Others

— metaplastic: biphasic epithelial (ductal in situ/invasive NST grade 2/3, or squamous) and sarcomatous elements (carcinosarcoma) or pure monophasic spindle cell carcinoma (cytokeratin/EMA/p63 positive).

The sarcomatous element is either fibrosarcomatous/malignant fibrous histiocytoma-like or chondro-, osteo-, leiomyo-, rhabdomyo-or liposarcomatous. Represents carcinoma with a spectrum of malignant spindle cell stroma which can be homologous or heterologous. Behaves as a high-grade carcinoma or sarcoma with haematogenous metastases. The epithelial component may be minor and require multiple blocks to demonstrate.

— pleomorphic carcinoma: high-grade ductal cancer with background spindle cells and >50% bizarre giant cells (cytokeratin positive). Presents with advanced disease.

— carcinoma with osteoclast giant cells (CD68 positive).

— signet ring cell carcinoma: lobular carcinoma or gastric carcinoma analogues.

— small cell: rare, aggressive, ± chromogranin/synaptophysin/CD56 positive.

— other neuroendocrine: invasive ductal carcinoma with endocrine differentiation; variable nests, spindle cells or large cells, or carcinoid-like.

— secretory: one-third are in children, indolent, good prognosis. Two-thirds are in adults and more aggressive. Tubular/solid/honeycomb patterns; PAS/AB-diastase positive luminal secretions.

— squamous cell: primary or secondary from breast skin or metastatic, e.g. lung. Also distinguish from metaplastic breast carcinoma.

— clear cell: glycogen rich and worse prognosis.

— mucoepidermoid: grade determines prognosis with cystic/mucin secreting better than solid/epidermoid variants.

— adenoid cystic: indolent with late recurrence. Salivary gland tumour analogue.

— apocrine: rare, cytoplasmic apical snouts, GCDFP-15 positive.

— adenomyoepithelioma: elderly, of low malignant potential and characterized by sheaths of proliferating clear myoepithelial cells around epithelial lined spaces. Occasionally malignant myoepithelioma (spindle cells with mitoses).

Pure carcinoma

Mixed carcinoma

— 50-90% of the tumour comprises a special type component.

Metastatic carcinoma

— often solitary, upper outer quadrant at a late stage in known carcino-matosis. The majority of childhood breast malignancy is metastatic, e.g. alveolar rhabdomyosarcoma. In adults, usually lung (small cell), malignant melanoma, lymphoma/leukaemia, but also ovary, contralateral breast (usually this represents a metachronous primary), gut, kidney, thyroid carcinomas and small intestinal carcinoid tumour. A relevant clinical history, absence of in-situ change and mul tiple intravascular deposits are pointers to metastases. Specific combinations of antibodies e.g. CK7/TTF-1 (lung), paranuclear dot CAM5.2/chromogranin/synaptophysin/CD56 (small cell), S100/HMB-45/melan A (melanoma), CD45/CD20/CD3/CD68/myeloperoxidase (lymphoma/leukaemia), CA125/CK7/WT-1 (ovary), CK20/CDX-2 (gut), RCC ab/EMA/vimentin (kidney), thyroglobulin/TTF-1 (thyroid) and immune markers of breast profile (e.g. ER/PR, cytokeratin 7, CEA, GCDFP-15) may be helpful in distinguishing between primary breast and non-mammary disease. Metastatic tumour should be considered in any breast lesion with unusual clinical, radiological, gross or his-tological features.

3. DIFFERENTIATION/GRADE

Well/moderate/poor, or Grade 1/2/3.

See protocol: Grading of Invasive Breast Carcinoma.

4. EXTENT OF LOCAL TUMOUR SPREAD

Border: pushing/infiltrative.

Lymphocytic reaction: prominent/sparse.

Quadrant(s):

— skin involvement (direct extension or lymphatics).

pT is based on the maximum dimension of invasive cancer and not whole size measurements that include adjacent DCIS.

The TNM classification applies to carcinoma of the female and male breast pTis carcinoma in situ: DCIS, LCIS or Paget's with no tumour pT1 tumour < 2 cm

pTImic

Figure 22.4. Breast carcinoma.

T1

mic

<0.1 cm

T1

a

0.1 cm < tumour < 0.5 cm

T1

b

0.5 cm < tumour < 1cm

T1

c

1 cm < tumour < 2 cm

pT2 2 cm < tumour < 5 cm pT3 tumour > 5 cm pT2 2 cm < tumour < 5 cm pT3 tumour > 5 cm

Figure 22.5. Breast carcinoma. |W
Figure 22.6. Breast carcinoma. |W
Figure 22.7. Breast carcinoma. |W
Figure 22.8. Breast carcinoma. |W

pT4 tumour any size with direct extension to chest wall (ribs, intercostal muscles, serratus anterior but not pectoral muscle) or skin*

(a) chest wall

(b) oedema including peau d'orange, skin ulceration or satellite nodulesf in the same breast

*Dermal invasion alone without ulceration, satellite nodules or inflammatory carcinoma does not constitute pT4.

fClinical or grossly apparent skin satellite nodules, not just histological foci.

Peau d'orange

Figure 22.9. Breast carcinoma.

