Introduction: The most common form of cancer is Nonmelanoma skin cancer (NMSC) which is seen in the Caucasian population [1]. It is most commonly used to refer to the two major types of skin cancers which are basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (SCC). These account for over 95% of all NMSC, with SCC accounting for approximately 20% of all cutaneous malignancies [2]. Squamous cell carcinoma (SCC) is a malignant neoplasm of epithelial cells, originates from keratinocyte exhibiting squamous differentiation which is characterized by the formation of keratin and the presence of intercellular bridges [3] .The rare histological variants of squamous cell carcinoma include verrucous, exophytic or papillary, spindle-cell (sarcomatoid), basaloid and adenosquamous carcinoma. Material And Methods: The patients of squamous cell carcinoma were examined for one year in 2021 at pathology department. All retrievable case files were obtained and necessary data were extracted regarding age, gender, site and histological type. Conclusions: The ability to identify SCC variants with divergent clinical behaviors is of great importance in the assessment of tumor risk. To this end, we have provided a detailed and descriptive outline for the histological distinction of the most commonly encountered SCC lesions, highlighting those variants which will be associated with more aggressive behaviors and a worse clinical prognosis. Understanding how to differentiate between these variants of SCC microscopically, with the additional benefit of immunohistochemical staining, will enable a more informed and timely selection of treatment options, ensuring the best possible results for the patient.
The most common form of cancer is Nonmelanoma skin cancer (NMSC) which is seen in the Caucasian population [1]. It is most commonly used to refer to the two major types of skin cancers which are basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (SCC). These account for over 95% of all NMSC, with SCC accounting for approximately 20% of all cutaneous malignancies [2]. Squamous cell carcinoma (SCC) is a malignant neoplasm of epithelial cells, originates from keratinocyte exhibiting squamous differentiation which is characterized by the formation of keratin and the presence of intercellular bridges [3] .The rare histological variants of squamous cell carcinoma include verrucous, exophytic or papillary, spindle-cell (sarcomatoid), basaloid and adenosquamous carcinoma. These variants frequently account for up to 15% of SCCs arise within the mucosa of the upper aerodigestive tract [1]. The objective of this study was to provide a baseline data on the pattern of rare variants of squamous cell carcinoma. This review is done to discriminate between various SCC lesions on the basis of histopathology and to highlight those variants of SCC with the greatest malignant potential. The detailed description of the histopathological features related to each SCC subtype and by highlighting the histomorphological differences which can be used in their identification. This will help the clinician in making a more efficient and better informed selection of treatment options, thus ensuring the most appropriate and effective care for the patient.
The patients of squamous cell carcinoma were examined for one year in 2021 at pathology department. All retrievable case files were obtained and necessary data were extracted regarding age, gender, site and histological type. The study consisted of 17 patients of squamous carcinoma with rare histological variants that reported at outpatient department of surgery. All cases were clinically examined and provisional diagnosis of squamous cell carcinoma was made. Biopsy was taken from the lesions and tissues were fixed in 10% buffered formalin and sent to pathology department for histological confirmation. Clinical details had been recorded from the histopathological examination form submitted along with specimen. All biopsy samples were grossed and tissue processing was done followed by routine H/E staining. The stained slides were thoroughly examined under light microscopy for histological diagnosis. Final diagnosis was made under light microscopy.
CASE 1:
The final diagnosis of Spindle Cell Variant of Squamous Cell Carcinoma (SCC) in a 43-year-old male with an ulcerative lesion on the lower limb refers to a rare and histologically distinct subtype of SCC. Spindle cell SCC is characterized by the presence of malignant squamous epithelial cells that exhibit a spindle-shaped morphology, differing from the typical squamous epithelial cells that are usually polygonal or cuboidal in shape. In the spindle cell variant, the malignant squamous cells undergo a transformation where they acquire a fusiform, or spindle-like, appearance. These cells can sometimes be mistaken for sarcomas due to their elongated shape and the way they may arrange themselves in a fascicular or herringbone pattern. Despite this appearance, they remain of squamous origin, and they retain certain cytological features that distinguish them from true sarcomas, such as keratinization, intercellular bridges, or positive immunohistochemical markers for squamous differentiation (e.g., cytokeratin).
