A 67-year-old woman presents to a surgeon with a painless, slowly growing ulcer in the periauricular region for the last 2 months. On physical examination, there is an irregular-shaped ulcer, 2 cm x 1 cm in its dimensions, with irregular margins and crusting over the surface. The woman is a fair-skinned individual who loves to go sunbathing. There is no family history of malignancy. After a complete physical examination, the surgeon performs a biopsy of the lesion under local anesthesia and sends the tissue for histopathological examination. The pathologist confirms the diagnosis of squamous cell carcinoma of the skin. When she asks about the cause, the surgeon explains that there are many possible causes, but it is likely that she has developed squamous cell carcinoma on her face due to repeated exposure to ultraviolet rays from the sun, especially ultraviolet B (UVB) rays. If the surgeon’s opinion is correct, which of the following mechanisms is most likely involved in the pathogenesis of the condition?

Intrastrand cross-linking of thymidine residues in DNA

Upregulation of expression of cyclin D2

Loss-of-function mutations of TP53

Activation of transcription factor NF-κB

DNA damage caused by the formation of reactive oxygen species

A 43-year-old woman presents to your clinic for the evaluation of an abnormal skin lesion on her forearm. The patient is worried because her mother passed away from melanoma. You believe that the lesion warrants biopsy for further evaluation for possible melanoma. Your patient is concerned about her risk for malignant disease. What is the most important prognostic factor of melanoma?

Depth of invasion of atypical cells

Level of irregularity of the borders

A 50-year-old woman with rheumatoid arthritis on methotrexate develops rapidly progressive painful ulcers on her legs with violaceous undermined borders. Biopsy shows neutrophilic dermal infiltrate with areas of necrosis, but no vasculitis or infection. Wound cultures are negative. Despite debridement, the ulcers worsen. C-ANCA and P-ANCA are negative. Evaluate the diagnosis and determine the management that addresses both the cutaneous condition and systemic disease.

Continue methotrexate, add TNF-alpha inhibitor and systemic corticosteroids

Discontinue all immunosuppression to allow wound healing

Increase methotrexate dose and add wound care

Discontinue methotrexate, start cyclosporine and prednisone

Start broad-spectrum antibiotics and surgical debridement

A 25-year-old woman presents with painful oral ulcers and a pustular rash at venipuncture sites. She has genital ulcers and a history of recurrent uveitis. Skin biopsy from a pustule shows neutrophilic infiltrate in the dermis without vasculitis or infection. HLA-B51 testing is positive. She is planning pregnancy. Evaluate the management strategy considering disease control and pregnancy planning.

Start infliximab, use contraception, then transition to low-risk therapy before conception

Start methotrexate for disease control

Start colchicine monotherapy and proceed with pregnancy

Start high-dose corticosteroids and azathioprine, delay pregnancy

Avoid all immunosuppression and manage symptoms only

Melanoma pathology for USMLE Step 1: High-Yield Pathology Lessons

Melanoma Intro - Sun's Sinister Side

ABCDE & Seven-Point Checklist for Melanoma Detection

Definition: Malignancy of melanocytes, pigment-producing cells primarily in the basal layer of the epidermis.
Etiology: Primarily UV radiation exposure (UVA & UVB) from sun or tanning beds, causing DNA damage.
Risk Factors: Fair skin, history of blistering sunburns, numerous nevi, family history.

📌 ABCDEs of Melanoma

Asymmetry
Border irregularity
Color variegation
Diameter > 6 mm
Evolving or Elevated

⭐ High-Yield: The most common driver mutation in cutaneous melanoma is an activating mutation in the BRAF kinase, specifically the V600E substitution.

Clinical Subtypes - The Four Faces

Superficial Spreading (SSM): Most common type (~70%).
- Dominant early radial growth phase.
- Common sites: Men (trunk), women (legs).
- Presents as an asymmetric, flat patch with variegated color.
Nodular (NM): Aggressive (~15-30%).
- Early and rapid vertical growth; poor prognosis.
- Often a uniform, dark, elevated, "blueberry-like" nodule that may ulcerate.
- Think "E" for Evolving/Elevated in the ABCDE mnemonic.
Lentigo Maligna (LMM): Sun-related (~5-15%).
- Arises from a precursor lesion (lentigo maligna) on chronically sun-damaged skin.
- Typically found on the face or neck of older individuals.
Acral Lentiginous (ALM): Non-sun-related (~5-10%).
- Most common type in individuals with darker skin tones.
- Arises on palms, soles, or beneath the nail (subungual).
- 📌 Hutchinson's sign: Pigment spread to the proximal/lateral nail fold is a key indicator.

⭐ Acral lentiginous melanoma is not related to UV exposure and is the most common subtype in Black and Asian populations.

Four Types of Melanoma: Superficial, Nodular, Acral, Lentigo

Pathology & Prognosis - Sizing Up the Threat

Breslow Depth: The single most important prognostic factor. Measured vertically in millimeters from the epidermal granular layer to the deepest invasive melanoma cells.
- Crucial thresholds: 0.8 mm, 1.0 mm, 2.0 mm, 4.0 mm.
- Deeper invasion (↑ Breslow) signifies ↑ metastatic potential.
Key Adverse Factors:
- Ulceration: Absence of an intact epidermis. Confers a higher risk stage for any given Breslow depth.
- Mitotic Rate: Number of mitoses/mm². A high rate (≥1/mm²) indicates active proliferation and worse prognosis.
- Lymphovascular Invasion: Presence of tumor cells in blood or lymphatic vessels.

⭐ The indication for sentinel lymph node biopsy (SLNB) is primarily driven by Breslow depth. It is generally recommended for melanomas >0.8 mm thick.

High‑Yield Points - ⚡ Biggest Takeaways

Breslow depth is the single most important prognostic factor for metastasis.

The BRAF V600E mutation is a common driver and a key therapeutic target.

Histology shows asymmetrical lesions with atypical melanocytes and pagetoid spread (upward migration).

Key immunohistochemical markers include S-100, HMB-45, and Melan-A.

Nodular melanoma carries the worst prognosis due to rapid vertical growth.

Acral lentiginous melanoma is the most common type in dark-skinned individuals.

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