Metastatic Squamous Cell Carcinoma of the Skin

Sunlight induced squamous cell carcinoma of the skin is common and produces low incidence of metastases. Non-actinic squamous cell carcinoma, however, possesses a metastatic potential even when well differentiated. A representative case of keratinizing squamous cell carcinoma arising in a lower extremity with development of widespread metastases is discussed. The prognostic factors associated with metastasizing de novo squamous cell carcinoma of the extremity include: site of origin, duration of lesion, degree of differentiation, sex of patient, and size of the primary lesion. Organs prone to metastasis include: regional lymph nodes, liver, lungs, and bone. As skin cancers of this variety metastasize, the clinician must recognize this potential when considering therapeutic strategy.     

Reduced expression of claudin-7 correlates with invasion and metastasis in squamous cell carcinoma of the esophagus

Claudins are transmembrane proteins that seal tight junctions, bind with peripheral protein zonula occludens (ZO)-1, and are known to play an important role in several normal tissues and cancers. However, the role of claudin-1 and claudin-7 expressions in esophageal squamous cell carcinoma remains to be clarified. In the present study, we confirmed the expressions of claudin-1, claudin-7, and ZO-1 in the prickle cell layer of the normal human esophageal squamous epithelium. The expressions of claudin-1 and claudin-7 at the invasive front of the esophageal squamous cell carcinoma were analyzed immunohistochemically to clarify their role in tumor progression. Reduced expression of claudin-7 at the invasive front of the esophageal cancer was significantly associated with the depth of invasion (P = .004), stage (P = .038), lymphatic vessel invasion (P = .001), and lymph node metastasis (P = .014). In contrast, significant association was not detected between claudin-1 expression and clinicopathologic factors except for histologic differentiation of the tumor (P = .0029). Comparison of claudin-7 expression at the invasive front of the primary tumor and its corresponding metastatic lymph nodes revealed significant reduction in claudin-7 expression in the metastatic lymph nodes (P = .007). These results suggest that the reduced expression of claudin-7 at the invasive front of esophageal squamous cell carcinoma may lead to tumor progression and subsequent metastatic events. Thus, claudin-7 can be a novel marker for the prediction of lymph node metastasis.     

Scalp junctional nevus with malignant transformation (melanoma) metastatic to parotid lymph node region,cervical lymph nodes and the back: a case report and review of literature

Parotid malignancy may occur as a primary neoplasm of the salivary tissue or as metastatic involvement of the parotid lymph nodes. Primary tumors of squamous cell carcinoma and malignant melanoma involving the skin of the head and neck have the potential to spread to lymph nodes of the parotid gland. Metastatic malignant melanoma to the back was exceptionally rare and no such reports have been noted in the literature. We reported an exceptional case of intraparotid lymph nodes metastasis of the right scalp junctional nevus with malignant transformation to malignant melanoma in a 48-year-old man. The patient presented with a mass in the parotid gland area, which was misdiagnosed as a primary parotid tumor and surgical removal was performed. Unfortunately, recurrence with newly developed metastatic lesions in the back and cervical lymph nodes occurred 1 year after initial surgical management. This case is presented highlighting the unusual features of metastatic junctional nevus with malignant transformation to malignant melanoma of intraparotid lymph nodes, cervical lymph nodes and the back, which should help us to reduce misdiagnosis and obtain the best results.     

Histopathological characteristics of metastasizing squamous cell carcinoma of the skin and lips