Histopathological Features:
Moderate to marked pleomorphism: The presence of significant variation in cell size and shape, which is a hallmark of malignancy. The more pronounced pleomorphism seen in this case suggests an aggressive tumor. These cells are elongated with tapered ends, and their cytoplasm is often abundant and eosinophilic. Their nuclei are elongated and hyperchromatic (dark-staining), showing irregularities in shape and size.
Differential Diagnosis:
Sarcomatoid carcinoma: This type of carcinoma can resemble a sarcoma, but it should be differentiated from the spindle cell SCC through immunohistochemistry and careful examination of its squamous differentiation features. Malignant spindle cell tumors like fibrosarcoma or leiomyosarcoma can appear similar but are distinct in their origin and lack of squamous differentiation.
Prognosis:
The prognosis of spindle cell SCC depends on factors such as tumor size, depth of invasion, and the presence of metastasis. Early detection and complete surgical excision with clear margins are crucial for improving outcomes. The aggressive nature of the variant may necessitate a more comprehensive treatment approach, possibly including radiation or chemotherapy in more advanced cases.
CASE 2:
A 57-year-old male presents with an ulcerative endophytic lesion on the great toe. Histopathological examination reveals the presence of malignant squamous epithelial cells, which demonstrate spindle cell morphology with moderate to marked pleomorphism. These findings are consistent with a diagnosis of spindle cell variant of squamous cell carcinoma (SCC). This variant of SCC is characterized by the presence of spindle-shaped malignant cells, which are elongated and exhibit considerable variability in size and shape (pleomorphism). The moderate to marked pleomorphism suggests a more aggressive tumor with a potential for increased invasiveness. The endophytic nature of the lesion indicates that the tumor is growing inward, which can complicate its treatment and may lead to deeper tissue involvement.
This form of SCC can be more difficult to diagnose due to its atypical presentation and histological features. Surgical intervention, typically with wide excision of the tumor, is the primary treatment. However, the extent of the disease and potential for metastasis would guide additional treatment options, such as radiation or chemotherapy. Close monitoring for recurrence or spread is essential.
CASE 3:
A 55-year-old male presents with an exophytic lesion in the oral cavity. Histopathological examination reveals well-differentiated squamous cell carcinoma (SCC) with pushing borders, which is consistent with a diagnosis of verrucous carcinoma. This type of carcinoma is a slow-growing, low-grade malignancy that typically exhibits a well-differentiated appearance, meaning the cancerous cells closely resemble normal squamous cells. The lesion has pushing borders, indicating that it is expanding into surrounding tissue without significant infiltration, a feature commonly associated with verrucous carcinoma. Verrucous carcinoma is characterized by its exophytic, cauliflower-like growth, and while it is a type of SCC, it generally has a more favorable prognosis due to its low likelihood of metastasis and aggressive spread. Treatment usually involves surgical excision, with a good long-term outlook when the tumor is managed appropriately.
CASE 4:
A 52-year-old and 72 year-old male presents with an exophytic lesion on the lip. Histopathological examination reveals well-differentiated squamous cell carcinoma (SCC) with pushing borders, consistent with a diagnosis of verrucous carcinoma. This slow-growing, low-grade variant of SCC is characterized by its exophytic, cauliflower-like appearance, with well-differentiated squamous cells that closely resemble normal tissue. The tumor’s pushing borders indicate that it is growing outward into the surrounding tissue without significant invasion, a feature commonly seen in verrucous carcinoma. Although verrucous carcinoma is a form of SCC, it typically has a better prognosis due to its less aggressive nature and lower risk of metastasis. Treatment usually involves surgical excision, and with appropriate management, the long-term outlook is generally favorable.