Figure 22.10. Breast carcinoma. |W

(d) inflammatory carcinoma.

Clinically sore and red due to tumour involvement of dermal lymphatics and often without an underlying palpable mass. It can be difficult to obtain tissue proof on FNA cytology or needle core biopsy. The malignant cells are usually ductal, NST, grade 3.

Figure 22.11. Breast carcinoma. |W

In-situ change

— intra-/extratumoral: > 1 mm outside the main tumour mass and its extent.

Pure DCIS of limited size (<4cm) tends to be unicentric (albeit ramifying through the involved duct system) and treated by breast-conserving surgery with adjuvant radiotherapy. If it is mammographi-cally extensive mastectomy is done. If it forms more than 25% of an invasive cancer and is present away from it in a local excision specimen, it constitutes an extensive intraductal component (EIC) which is an indication for considering proceeding to mastectomy and/or radiotherapy. DCIS is also assessed for oestrogen receptor status as a guide to potential hormonal treatment response.

— architectural pattern: solid/cribriform/(micro-)papillary/comedo.

— cytonuclear grade: shows less heterogeneity and higher interobserver agreement than architectural pattern. It is now the favoured method for grading ductal carcinoma in situ using either nuclear features alone (NHS Breast Screening Programme) or combined with the presence of comedonecrosis (Van Nuys classification). High grade correlates with a greater frequency of concurrent or subsequent invasive carcinoma.

Not infrequently there is correlation between DCIS architectural pattern and cytonuclear grade, e.g. comedonecrosis is high grade and cribriform low grade. However, this is not always the case, e.g. solid or micropapillary, although usually low to intermediate grade, can be high grade.

5. LYMPHOVASCULAR INVASION

Present/absent.

Intra-/extratumoral: >1mm outside the main tumour mass.

Figure 22.12. Breast carcinoma: axillary lymph nodes. |W

The commonest site for vascular invasion is at the tumour edge and it is present in about 25-35% of cases.

6. LYMPH NODES

Site/number/size/number involved/apical node/extracapsular spread. Regional nodes: axillary (levels I, II, III and intramammary), ipsilateral infraclavicular (©), internal mammary (®) and supraclavicular (@). Any other nodal metastasis is regarded as a distant metastasis pM1, including cervical or contralateral internal mammary. A regional lym-phadenectomy will ordinarily include a minimum of six lymph nodes (level I) and in practice more often between 15 and 30 (levels I, II and III).

Axillary lymph nodes

They receive >75% of the lymphatic flow.

Level 1: low axilla. Nodes lateral to the border of pectoralis minor muscle

Level 2: mid-axilla. Nodes between the medial and lateral borders of the pectoralis minor muscle Level 3: apical axilla. Nodes medial to the medial margin of the pec-toralis minor muscle.

pN0 no regional lymph nodes metastasis pN1 a. metastasis in 1-3 ipsilateral node(s)

b. internal mammary node(s) with microscopic metastasis by sentinel node biopsy but not clinically apparent*

*Clinically apparent = detected by clinical examination or by imaging studies (excluding lymphoscintigraphy) or grossly visible pathologically.

pN2 a. metastasis in 4-9 ipsilateral axillary nodes b. in clinically apparent internal mammary node(s) but without axillary nodes pN3 a. metastasis in >10 axillary nodes or infraclavicular node(s)

b. metastasis in clinically apparent internal mammary node(s) with axillary nodes, or metastasis in >3 axillary nodes and in internal mammary nodes with microscopic metastasis by sentinel node biopsy but not clinically apparent.

c. metastasis in supraclavicular node(s).

Sentinel node staging is designated pN0 or pN1(sn).

Cytokeratin markers are useful where the morphological appearances are suspicious, but not diagnostic of metastatic carcinoma, e.g. sinusoidal lobular carcinoma cells vs. sinus histiocytosis. The significance of nodal micrometastases (<2mm: pNlmi) remains uncertain, with some regarding it as an adverse prognostic indicator but others less convinced. From a practical viewpoint it does influence choice of systemic adjuvant chemotherapy and hormonal therapy and should be reported. The biological status of isolated tumour cells (<0.2mm: pN0) is not established. Histological levels of serial slices and cytokeratin immunostaining may be necessary, particularly if sentinel node biopsy (95% positive predictive value for axillary node metastasis) alone is used for staging purposes in clinically node-negative patients. Other recommended approaches to axillary disease are axillary node sampling (3 or 4 level I nodes for staging only) or axillary node clearance (for staging and treatment). Axillary node involvement is seen in 40-50% of cases. Of these patients with axillary nodal disease there can also be involvement of the internal mammary chain (22%) and supraclavicular nodes (20%). Distant metastases are to the skeleton, lung and pleura, liver, ovary, adrenal gland and CNS. Presentation with metastatic tumour in axillary nodes is usually due to either breast carcinoma or malignant melanoma and this can be resolved with immunostaining. The source of the breast carcinoma is usually the ipsi-lateral breast or axillary tail of breast and the lesion can be clinically difficult to locate as its size is often less than 2 cm in diameter. Interestingly, invasive lobular carcinoma has a greater tendency than ductal tumours to metastasize to retro-/peritoneum, meninges, gastrointestinal and female genital tracts.

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