AIMS: The reported incidence of metastasis from squamous cell carcinoma (SCC) of the skin and lip varies between 0.5% and 16%. Clinical and histopathological criteria have been proposed to identify tumours that may have an increased risk of metastasis. The aim of this study was to define such high-risk tumours, especially since the incidence of SCC of the skin is increasing. METHODS AND RESULTS: Histopathological features of metastasized skin and lip tumours and a matched group of non-metastasizing tumours were reassessed. Characteristics studied were: tumour width, excision margins, histological subtype, Clark level, Breslow depth, tumour differentiation, inflammation, perineural and angio-invasive growth, ulceration and desmoplasia. Data were statistically analysed separately for skin and labial lesions. Desmoplasia, Clark level, Breslow depth, maximum diameter, angio-invasion, grading, perineural invasion, plasma cells and eosinophilic inflammatory response proved to be statistically significantly related to metastasis of skin tumours. Breslow depth, plasma cells and grading appeared to be statistically significantly related to metastasis of SCC of the lips. CONCLUSIONS: A typical metastatic SCC showed: a tumour width of at least 15 mm, a vertical tumour thickness (=Breslow) of at least 2 mm, less differentiation, presence of desmoplasia and an inflammatory response with eosinophils and plasma cells.     

A review of prognostic factors in squamous cell carcinoma of the vulva: Evidence from the last decade

Squamous cell carcinoma of the vulva is a rare gynecologic cancer that is associated with significant patient morbidity and mortality, particularly for recurrent disease. This review summarizes the evidence and continued challenges, regarding the traditional clinicopathologic factors used to prognosticate vulvar squamous cell carcinoma. Articles published within the last 10 years (2010–2020) were identified. Relevant articles concerning the following fifteen prognostic factors were reviewed: HPV/p16 status, vulvar intraepithelial neoplasia, patient age, tumor stage, tumor grade, tumor size, depth of invasion, stromal changes, histologic patterns of invasion, lymphovascular space invasion (LVSI), perineural invasion, lymph node metastases, tumour focality, margin status and lichen sclerosus (LS). The relationship between each prognostic factor and progression-free survival (PFS) and overall survival (OS), including hazard ratios, 95% confidence intervals and p-values, were extracted.     

Metastatic tumors to the parotid and submandibular glands--analysis and differential diagnosis of 108 cases

The distinction between primary salivary gland tumors and metastases of other primary tumors in salivary glands is of special importance for therapy and prognosis. In the files of the Salivary Gland Register, 10,944 cases were collected during 1965 and 1985. Among these cases, there were 108 cases of metastatic tumors to the parotid and submandibular gland. The pathohistological analysis of these tumors revealed the following data: 47 cases (43%) of metastatic tumors were localized in the parenchyma of the parotid gland (37 cases) or of the submandibular gland (10 cases). 61 cases (57%) displayed metastases in the lymph nodes of the parotid gland (38 cases) or of the submandibular gland (23 cases). The sublingual gland was free of metastatic tumors. 65 metastatic tumors originated from primary tumors in the neighborhood (head and neck). 32 tumors were carcinomas of the skin, 17 tumors were melanomas, and 13 tumors were nasopharyngeal cancers. Metastases of thyroid cancers were found in 3 cases. The relative frequency of metastases in the lymph nodes of the salivary glands is due to the intense drainage with lymph vessels and the presence of many lymph nodes which are localized especially in the gland parenchyma or around the parotid gland. 21 metastatic tumors originated from primary tumors distant from the head and neck region. There were metastases of lung cancers (7 cases), renal cancers (6 cases), mammary cancers (6 cases), colonic cancer (1 case) and uterus cancer (1 case). Clear cell carcinomas in salivary gland tissue should always be checked for a metastasis of a primary renal cancer.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphological parameters associated with perineural invasion (PNI) in carcinoma of the cervix uteri

The study determines morphological features that are associated with perineural invasion (PNI) in patients with cervical carcinoma (CX). Histological slides from 194 patients from surgically treated squamous cell carcinoma were re-examined for PNI and correlated to morphological factors of tumor growth. Material from 68 patients (35.1%) represented PNI. PNI was significantly correlated with advanced tumor stage (P < .001). Patients with deep cervical stromal invasion (>66%) showed more PNI than those with more superficial invasion (41% vs 16.9%; P = .001). Tumors with spray-like PI showed significantly more PNI (48.4%) when compared with finger-like PI (26.7%) and those with pushing borders (18.8%; P = .007). Strong peritumoral desmoplastic stromal reaction and absence of peritumoral inflammation were associated with a higher frequency of PNI (P < .001). PNI is associated with advanced tumor stage, deep cervical stromal invasion (>66%), high grade of tumor cell dissociation (ie, spray-like pattern of invasion), strong peritumoral desmoplastic stromal reaction, and reduced peritumoral inflammation.     