CASE 5:
An 86-year-old female presents with a polypoid lesion on the tongue. Histopathological examination reveals malignant squamous epithelial cells exhibiting papillary architecture with a fibrovascular core, consistent with a diagnosis of papillary squamous cell carcinoma (SCC). This variant of SCC is characterized by the formation of finger-like projections (papillary structures) made up of malignant squamous cells, with a central fibrovascular core supporting the structures. The papillary pattern is a distinguishing feature of this subtype, which can make it appear less aggressive compared to other forms of SCC. However, papillary SCC still has malignant potential, and its treatment typically involves surgical excision with close monitoring for recurrence or metastasis, depending on the tumor’s stage and extent. The prognosis is generally more favorable when detected early and appropriately treated.
CASE 6:
A 75-year-old male presents with an ulceroproliferative lesion in the aryepiglottic fold. Histopathological examination reveals malignant squamous epithelial cells exhibiting papillary architecture with a fibrovascular core, consistent with papillary squamous cell carcinoma (SCC). This form of SCC is characterized by the formation of papillary projections made up of malignant squamous cells, with a central fibrovascular core that supports the structure. The ulceroproliferative nature of the lesion suggests an aggressive growth pattern, with the potential for both local tissue invasion and recurrence. Although papillary SCC is often less aggressive than other SCC subtypes, the presence of an ulceroproliferative lesion in a critical area like the aryepiglottic fold raises concern for functional impairment and possible metastasis. Treatment typically involves surgical excision with appropriate margins, and additional therapies such as radiation may be considered based on the tumor's stage and extent.
CASE 7:
A 52-year-old female presents with an ulceroproliferative lesion in the maxilla. Histopathological examination reveals malignant squamous epithelial cells exhibiting papillary architecture with a fibrovascular core, consistent with papillary squamous cell carcinoma (SCC). This subtype of SCC is characterized by the formation of papillary projections composed of malignant squamous cells, with a fibrovascular core providing structural support. The ulceroproliferative nature of the lesion suggests that the tumor is both ulcerating and proliferating, indicating active growth and the potential for local tissue invasion. While papillary SCC is generally considered a less aggressive variant of squamous cell carcinoma, its presence in the maxilla raises concerns regarding possible extension into adjacent structures such as the sinuses, oral cavity, or bone. Treatment typically involves surgical excision with clear margins, and depending on the tumor's stage, radiation therapy may be considered. Early detection and complete removal are essential for a favorable prognosis and to minimize the risk of recurrence.
CASE 8:
A 76-year-old female presents with a polypoid lesion in the anal region. Histopathological examination reveals malignant squamous epithelial cells exhibiting papillary architecture with a fibrovascular core, consistent with papillary squamous cell carcinoma (SCC). This variant of SCC is characterized by the formation of finger-like projections (papillary structures) composed of malignant squamous cells, with a fibrovascular core providing support to the papillae. The polypoid nature of the lesion suggests an outward-growing tumor that may cause symptoms such as bleeding or discomfort. Papillary SCC, though generally less aggressive than other forms of SCC, still carries malignant potential and can invade surrounding tissues. In the anal region, the tumor could potentially affect nearby structures and may require careful surgical excision to ensure clear margins. Additional treatments such as radiation therapy might be considered, depending on the tumor's extent. Early diagnosis and complete surgical removal are crucial for a favorable outcome and to reduce the risk of recurrence.
CASE 9:
An 85-year-old female presents with a polypoid lesion on the upper eyelid. Histopathological examination reveals malignant squamous epithelial cells exhibiting papillary architecture with a fibrovascular core, consistent with a diagnosis of papillary squamous cell carcinoma (SCC). This subtype of SCC is characterized by the formation of papillary structures, where the malignant squamous cells are arranged in finger-like projections supported by a fibrovascular core. The polypoid nature of the lesion indicates that the tumor is growing outward, which could lead to symptoms such as swelling, irritation, or potential interference with vision. Although papillary SCC is generally less aggressive than other forms of SCC, it still carries the risk of local invasion and recurrence, especially in sensitive areas like the eyelid. Treatment typically involves surgical excision with clear margins to ensure complete removal, and radiation therapy may be considered if there is concern for residual disease. Early intervention and appropriate management are essential for a favorable prognosis and to minimize functional and cosmetic impact.
