metastatic to the skin: a clinicopathologic and immunohistochemical study of 79 cases

The distinction of metastatic carcinomas to the skin from poorly differentiated primary cutaneous carcinomas and sometimes primary benign adnexal tumors can pose a significant diagnostic challenge. The purpose of this study was to evaluate the role of p63 and podoplanin (D2-40) immunoreactivity for separating primary skin tumors vs. cutaneous metastases of carcinomas from internal organs. Thirty seven primary tumors and 42 cutaneous metastatic adenocarcinomas were evaluated. The 37 primary cutaneous tumors included 14 cases of benign adnexal tumors, 9 malignant skin adnexal neoplasms, and 14 primary squamous and basal cell carcinomas. The 42 metastatic adenocarcinomas all corresponded to metastases from patients with a well-documented history of a primary tumor at another location. We found variable positivity with podoplanin in all primary cutaneous neoplasms including spiradenoma (6/6), hidradenoma (2/4), cylindroma (3/3), desmoplastic trichilemmoma (1/1), poorly differentiated squamous cell carcinoma (4/4), sebaceous carcinoma (1/1), basal cell carcinoma (4/10), trichilemmal carcinoma (2/2), eccrine carcinoma (3/3), microcystic adnexal carcinoma (1/1), adnexal carcinoma NOS (1/1), and porocarcinoma (1/1). In contrast, all metastatic carcinomas were negative (0/42) for podoplanin. In regards to p63, all cases of primary cutaneous tumors were positive for p63 (37/37); in contrast, all cutaneous metastatic carcinomas were negative (0/42). Sensitivity, specificity, and positive and negative predictive values of podoplanin and p63 immunoreactivity to separate primary skin neoplasms from metastatic carcinomas were 78.4, 100.0, 100.0 and 84.0% for podoplanin, respectively, and 100.0, 100.0, 100.0 and 100.0% for p63, respectively. The differences in p63 and podoplanin immunohistochemical expression between primary skin tumors and metastatic carcinomas to the skin were statistically significant (p < 0, 0001). The results of our study suggest that the combined expression of p63 and podoplanin are a useful adjunct for the diagnosis of skin tumors in the clinical setting of a questionable metastasis and may be relatively specific for distinguishing primary skin tumors from metastatic carcinomas to the skin.

Merkel cell carcinoma with an unusual immunohistochemical profile

The clinical and morphological picture of Merkel cell carcinoma (MCC) may be rather challenging; therefore, the immunohistochemical profile plays a relevant role in confirming the microscopic diagnosis. A panel of antibodies including cytokeratins 20, 7 and epithelial membrane antigen, and neuron-specific enolase is used in confirming the morphological diagnosis of MCC. The majority of MCCs express CK20 and are CK7-negative. Herein, we present a case of primary cutaneous neuroendocrine carcinoma with an atypical immunohistochemical pattern. A 83-years old woman presented with a painless plaque, red to violaceous in colour, located in the leg. The skin tumor was excided, formalin-fixed and paraffinembedded. Tissue sections were immunostained with a panel of antibodies routinely utilized in complex primary skin tumors for evidencing epithelial and neuroendocrine differentiation of tumor cells. The neuroendocrine differentiation of tumor cells was evidenced by their immunoreactivity for synaptophysin, chromograninA and neuron-specific enolase. Tumor cells also showed diffuse cytoplasmic staining for CK7. No immunoreactivity was detected for CK20 and thyroid transcription factor-1. Our data, together with previous rare reports of CK20−/CK7+ MCCs, lay stress on the importance of routinely utilizing a panel of antibodies in the differential diagnosis of complex primary carcinomas of the skin and may have important implications in expanding the differential diagnosis of skin tumors. In particular, caution should be taken in excluding the diagnosis of MCC only on the basis of the absence of reactivity of tumor cells for CK20, favouring the wrong diagnosis of less aggressive skin tumors.

The malignant wound assessment tool: a validation study using a Delphi approach

Malignant wounds, caused by the direct invasion of cancer into the skin, occur in cancer patients with primary skin tumours and as cutaneous metastasis in approximately 10% of patients with metastatic internal malignancies. Malignant wounds have a profound impact on patients, family members and health care providers. The assessment of the patient with malignant wounds can be complex and there is no widely accepted, consistent approach. Valid, descriptive survey research methods were used to develop the Malignant Wound Assessment Tool (MWAT). The authors developed two versions of the MWAT: a brief clinical version (MWAT-C) and a more detailed research version (MWAT-R). Domains include clinical wound features, physical effects and emotional and social impacts of the wound. The two tools underwent content and construct validity testing using a Delphi process. An international panel of professionals with clinical or research expertise related to malignant wounds was formed. Panelists participated in two rounds of review for each tool. Development and face validity testing of the MWAT-C and MWAT-R tools through the Delphi process have resulted in tools ready for clinical application and will support clinical and research activities to improve care for patients with this devastating condition.

Metastatic Interdigitating Dendritic Cell Sarcoma Masquerading as a Skin Primary Tumor: A Case Report and Review of the Literature

We report an unusual case of a lymph node interdigitating dendritic cell sarcoma (IDCS), metastatic to skin, in a 73-year-old patient. The patient initially presented as having a primary skin tumor with lymph node metastasis. The metastatic IDCS was initially read as an atypical fibroxanthoma. However, the morphology seen on the lymph node excision, paired with immunohistochemistry and electron microscopy studies, was diagnostic for an IDCS. Additional immunohistochemistry was performed on the shave biopsy, confirming that the skin tumor was a metastasis. IDCS is a rare tumor that belongs to the histiocytic and dendritic cell group of tumors. Diagnosing this entity is difficult without the aid of ancillary testing such as immunohistochemistry and electron microscopy. In the workup of a spindle cell neoplasm, IDCS should be included in the differential diagnosis.