Salivary duct carcinoma

Twelve cases of salivary duct carcinoma were examined clinically, pathologically and by flow cytometry to quantify their histological features as well as attempt to identify factors predictive of patient outcome. All of the tumours arose in the parotid gland. Eight of the twelve patients were male. Four patients died of disease (median survival 12.5 months); three are alive with disease; and five are alive with no evidence of disease (mean follow-up of 50 months). Two tumours arose in a pre-existing pleomorphic adenoma. Positive lymph nodes were present in eight of ten patients sampled; patients with two or more positive lymph nodes tended to die of their disease or be alive with metastases. Comedo necrosis, perineural invasion and vascular invasion were common findings by light microscopy. Ten of the twelve tumours were aneuploid. Neither clinical stage, tumour size, aneuploidy nor histological features correlated with patient outcome. This study confirms the aggressive nature of salivary duct carcinoma.     

Primary and metastatic high-grade carcinomas of the salivary glands: A cytologic-histologic correlation study of twenty cases

We reviewed the clinical and fine-needle aspiration (FNA) findings in 20 patients with poorly differentiated carcinomas presenting initially as parotid or as submandibular masses. There were 11 primary tumors and nine metastatic malignancies in 14 males and six females ranging in age from 39 to 89 yr (median = 66). The tumor types included three primary carcinomas with oncocytic features, three additional cases of high-grade parotid carcinoma, one case of primary neuroendocrine carcinoma, two examples of malignant mixed tumor, one high-grade mucoepidermoid carcinoma, and a single example of malignant lymphoepithelial lesion. Six patients with metastatic carcinoma had previous diagnoses of malignancy. In the three remaining individuals, primary carcinomas of the lung (two cases), and an unknown primary site presented initially as parotid masses. Five examples of metastatic squamous cell carcinoma, one metastatic basal cell carcinoma, and two metastatic renal cell carcinomas were identified. One parotid lymphoepithelioma was interpreted cytologically as an atypical lymphoproliferative process suggestive of Hodgkin's disease. Nineteen cases (95%) were correctly classified as carcinoma at the time of FNA. High-grade carcinomas aspirated from the parotid may be primary, but are frequently metastatic to either the gland, or to an intraparotid lymph node. Our experience indicates that some metastatic carcinomas present at this site, without a previous history of malignancy. Distinguishing primary from metastatic lesions has important therapeutic implications. © 1995 Wiley-Liss, Inc.     

Immunohistochemical comparison of p16 expression in actinic keratoses and squamous cell carcinomas of the skin.

There are approximately 200,000 new cases of cutaneous squamous cell carcinoma diagnosed each year in the United States, with between 1300 and 2300 deaths per year from metastatic disease. The tumor suppressor p16, encoded by the CDKN2/INK4a locus, has been reported mutated in >or=24% of squamous cell carcinomas. Mutations of the p16 gene have also been found in actinic keratoses, the first identifiable lesion in the continuum from normal skin to squamous cell carcinoma. We hypothesized that there may be an appreciable difference in expression of p16 between normal skin, actinic keratoses, squamous cell carcinoma in situ, and invasive squamous cell carcinoma. Ten actinic keratoses, 10 in situ squamous cell carcinomas, and 10 invasive squamous cell carcinomas were examined using the immunoperoxidase method with antigen retrieval for anti-p16(INK4a) antibody. All 10 actinic keratoses were positive for weak to moderate p16 staining in the lower third to lower half of the epidermis (especially the basal keratinocytes). This staining was significant when compared with the lack of staining seen in normal skin controls. Twenty percent of in situ squamous cell carcinomas had moderate to strong staining in only the lower half to lower two thirds of the epidermis, whereas 70% of the in situ squamous cell carcinomas exhibited full-thickness p16 staining, with no staining in the dermis. Thirty percent of invasive squamous cell carcinomas had full-thickness staining of the in situ component of the lesion, and 100% of invasive squamous cell carcinomas exhibited moderate to strong staining of the invasive component of the lesion. These findings indicate correlation between the increased expression of p16 during the progression of skin from actinic keratosis to in situ squamous cell carcinoma to invasive squamous cell carcinoma. These data may lend further support to the view of the actinic keratosis as a precursor lesion to squamous cell carcinoma.     