CASE 10:
A 40-year-old male presents with an endophytic lesion on the nose. Histopathological examination reveals malignant squamous epithelial cells with abundant keratinization, forming keratin pearls, consistent with a diagnosis of keratoacanthoma-type squamous cell carcinoma (SCC). This subtype of SCC is characterized by rapid growth and the formation of keratin pearls, which are concentric layers of keratin seen in the center of the tumor. The endophytic nature of the lesion suggests the tumor is growing inward into the surrounding tissue, which can sometimes complicate treatment. While keratoacanthoma-type SCC tends to exhibit more benign features in terms of growth pattern, it still carries malignant potential and can invade deeper tissues. Surgical excision with clear margins is the typical treatment, and close monitoring is necessary due to the risk of recurrence or local spread. Early detection and management are important for ensuring a favorable prognosis.
CASE 11:
A 52-year-old female presents with an endophytic lesion in the eye area. Histopathological examination reveals malignant squamous epithelial cells with abundant keratinization, forming keratin pearls, consistent with a diagnosis of keratoacanthoma-type squamous cell carcinoma (SCC). This subtype of SCC is characterized by the rapid development of keratin pearls, which are concentric layers of keratin formed within the tumor, a hallmark of the keratoacanthoma variant. The endophytic nature of the lesion suggests the tumor is growing inward, potentially affecting deeper structures and complicating treatment. Although keratoacanthoma-type SCC is typically regarded as a rapidly growing but locally aggressive tumor, it can still carry malignant potential and invade surrounding tissues. Treatment generally involves surgical excision with clear margins, and depending on the tumor's size and extent, additional treatments such as radiation therapy may be considered. Early diagnosis and complete removal are crucial for a favorable prognosis, particularly in a sensitive area like the eye, where both functional and cosmetic outcomes are significant considerations.
CASE 12:
A 38-year-old male presents with an ulcerative lesion on the skin. Histopathological examination reveals malignant squamous epithelial cells with abundant keratinization, forming keratin pearls, consistent with a diagnosis of keratoacanthoma-type squamous cell carcinoma (SCC). This subtype of SCC is characterized by rapid tumor growth and the formation of keratin pearls, concentric layers of keratin within the tumor. The ulcerative nature of the lesion suggests that the tumor is not only growing rapidly but also ulcerating, which can lead to local tissue destruction. While keratoacanthoma-type SCC is often considered a more benign variant due to its growth pattern, it still has malignant potential and can invade deeper tissues if left untreated. Treatment typically involves surgical excision with clear margins to ensure complete removal, and close follow-up is important to monitor for recurrence or local spread. Early detection and intervention are crucial for a favorable prognosis and to prevent complications associated with the ulcerative form of the tumor.
CASE 13:
A 54-year-old male presents with an ulceroproliferative lesion in the anal region. Histopathological examination reveals malignant tumor nests composed of basaloid cells with hyperchromatic nuclei, consistent with a diagnosis of cloacogenic carcinoma. Cloacogenic carcinoma is a rare and aggressive malignancy that originates from the cloacal epithelium, which is found in the anal canal. The basaloid cells, which are small, hyperchromatic, and often arranged in nests, are a distinctive feature of this carcinoma. The ulceroproliferative nature of the lesion indicates that the tumor is both ulcerating and proliferating, suggesting rapid growth and potential local invasion. Cloacogenic carcinoma can be difficult to treat due to its aggressive behavior and tendency to recur. Management typically involves surgical excision with clear margins, and adjuvant therapies such as radiation or chemotherapy may be considered, depending on the tumor's stage and spread. Early detection and comprehensive treatment are essential to improving the prognosis and reducing the risk of recurrence or metastasis.