Lymphoepithelioma-like carcinoma of the skin: New case of an exceedingly rare primary skin tumor

Lymphoepithelioma-like carcinoma of the skin (LE-lCS) is a very rare, primary skin neoplasm of uncertain origin. The tumor reveals striking morphological similarity to undifferentiated nasopharyngeal carcinoma (lymphoepithelioma). However, the primary skin tumors have never been associated with Epstein-Barr virus (EBV), in contrast to those at some extracutaneous sites. Since the first description by Swanson et al. in 1988, only 46 cases have been documented over the last 20 years. This case report presents an 89-year-old woman with a 0.5 cm plaque-like, discolored lesion on her left cheek of one-month duration. The patient underwent surgical excision and is disease free one year later. The histopathological, immunohistochemical and EBV in situ hybridization features are described. The clinical and pathological differential diagnosis is discussed. This case supports the contention that LE-lCS is not associated with EBV.

Malignant nodular hidradenoma of the skin: report of seven cases

Malignant nodular hidradenoma (MNH) is an infrequent, highly malignant, primary skin tumour derived from eccrine sweat glands. Most tumours occur in elderly individuals. MNH has very poor prognosis, high recurrence and a high rate of metastases. The best method of treatment is still unclear: radical surgical excision is widely used, and selective lymph node dissection is also suggested. The value of the adjuvant radiotherapy and chemotherapy has not been confirmed. Seven MNH patients (4 men, 3 women, age 60-87 years) were treated between 1991 and 2007 in the Dermatology Unit of San Donato Hospital of Arezzo and in the Section of Dermatology of University of Siena, Italy. Tumours varied from 0.8 to 4.4 cm in size. All patients underwent local excision; five also had lymph node dissection. One patient underwent adjuvant radiotherapy, and three received chemotherapy. Six of seven patients died, with survival varying from 15 to 45 months. Distant metastases occurred in two patients. Survival time was inversely proportional to the size of the tumour. MNH is an aggressive tumour and should be diagnosed and excised as early as possible. Histological parameters are paramount, but correct diagnosis also calls for attention to clinical presentation and any history of recurrence or recent enlargement of long-standing lesions. In our experience, radiotherapy and chemotherapy do not seem to prolong survival.

Primary malignant skin tumours in Ghanaians: a prospective study of 31 cases

Background: The incidence of malignant tumours of the skin is increasing worldwide. In Ghana the clinical picture is complicated by late presentation and traditional forms of treatment; data on these conditions are also scanty. Patients and Methods A four year (2003 to 2007) prospective study of patients presenting at a Plastic and Reconstructive Surgical clinic in Ghana with malignant primary skin tumours was undertaken. The patients were examined clinically; the diagnosis was confirmed by biopsy. The patients had wide excision of their lesions with either direct closure of the defect or skin grafting as appropriate. Block dissection of palpably enlarged regional lymph nodes was performed where indicated. Results: Thirty one patients with primary malignant skin tumours were seen. The ages of the patients range from 14 to 100 years, with a mean age of 61.5 years. Thirteen (42%) patients had malignant melanoma, 13 (42%), had squamous cell carcinoma one (3%) had basal cell carcinoma and four (13%) had sarcomas comprising two cases of Kaposi sarcoma, one synovial sarcoma, and another of unknown origin. Patients with malignant melanoma had a mean age of 73.4 years while those with non-melanoma malignancies had a mean age of 53.0 years. Of the 13 patients with malignant melanoma only five (38.5%) were alive by the end of the study period; eight (61.5%) had died of disseminated disease. The primary lesion was confined to the foot, especially the sole. All the 13 patients with squamous cell carcinoma were alive by the end of the study period and most lesions developed from chronic ulcers and scars. Conclusions: Malignant melanoma and squamous cell carcinoma are the main primary skin cancers in Ghanaians. Most patients present late with advanced disease; most melanomas were inoperable, requiring only palliative surgery while most of the squamous cell carcinomas required extensive surgery. Keywords: malignant skin tumours, squamous cell carcinoma, basal cell carcinoma, melanoma.Nigerian Journal of Plastic Surgery Vol. 4 (1) 2008: pp. 7-13

TLR7 and TLR8 as targets in cancer therapy

Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/8-mediated activation of the central transcription factor nuclear factor-kappaB, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2- and caspase-dependent proapoptotic activity against tumor cells.

Expression of p63 in Cutaneous Metastases

p63 is an oncogene belonging to the p53 gene family. In normal human skin, p63 is expressed by the least-differentiated keratinocytes of the epidermis and its appendages, by myoepithelial cells of sweat glands, and by a wide variety of primary tumors arising therefrom. The expression of p63 by metastatic skin tumors has been more controversial. In this study, we assessed the usefulness of p63 detection in the differential diagnosis between primary and secondary (metastatic) skin tumors. The expression of p63 was studied in 45 cases of cutaneous metastases, mostly of known primary origin, and 94 benign and malignant epithelial primary skin tumors. p63 was expressed by 85 (89%) of 96 primary skin tumors and 5 (11%) of 45 cutaneous metastases. These results suggest that p63 may be a useful adjunct in the diagnosis of skin carcinomas; however, contrary to what has been previously claimed, expression of p63 does not rule out the metastatic origin of a cutaneous carcinoma.