Martin C. Mihm

Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy

The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice.

Neural and Neuroendocrine Neoplasms

Clinical: Benign reactive proliferation of nerves and fibroblasts in response to trauma. Often presents as a small, firm painful lesion typically associated with trauma found at any age or body site.

Endocrine Mucin-Producing Sweat Gland Carcinoma: An Uncommon Presentation.

ABSTRACT Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, often underrecognized, low-grade sweat gland carcinoma of the skin of the eyelid. To date, only 20 cases of this carcinoma have been reported, most frequently in Caucasian females with an average age of 70 years. Although the diagnosis is primarily made with immunohistochemical stain, compared to endocrine ductal carcinoma in situ, clinical detection serves as a potentially curative treatment. Further, its benign appearance clinically makes this tumor often misdiagnosed and undertreated. This disease commonly presents in Caucasian women of advanced age, aiding in the diagnosis of this tumor, which presents an even more critical diagnosis in a patient with a rare presentation. In the available literature, we could find no case of EMPSGC in younger African American women. The following case is the first case presented in the literature. Here, we present a case of an atypical presentation of the tumor in a young African American female, as well as a review of literature on the pathophysiology, clinical presentation, and treatment of EMPSGC.

Vascular Neoplasms and Malformations

This chapter will cover vascular anomalies according to the subcategories of vascular neoplasms (benign and malignant), vascular neoplasms of uncertain behavior, vascular malformations and vascular dilatations. Importantly vascular neoplasms are regarded as lesions, which undergo cellular proliferations, while vascular malformations are the result of aberrations in morphogenesis.

Blistering Disorders and Acantholytic Processes Affecting the Epidermis of the Vulva

Although uncommon, vulvar involvement can be the initial or even the sole manifestation of a blistering or acantholytic condition. Classification of these vesiculobullous conditions is based on the anatomic location of the blister—whether the separation is within the stratum corneum, within the epidermis, or below the epidermis.

Vasculitic and Vasculopathic Disorders

This chapter is organized according to large, medium and small vessel vasculitis as proposed by the Chapel Hill Consensus Conference on the nomenclature of systemic vasculitis. The subset of small vessel vasculitic lesions will be addressed according to the predominant inflammatory cell infiltrate or feature (neutrophilic, urticarial, fibrosing, lymphocytic and granulomatous). The final section will address neutrophilic dermatoses and vasculopathies.

Cutaneous Lymphomas and Hematopathology

Lymphomas and non-neoplastic infiltrates of the skin are not uncommon lesions to encounter in routine dermatopathology specimens. When confronted with these entities in routine hematopathology practice (bone marrow biopsies and lymph nodes), diagnosis of hematopoietic neoplasms depends first on recognizing the overall architectural pattern. Analogous to their lymph node and bone marrow counterparts, diagnosis of cutaneous lymphomas and other malignant hematopoietic proliferations depends in part on the pattern of infiltration. Certain lymphomas have the propensity to form nodular aggregates while others invade in diffuse sheets of malignant cells. There are lymphomas that preferentially involve the epidermis and superficial dermis and those that arise primarily in the subcutaneous tissue. Given that skin contains numerous blood vessels and adnexal structures, infiltrates can either primarily or secondarily involve these compartments in varying degrees. After pattern determination, the diagnostician must also decide the size of the malignant cells since some tumors are comprised of small cells, others large cells, and still others mixed cell populations. The background milieu is also important: Are there lymphocytes, plasma cells, eosinophils, neutrophils, or perhaps histiocytes? All of these elements should be taken into consideration before the application of immunohistochemical stains, cytochemical stains, flow cytometry, or gene rearrangements.

Parasitic Infections and Bite Reactions

Clinical: Insect bites clinically appear as excoriated, pruritic papules, nodules, erosions, bullae, vesicles, erosions or ulcers.

Interface (Lichenoid) Dermatoses

Clinical: Commonly remembered as the “five P’s” – purple, polygonal, planar, and pruritic papules (and/or plaques) with a fine overlying scale (known as Wickham’s striae). LP commonly manifests as grouped papules on the distal extremities and/or trunk, also with frequent involvement of oral mucosa.

Non-melanoma Neoplasms

Clinical: Actinic keratoses are considered pre-cancerous and present clinically as pink to erythematous, dry, gritty and scaly papules or plaques on the sun-exposed skin of older individuals. Frequently the face, helical ears, scalp, dorsal hand and forearms are most affected. Actinic keratoses appear more in men who burn easily (Fitzpatrick skin type I). Actinic cheilitis is the oral equivalent of AK presenting often on the middle portion of the lower lip as a painful scaly papule or plaque. Marked hyperkeratosis or cutaneous horns occur occasionally. It is thought that 0.1–10 % of all AKs progress into squamous cell carcinoma, although a small number likely regress on their own secondary to the immune response. Certain features are associated with greater risk of transformation into squamous cell carcinoma including inflammation, size greater than 1 cm, rapid growth, erythema, ulceration and bleeding. Several clinical variants of AKs exist including hyperplastic or hypertrophic AK (predominantly on dorsal hands or forearms), acantholytic AK (mimics BCC clinically), lichenoid AK (more red than typical AK) and pigmented AK (affecting mostly cheeks and forehead, which can be confused clinically with lentigo maligna due to AKs having associated lentigo). Cumulative lifetime sun damage appears to be the biggest risk factor for developing AKs.