CASE 14:
A 71-year-old female presents with an ulceroproliferative lesion in the rectum. Histopathological examination reveals malignant tumor nests composed of basaloid cells with hyperchromatic nuclei, consistent with a diagnosis of cloacogenic carcinoma. Cloacogenic carcinoma is a rare and aggressive type of carcinoma that arises from the cloacal epithelium, typically located in the rectal or anal region. The basaloid cells, which are small, darkly staining, and arranged in nests, are characteristic of this cancer subtype. The ulceroproliferative nature of the lesion suggests rapid tumor growth and potential local invasion, which can lead to complications such as bleeding, pain, or obstruction. Cloacogenic carcinoma is known for its aggressive behavior and high tendency to recur, making early diagnosis and prompt treatment crucial. Management usually involves surgical resection with clear margins, and additional treatments such as radiation or chemotherapy may be necessary depending on the tumor’s stage and extent of spread. Close monitoring after treatment is essential to manage recurrence and ensure a favorable outcome.
CASE 15:
A 52-year-old male presents with an ulceroproliferative lesion on the lower limb. Histopathological examination reveals predominantly malignant epithelial cells, with areas showing acantholysis of central cells, consistent with a diagnosis of acantholytic squamous cell carcinoma (SCC). This subtype of SCC is characterized by the presence of acantholysis, where there is a loss of adhesion between keratinocytes, leading to the formation of intraepidermal spaces and allowing malignant cells to separate. The acantholytic areas are typically seen in the central portion of the tumor, while the peripheral areas maintain cell cohesion. The ulceroproliferative nature of the lesion suggests that the tumor is not only proliferating but also ulcerating, which can result in local tissue destruction and symptoms such as pain or bleeding. Acantholytic SCC tends to be more aggressive and may invade deeper tissues. Treatment usually involves surgical excision with clear margins, and depending on the extent of the disease, adjuvant therapies such as radiation or chemotherapy may be considered. Early intervention is crucial to prevent further complications and to improve the prognosis.
CASE 16:
A 68-year-old male presents with an ulceroproliferative lesion on the tongue. Histopathological examination reveals malignant, singly scattered epithelial cells surrounded by abundant lymphoid stroma, consistent with a diagnosis of lymphoepithelial carcinoma. This rare form of carcinoma is characterized by the presence of malignant epithelial cells that are often interspersed within a dense infiltrate of lymphoid tissue. The tumor typically exhibits an aggressive growth pattern with the epithelial cells being separated by the surrounding lymphoid stroma, which is a distinctive feature of lymphoepithelial carcinoma. The ulceroproliferative nature of the lesion suggests that the tumor is rapidly growing and ulcerating, potentially causing local pain, bleeding, or difficulty in swallowing. Lymphoepithelial carcinoma is known for its association with Epstein-Barr virus (EBV) in some cases, though it can occur independently. Treatment generally involves a combination of surgical excision, radiation therapy, and possibly chemotherapy, depending on the tumor's stage and extent. Early detection and prompt treatment are crucial for improving the prognosis and reducing the risk of recurrence or metastasis.
Various studies have documented the increase in the incidence of SCC over the past several decades which are attributed to increase in sun exposure, UV exposure, the advancing age, enhanced public awareness of skin cancer, and more frequent skin examinations by physicians [4]. There is a histo-pathologic diversity of SCCs, many of which are associated with indolent behavior to markedly different clinical behaviors [5]. These variants are distinguished microscopically which is critically important in the clinical diagnosis and treatment of SCC. The early treatment of high-risk tumors results in better patient outcomes with a lower risk of tumor metastasis and recurrence [6]. The common SCC seen as a result of excess sun exposure are invasive SCC (SCCI), clear-cell SCC, spindle cell (sarcomatoid) SCC, and SCC with single cell infiltrates, while lymphoepithelioma-like carcinoma of the skin (LELCS), and verrucous carcinoma (VC), are very uncommon SCC variants with no direct correlation to sun exposure [7].