Clinicopathologic features of cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

The clinicopathologic features of 32 cutaneous squamous cell carcinomas of the head and neck in 12 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were examined to determine the frequency of clinically aggressive and histologically poorly differentiated carcinomas in this group of patients. Two thirds of the neoplasms were multiple and 56% were high grade (grade 3 or 4). One of the 12 patients had recurrent carcinoma, two patients had recurrent and metastatic disease, and two patients had metastatic tumor without recurrence. Two patients died of tumor, one patient is alive with extensive recurrent and metastatic disease, and one patient died of an uncertain type of carcinoma. An additional patient with squamous cell carcinoma of the face died of cutaneous squamous cell carcinoma that arose on the chest. This study shows that cutaneous squamous cell carcinomas of the head and neck in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma are often high grade and have the potential for recurrence and metastasis.     

Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas.

Matrix metalloproteinases compose a family of enzymes involved in degradation of the extracellular matrix. Tumor cells must penetrate the basement membrane and traverse the extracellular matrix in order to invade surrounding structures and metastasize to distant sites. Gelatinases, particularly gelatinase A (matrix metalloproteinase-2), demonstrate degradative activity against components of the basement membrane and may be involved in the progression of in situ squamous cell carcinoma lesions. Matrix metalloproteinase-2 overexpression has been correlated with tumor invasiveness and metastasis in a wide variety of cancer types, including squamous cell carcinoma arising on mucous membranes. However, correlation between matrix metalloproteinase-2 overexpression and the spread and prognosis of cutaneous squamous cell carcinoma has not been characterized in the literature at present. In this study, we used immunohistochemical techniques to examine the expression of matrix metalloproteinase-2 in 10 actinic keratosis, 15 in situ, 13 invasive, 13 primary (with documented metastatic disease), 11 metastatic, and 8 recurrent squamous cell carcinoma cases. We found that while the average staining intensity (scale 0-3+, 3+ being strongest) of actinic keratosis and in situ lesions was not statistically significant (0.87-1.3 and 0.75-1.4, respectively), the average staining intensity of invasive squamous cell carcinomas (1.6-2.5) was significantly greater than that of actinic keratosis and in situ lesions. Likewise, while the average staining intensity of primary squamous cell carcinomas and metastatic squamous cell carcinomas was not found to be statistically significant (3.1-3.5 and 3.1-3.8, respectively), the average staining intensity of these lesions was significantly higher than that of invasive lesions. We also found that the intensity of matrix metalloproteinase-2 staining correlates with cellular atypia, inflammation, neovascularization, and the invasive tumor front, as well as tumor aggressiveness, and may play a role in the pathogenesis, invasion, and metastasis of cutaneous squamous cell carcinoma.     

Angiogenesis in the progression of cutaneous squamous cell carcinoma: an immunohistochemical study of endothelial markers

OBJECTIVE:

To demonstrate the role of angiogenesis in the progression of cutaneous squamous cell carcinoma.

INTRODUCTION:

Angiogenesis is a pivotal phenomenon in carcinogenesis. Its time course in cutaneous squamous cell carcinoma has not yet been fully established.

METHODS:

We studied the vascular bed in 29 solar keratoses, 30 superficially invasive squamous cell carcinomas and 30 invasive squamous cell carcinomas. The Chalkley method was used to quantify the microvascular area by comparing panendothelial (CD34) with neoangiogenesis (CD105) immunohistochemical markers. The vascular bed from non-neoplastic adjacent skin was evaluated in 8 solar keratoses, 10 superficially invasive squamous cell carcinomas and 10 invasive squamous cell carcinomas.

