CASUISTIC INTRODUCTION IN OPHTALMIC PATHOLOGY FOR TRAINEES AND GENERAL PATHOLOGISTS

Case 7

Maria-Rosa Bella Cueto

Hospital Universitari Parc Taulí

Sabadell (Barcelona). Spain.

I declare no conflict of interests

CLINICAL INFORMATION

• Man 83 years old

• Lesion in the lateral free margin of the upper left eyelid, of 5 mm, since one year ago, suggestive of basocellular carcinoma

• Rapid grow in the last two months, reaching 30 x 20 mm.

CK20

CAM5.2

SPT

CROM ENE

TTF-1

NF

IMMUNOHISTOCHEMISTRY

Positive:

- CAM 5.2

- AE1/AE3

- CK20

- 34βe12

- BerEP4

- EMA

- Chromogranin

- Synaptophysin

- CD56

- Enolase

- Neurofilaments

Sometimes positive:

- CK7

Negative:

- TTF-1

Ki67 45%

DIAGNOSIS:

- MERKEL CELL CARCINOMA

- 30 mm (post-fixation: 23 mm)

- No lymphatic , venous or perineural invasion

- Free margins (2 mm)

- pT2 pNX

FOLLOW-UP

• Radiotherapy 45 Gy• Radiodermitis g.1• 12 months later: “in transit” metastasis: nodular lesion (2,2 cm.) affecting

dermis and subcutaneous tissue in temporal anterior region. Resection with free margins.

• Now free of disease, five years after the first surgery.

• Primary cutaneous neuroendocrine carcinoma

• Toker 1972: Trabecular carcinoma of the skin

• Cell of origin? Merkel cell

– Some kind of cutaneous stem cell

• Composite cases (squamous cell carcinoma, basocellular carcinoma, skin appendages carcinoma)

• Incidence: ≈ 1/100.000 persons/year

MERKEL CELL CARCINOMA

CLINICAL FEATURES - AEIOU

• Asymptomatic• Expanding rapidly• Immune suppression• Older than 50 years• Ultraviolet exposed site

– Periorbitary region: 5-20%– Eyelid: 2,5 -10%

upper>lower

• Spontaneous regression– after incisional biopsy or FNAB

• Presentation in lymph node without known primary➢Spontaneous regression?➢Origin in lymph node?

Clinical differential diagnosis: skin tumours, chalazion, dermoid cyst

PATHOPHYSIOLOGY

• Merkel cell polyomavirus (MCPyV)

– Integrated to the genoma

– Large T and small T antigens

• Interfere with P53 and RB1 function

– IHC CM2B4 (Large T antigen)

– Few somatic mutations

– (Better prognosis)?

• UV radiation related

– High number of mutations associated to UV damage

– Epidermotropism

– Mutations in TP53 and RB1 genes

– Composite tumours or divergent differentiation

– (Poorer prognosis?)

– Larger cells

DIFFERENTIAL DIAGNOSIS

• Blue small cell morphology

– Basal cell carcinoma

– Melanoma

– Sebaceous carcinoma

– Lymphoma

– PNET/Ewing sarcoma

– ….

– Metastasis of lung small cell carcinoma

– Exceptional cases: MCC TTF-1+ or CK20-, LSCC CK20+

Neuroendocrine markersDot pattern (CK20, neurofilaments)

Specific tumour markersGlycogen, EWS/FLI-1

TTF-1

CM2B4

Basal cell carcinoma

• Merkel cell carcinoma has its own staging system

• Eyelid carcinoma staging excludes Merkel cell carcinoma

pT Merkel cell carcinoma

• pTis: In situ primary tumor

• pT1 : ≤ 2 cm

• pT2: > 2 cm ≤ 5 cm

• pT3: > 5 cm

• pT4: Primary tumour invades fascia, muscle, cartilage or bone

Better consider clinical or fresh size

pN Merkel cell carcinoma

• pNX: cannot be assessed (previously removed for other causes or not removed

• pN0: no lymph node metastasis

• pT1: metastasis in lymph regional nodes– pN1a(sn): clinically occult, identified only by sentinel node biopsy

– pN1a: clinically occult in lymph node dissection

– pN1b: clinically or radiologically detected, microscopically confirmed

• pN2: In transit metastasis without lymph node metastasis

• pN3: In transit metastasis with lymph node metastasis

STAGING AJCC/UICC 8TH ED.

STAGING AJCC/UICC 8TH ED.

pM Merkel cell carcinoma

• pM0: No distant metastasis detected on clinical or radiological exams

• pM1: Distant metastasis microscopically confirmed– pM1a: to distant skin, distant subcutaneous tissue, or distant lymph(s) node(s

– pM1b: to lung

– pM1c: other distant sites

In transit metastasis:

Metastasis discontinuous from primary tumour,

located between the primary tumour and the draining

regional nodes, or distal to the primary tumour

Prognostic stage groups

• From 0 to IV

• Changes from 7th to 8th ed.

OTHER PRONOSTIC FACTORS

• Heavy peritumoral lymphocytic infiltrate

• Greater tumour thickness (Breslow)

• Infiltrative tumour growth

• Lymphovascular invasion

• >10 mitotic figures /hpf

• Invasion in subcutaneous tissue

• P63 expression

5 YEAR SURVIVAL:

- N0: 75%

- N1: 60%

- M1: 25%

CLINICAL MANAGEMENT

• Confirm diagnosis (incisional biopsy)• Clinical/radiological N status

➢ N0: Excision of the tumour (5mm margin)+ sentinel lymph node biopsy➢ Positive: Excision of the tumour (5mm margin) + lymphadenectomy

• Pathological N status:➢pN0: Radiotherapy to primary site ± draining lymph nodes chain➢Positive: Clinical/radiological M status

➢M0: Radiotherapy primary site + lymphadenectomy or Radiotherapy to draining lymph nodes chain

➢M1: consider the following alone or multimodal treatment: Radiotherapy, surgery, chemotherapy, immunotherapy

PD-L1 inhibitors as adjuvant or neoadjuvant therapy?

MERKEL CELL CARCINOMA - FINAL REMARKS

• AEIOU

• Usually typical morphology and immunohistochemical pattern

• Two physiopathological pathways

• Spontaneous regression

• Specific TNM - in transit metastasis

• Promising role of immunotherapy

Torre de l’AiguaParc TaulíSabadell

rbella@tauli.cat