The Addams family of cancers

Prof Carol-Ann Benn educates us on the Addams family of cancers that can be found in the breast that are not breast cancers.

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We are looking at cancers that we find in the breast that are actually not breast cancer. They may start in the breast or start elsewhere and metastasise to the breast. A bit like the Addams family, that weird, quirky non-traditional family. 

These cancers are akin to taking a wrapped something out the cupboard (analogy post-breast core biopsy) and having to unwrap it with special stains, only to find that it’s not a breast cancer. This is when the physician or surgeon needs to be Lurch the butler and ensure good service by discussing all newly diagnosed cancers in a robust multi-disciplinary meeting (MDM). 

Mortica

The smarts of the Addams family is definitely Morticia. So, let’s call our friendly pathologist Morticia, considering they will be analysing the tissue (the tissue is the issue with these tumours) and insist on a detailed pathology review.

If a mass or concerning area is seen in the breast, a core biopsy is done. Occasionally abnormal looking skin, moles, or lesions are seen on the breast or the nipple areolar skin and these may require a dermatological punch biopsy.

Finding a large mass can provide a clue where the primary is, but other times the metastases can be bigger than the primary cancer or look different histologically. Sometimes the cancer masses may be found in an area of the body far away from the primary site.

Identifying the tissue of origin

Besides the special stains, such as oestrogen and progesterone receptor, HER2 negative receptor, and Ki-67 (proliferation index), cancers that we are uncertain where they start are called neoplasm NOS (not otherwise specified). 

The pathologist (Mortica) uses immunohistochemical stains (IHC) to work out where it started. Some sarcomas and poorly differentiated and anaplastic (rapidly dividing and not resembling normal cells) neoplasms that may arise from epithelial or mesenchymal lineage may be hard to confirm on IHC. Identifying the tissue of origin is of utmost importance to ensure correct treatment. 

Morticia’s first step is to differentiate the neoplasm into one of the three major cell embryological lines: epithelial, mesenchymal, or hematopoietic.

• Epithelial (solid tissue tumours, such as breast, GI tumours, lung, and gynae).
• Mesenchymal (sarcomas).
• Haematopoietic (lymphomas and derived from blood elements).

Following this, various other stains are used to work out what the cancer is. Cytokeratins (CK) are found in epithelial cells of all types and are specific markers for an epithelial cell lineage. They have subtypes numbered 1 through 20, and their expression is frequently organ- and tissue-specific. Often cytokeratins, such as CK7 and CK20, can be used to better characterise an epithelial tumour. 

Vimentin is a stain that is present in most mesenchymal cells (found in almost all sarcomas and melanomas) but can be variable in lymphomas and even some carcinomas. Renal, endometrial, thyroid, and ovarian which all can metastasise to the breast may have vimentin or cytokeratin co-expression. 

Cancers that don’t express vimentin are colonic; small intestine, prostate, and a couple of other rare tumours. A good broad marker for hematopoietic (starts from blood or lymph cells) neoplasms is CD45. Lymphoid neoplasms are hard to distinguish and may require additional stains.

Uncle Fester

Who is Uncle Fester? The ugly often big breast lump that isn’t breast cancer. Breast Festers are sarcomas, malignant phyllodes tumours, and desmoid tumours. They are really ugly. 

Sometimes it’s difficult to differentiate between a metaplastic breast cancer (a variant of triple-negative breast cancers), a breast sarcoma, and a malignant phyllodes tumour. This is the Uncle Fester imposter. 

Often these tumours have areas of necrosis (dead tumour) seen on the core biopsy and present as rapidly-growing purple funny masses. Real psychopaths that are hard to diagnose and have unpredictable behaviour. They are diagnosed by mammogram, ultrasound, and core biopsy, and all require staging CT scans and breast MRI to assist with treatment planning.

Breast sarcomas

Breast sarcomas can be primary from the breast parenchyma or secondary related to radiation (and must occur a minimum after two years (usually four) in the radiation field). They are extremely rare. 

Another secondary sarcoma (even rarer) is related to post-mastectomy lymphoedema (I’ve only ever seen two). There are no known risk factors associated with primary breast sarcomas, besides certain rare genetic syndromes (Li-Fraumeni syndrome and hereditary retinoblastoma), and environmental exposures to certain phenoxyacetic acid–containing herbicides. 

Angiosarcomas and other sarcomas spread locally, and then to lungs and liver. These horrible tumours are not very sensitive to radiation or chemotherapies if advanced or spread, and studies looking at cardiac medicines (beta-blockers) and other oncology drugs show varying results. It’s so important that they are discussed multiple times in a robust MDM and treated in specialist units.