RESULTS:

The microvascular area in CD105-stained specimens significantly increased in parallel with cutaneous squamous cell carcinoma progression. However, no differences between groups were found in CD34 sections. Solar keratosis, superficially invasive squamous cell carcinoma and invasive squamous cell carcinoma samples showed significant increases in microvascular area for both CD34- and CD105-stained specimens compared with the respective adjacent skin.

DISCUSSION:

The angiogenic switch occurs early in the development of cutaneous squamous cell carcinoma, and the rate of neovascularization is parallel to tumor progression. In contrast to panendothelial markers, CD105 use allows a dynamic evaluation of tumor angiogenesis.

CONCLUSION:

This study demonstrated the dependence of skin carcinogenesis on angiogenesis.     

Analysis of promoter hypermethylation of death-associated protein kinase and p16 tumor suppressor genes in actinic keratoses and squamous cell carcinomas of the skin.

Death-associated protein kinase is a serine/threonine protein kinase implicated in promoting apoptosis and tumor suppression, whereas p16 is a tumor suppressor gene that inhibits cyclin-dependent kinase 4 and 6 activity and arrests the cell cycle in the G1 phase. Hypermethylation of death-associated protein kinase or p16 gene with resultant gene inactivation has been described in a wide variety of human cancers. Promoter methylation of the death-associated protein kinase and p16 gene has been found in about 55% and 30% cases of head and neck squamous cell carcinoma respectively but has not yet been analyzed in cutaneous premalignant and malignant lesions. A total of 33 cases were examined for evidence of death-associated protein kinase and p16 hypermethylation and these consist of 9 cases of spongiotic dermatitis as nonneoplastic skin control, 9 cases of actinic keratosis, 8 cases of squamous cell carcinoma in situ, and 7 cases of invasive squamous cell carcinoma. Death-associated protein kinase promoter methylation was detected in 1 case of squamous cell carcinoma in situ and 1 case of nonneoplastic skin control but none of the cases of invasive squamous cell carcinoma or actinic keratosis. P16 promoter methylation was detected in 1 case of invasive squamous cell carcinoma and 1 case of nonneoplastic skin control but none of the cases of squamous cell carcinoma in situ or actinic keratosis. Promoter hypermethylation of the death-associated protein kinase and p16 genes does not appear to play an important role in the development of cutaneous squamous cell carcinoma. The data thus suggest that the mechanisms of ultraviolet-induced cutaneous carcinomas differ from those involved in the development of head and neck squamous cell carcinoma, a malignant disease induced by tobacco and alcohol exposure.     

HPV-assoziierte Ver?nderungen an Vulva und Vagina

Non-neoplastic HPV-induced alterations of the vulva and vagina are frequent. The traditional three-tier grading system of vulvar intraepithelial neoplasia (VIN) will be replaced by the definition of usual and simplex type of VIN. The usual type is characterized by a strong association to high-risk HPV infections, the occurrence at younger age and multifocality, mostly associated with non-keratinizing squamous cell carcinoma. The differentiated (or simplex) type is rare and shows an association to older age and p53 alterations and is typically diagnosed co-incidentally with keratinizing squamous cell carcinoma. Vaginal intraepithelial neoplasia (VAIN) is still graded into VAIN 1-3 where VAIN?1 and 2 are mostly associated with low-risk HPV infections and a high spontaneous regression rate whereas VAIN 3 represents a high-risk HPV-associated lesion with capable progression into (micro-)invasive carcinoma. The differential diagnosis between a non-neoplastic condylomatous lesion and VIN common type and VAIN may be aided by p16 immunohistochemistry. The HPV-associated invasive vulvo-vaginal cancers are verrucous carcinoma (low-risk HPV) and the high-risk HPV-induced (non-keratinizing) squamous cell carcinoma (NOS), the condylomatous (warty) carcinoma and the very rare vaginal squamo-transitional carcinoma.     