The head and neck cancer is more common in developing countries as compare to developed world (4). Squamous cell carcinoma (SCC) is by far the most important and most common malignant mucosal neoplasm to affect the head and neck, which account for over 90% of all malignant neoplasm. According to some studies incidence of squamous cell carcinoma was found higher in Pakistan and other South East Asian countries. In south East Asia, smoking, betel nut, and tobacco chewing habits are the factors which cause high incidence in vast population [5]. SCC is divided into three histologic categories: in situ, superficially invasive or deeply invasive carcinomas, with additional modifiers based on histologic grade, including well, moderately or poorly differentiated. Morphologically SCC can be ulcerative, flat, polypoid, verrucous or exophytic. Multiple variants of this disease including verrucous carcinoma, spindle cell, acantholytic, verrucous, lymphoepithelioma-like, adenosquamous, papillary, basaloid and keratoacanthoma. These variants make up in aggregate about10-15% of all oral SCCs. In histology and prognosis, each of these variants differs, but the treatment is identical to the more common form [4]. Verrucous type is a very well-differentiated SCC that has a minimal metastatic potential and has an excellent prognosis with approximately 75% of 5-year survival rate [8]. Basaloid SCC is more aggressive form [10]. It requires aggressive multimodality treatment with a 2-year survival rate is 40% [9]. Acantholytic SCC and adenosquamous cell carcinoma occurs usually in the sun-exposed areas with a relative poorer prognosis as compared with conventional SCC. SCSC metastasizes more commonly to the regional lymph nodes in upto 25% cases as compared to distant metastasis (5-15%). The 5-year survival rate varies between 65-95% [10]. PSCC has a better prognosis when compared with location and stage-matched conventional OSCC [11].
SCC affects more men than women, usually in the middle to later decades of life, although any age can be affected. Two studies carried out in India reported a higher M: F ratio of 2.2:1 and 4.2:1 respectively [12]. The most important risk factors are tobacco and alcohol [1]. Viruses (human papilloma virus, Epstein-Barr virus) are also linked to the development of SCC [5]. The invasive squamous cell carcinoma is a malignancy of the keratinocytes from the epidermis that invade the dermis and underlying subcutaneous tissue. Mucosal SCC arises anywhere in the head and neck, although the tongue is most affected in the oral cavity, the maxillary sinus in the sinonasal tract and the glottis in the larynx [11]. ‘Conventional’ SCC is composed of variable degrees of squamous differentiation, with well-differentiated cells almost perfectly recapitulating normal squamous epithelium, but demonstrates invasion of basement membrane by nests of tumour cells. SCC exhibits disorganized growth, a loss of polarity, dyskeratosis, keratin pearls, intercellular bridges, an increased nuclear to cytoplasmic ratio, nuclear chromatin irregularities, prominent eosinophilic nucleoli and increased atypical mitotic figures. Keratinizing-type is not seen as frequently as the non-keratinizing or poorly differentiated types. With the increase of grade mitotic figures and necrosis tend to increase. A rich inflammatory infiltrate of lymphocytes and plasma cells at the interface of tumour and stroma along with a dense desmoplastic fibrous stroma is also seen. The poorly differentiated carcinoma show mild resemblance to squamous epithelium with only rare foci of squamous differentiation. Perineural invasion is associated with metastatic spread [12]. The differential diagnosis of SCC is papilloma and pseudoepitheliomatous hyperplasia. The histologic distinction of papilloma from well-differentiated SCC depends on disorganized growth and morphologic and microscopic features of malignancy.
The ability to identify SCC variants with divergent clinical behaviors is of great importance in the assessment of tumor risk. To this end, we have provided a detailed and descriptive outline for the histological distinction of the most commonly encountered SCC lesions, highlighting those variants which will be associated with more aggressive behaviors and a worse clinical prognosis. Understanding how to differentiate between these variants of SCC microscopically, with the additional benefit of immunohistochemical staining, will enable a more informed and timely selection of treatment options, ensuring the best possible results for the patient.
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