Phyllodes tumours

These are fibroepithelial breast tumours with a wide range of behaviour (much like Uncle Fester). Behaviour is based on whether they are histologically benign, borderline, or malignant with the benign ones behaving similarly to fibroadenomas and malignant lesions behaving similarly to other breast sarcomas.

Malignant phyllodes tumours, also known as cystosarcoma phyllodes, are the commonest type of primary breast sarcoma followed by stromal sarcomas and angiosarcomas (which are the commonest type of secondary sarcoma).

Desmoid tumours

These are extremely rare mesenchymal tumours that can occur anywhere and can also occur in the breast. They arise within connective tissue and are distinct from soft tissue sarcoma because they are locally aggressive yet with rare reports of metastatic potential. 

Desmoid tumours can be associated with familial adenomatous polyposis, pregnancy, and previous trauma. Weirdly, 44% of patients with breast desmoid tumours have had previous breast surgery, (supporting a theory that trauma predisposes to desmoid tumour development). 

Metaplastic breast cancers 

This is the Uncle Fester imposter which is breast cancer, usually triple-negative, that has sarcomatous areas in it. Usually treated with chemotherapy and must be managed in a specialist unit. Careful pathology ensures the imposter is not missed. 

Thing

Cancers found on the breast skin is Thing (the hand) in the Addams family. The skin is our biggest organ and we often forget that the breast has different skin structures on the areolar that can become cancerous. 

Remember, if moles on the breast show change in size, irritation, change in colour, they may be a melanoma. Mole mapping is essential if you have lots of moles. Melanoma treatment today is really specialised, and the melanoma is treated according to the depth and behaviour.

Scaly purple plaques on the skin or red plaques could mean (particularly if you are a sun-bunny or older or fair), a squamous or basal cell carcinoma. 

If the cancer is from the skin, make sure a multi-disciplinary unit with an interest in these is part of your go-to prior to treatment. 

Weird skin cancers specific to the breast can arise from the sweat glands and can be found on the areolar of the breast (this is called a syringomatous carcinoma) and is managed surgically.

Wednesday 

How about the painful pale and mysterious Wednesday (lymphomas)? Lymph nodes in the axilla (armpit), in the breast, and sometimes on the skin of the breast can be extremely difficult to diagnose when they are lymphomas. They require multiple special stains on the core biopsy and require many MDM discussions about their behaviour. Rarely do we have to take out a lymph node (gland) to have a more detailed assessment, although this should not be the first choice. 

Lymphomas are treated by specialist haematologists and medical oncologists and again if diagnosed early are imminently treatable. Do not let the mysterious Wednesday confuse your team. 

Pugsley

Breast neuroendocrine tumours look benign, like Pugsley (Wednesday’s unassuming brother). They present in many forms from masses to nipple discharges to ulcerations on the skin. 

The primary neuroendocrine neoplasm (NENs) are divided into three different entities: well-differentiated neuroendocrine tumours (NETs), extremely aggressive neuroendocrine carcinomas (NECs), as well as invasive breast cancers of no special type (IBCs-NST) with neuroendocrine differentiation. 

They are challenging to diagnose because they are unusual and need a detailed multi-disciplinary assessment. There are no standardised guidelines for how to treat and outcomes can be variable.

Neuroendocrine cells are distributed throughout the whole body, NENs appear in nearly all organ systems; gastroenteropancreatic system and the bronchopulmonary system as well as skin, thyroid gland, bladder, and larynx.

Gomez

Metastatic presentations to the breast, like Gomez, can charm and confuse. The most common cancers metastasising to the breast ranging from malignant melanoma, lymphoma, lung cancer, ovarian carcinoma, soft tissue sarcoma, and cancers from the gastrointestinal (stomach and colon) and genitourinary tumours (bladder and kidney). 

Occasionally osteosarcoma, thyroid neoplasms, and gynae derived cancers from the cervix, vagina, endometrium, and ovary can be found in the breast as well as spreading to the axillary lymph nodes.  

All these present with a variety of breast concerns from commonly masses and glands to tenderness, pain, and rarely nipple discharges.

A solitary lesion is most common and remember like Gomez’s charm, they can and do often look similar to primary breast cancers on mammography. 

Clues are they are more likely to be multiple, bilateral, and the tumour cells usually round with fairly well-defined margins (cannonball appearance). Microcalcifications aren’t a distinguishing feature, although their margins may not be well-defined, spiculations aren’t seen. Diagnosis by core biopsy and detailed pathology interpretation (we all know Gomez’s love for Morticia) ensures appropriate oncology treatment and ensures avoiding unnecessary mastectomies. 

Whilst we understand the four traditional breast cancer families (triple-negative, HER2, luminal A, and luminal B), we now understand that occasionally the Addams family of non-breast cancers can live on the breast street. The neighbourhood watch of the MDM will ensure that this is picked up and managed appropriately.

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