Fine-needle aspiration biopsy of metastatic small cell carcinoma from extrapulmonary sites

Like a pulmonary counterpart, extrapulmonary small cell carcinoma (SCC) is an aggressive tumor with a high rate of metastasis. Forty-nine fine-needle aspiration biopsies (FNABs) (36 patients) of various primary sites other than the lung diagnosed as metastatic SCC (including Merkel cell carcinoma) were reviewed. FNABs were derived from lymph nodes (20), liver (7), bone (2), breast (1), pancreas (1), and skin/soft tissue (18). Primary tumor sites included the prostate (14), skin (11; Merkel cell carcinoma), cervix (5), urinary bladder (3), urethra (1), ovary (1), and parotid (1). Aspirates revealed predominantly dispersed single tumor cells with occasional clustering. Tumor cells were small with scant cytoplasm, fine powdery chromatin, and inconspicuous nucleoli. Nuclear molding, mitotic figures, and apoptotic bodies were frequently observed. In four cases, findings from the FNABs were used to render the initial diagnosis of SCC. FNAB is useful for determining whether metastases contain a SCC component, a finding that may alter clinical management. Cytologically, SCC from different primary sites cannot be differentiated, and its distinction requires clinical and radiographic correlation. Diagn. Cytopathol. 1998;19:177–181. © 1998 Wiley-Liss, Inc.     

Human papillomaviruses and non-melanoma skin cancer: basic virology and clinical manifestations

Human papillomaviruses (HPV) infect cutaneous and mucosal epithelia and induce benign and malignant lesions. Non-melanoma skin cancer (NMSC), encompassing basal cell carcinoma and squamous cell carcinoma (SCC), is the most frequent cancer in the Caucasian population, and the incidence has increased dramatically worldwide. Ultraviolet (UV) radiation is a major risk factor for NMSC, and cutaneous HPV is also considered to play an active role during the pathogenesis of these cancers. The first evidence for the involvement of HPV in NMSC was reported in patients with Epidermodysplasia verruciformis (EV). HPV types detected in skin tumours of these patients are referred to as EV/cutaneous HPV types belonging to the beta- and gamma-papillomaviruses (PV). Epidemiological studies have shown a higher risk of several EV/cutaneous HPV types for NMSC. Furthermore, in vitro and animal models show transforming properties of some PV types. The anti-apoptotic activities, and the delay of DNA repair mechanism caused by some EV/cutaneous HPV E6 proteins in response to UV-induced mutations, may lead to the persistence of DNA-damaged keratinocytes. Thus, specific EV/cutaneous HPV types as co-factors in association with UV-radiation and the immune system seem to be involved in the early pathogenesis of cutaneous SCC.     

Cystic Squamous Cell Carcinoma of the Thyroid A Possible New Subgroup of Intrathyroidal Epithelial Thymoma

In the thyroid gland, both squamous cell carcinoma and intrathyroidal epithelial thymoma are rare tumors with squamous features, but their prognoses differ; the former is usually fatal, and the latter is favorable. We describe a 38-yr-old female patient with a cystic tumor diagnosed cytologically as squamous cell carcinoma, who was treated with subtotal thyroidectomy. The tumor was located intrathyroidally in the middle third of the left lobe, and no invasion to the surrounding tissues was found. Histologic examination disclosed a cyst lined by epithelial cells with squamous cell differentiation. The tumor cells had ill-defined cell borders and large nuclei with prominent nucleoli. Invasion of the tumor capsule, a few mitoses, and infiltration of lymphocytes in the tumor periphery were noted, but neither necrosis nor metastasis to lymph nodes was observed. The patient has been free from recurrence for 3 yr after thyroid lobectomy. We propose that this type of cystic intrathyroidal squamous cell carcinoma may represent a cystic variant of intrathyroidal epithelial thymoma.     

The genetics of skin cancer

Recent advances in molecular genetics have led to a better understanding of the biological underpinnings of skin cancer formation. As with most cancers, the RB, p53, and RAS pathways appear to play prominent roles in the pathogenesis of several skin cancer types. Although various components of these pathways may be differentially altered in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma, the final biochemical expression of these defects may be the same. With the unraveling of these genetic mechanisms, a more targeted approach to diagnosis and treatment may be possible in the near future.