Part XIV · Special populations and uncommon presentations · Chapter 83

Sex, gender, and uncommon disease contexts

What transfers from the evidence base, what does not, and who decided that nobody would find out.

1 · Male breast cancer and its evidence deficit

Male breast cancer is managed by extrapolation from postmenopausal hormone receptor positive female disease. That is a defensible starting position and it is not a neutral one, because the points at which it fails are not marked.

The largest characterisation is a retrospective joint analysis of cases diagnosed over 20 years. Of 1,822 patients enrolled, 1,483 were analysed. Median age at diagnosis was 68.4 years. Among the non-metastatic cases, 99.3% were oestrogen receptor positive, 81.9% progesterone receptor positive, and 96.9% androgen receptor positive. Adjuvant endocrine therapy was given to 76.8%, and it was tamoxifen in 88.4% of those. Breast-conserving surgery was performed in 4% and sentinel node biopsy in 18%1.

Two facts in that paragraph deserve separating. The receptor distribution is a biological finding. The surgical figures are a practice finding, and they describe a population being treated with an older algorithm than the one applied to women with the same stage.

The endocrine standard is tamoxifen rather than aromatase inhibitor monotherapy, and the reason is mechanistic rather than conventional. In a postmenopausal woman the ovary has stopped producing oestrogen, so almost all circulating oestradiol arises from peripheral aromatisation. Inhibiting aromatase removes nearly the entire supply. In a man the testis is still an active endocrine organ. It supplies testosterone as substrate and contributes directly to circulating oestradiol. Lowering oestradiol relieves negative feedback at the hypothalamus and pituitary. Luteinising hormone rises, testicular androgen output rises, and the additional substrate partly restores what the inhibitor removed. An aromatase inhibitor given to a man is therefore not the same intervention as the same drug given to a postmenopausal woman. It is that drug working against an intact gonadal axis. This is why guidelines recommend tamoxifen as the preferred adjuvant endocrine therapy, and reserve aromatase inhibition for use with a gonadotropin-releasing hormone analogue or after orchiectomy2.

The clinical data are consistent with the mechanism and are thin. In a registry analysis matching male and female patients on six prognostic variables, 5-year overall survival among tamoxifen-treated patients was 89.2% in men and 85.1% in women, which did not differ. Among aromatase inhibitor treated patients it was 73.3% in 30 men and 85.0% in 60 women, a difference that reached significance3. Thirty men is the entire comparison. A prospective cohort of 448 men found reduced disease-free survival in those not receiving tamoxifen4.

Caution

The evidence deficit here is not accidental and it is not only a matter of rarity. No randomised trial has compared endocrine strategies in men. Most breast cancer trials specified female sex in their eligibility criteria without a stated rationale, so the population was excluded rather than unrecruited. Rarity explains why a dedicated trial is difficult. It does not explain why men were kept out of trials that had nothing sex-specific in their design. The ethics and the design remedies belong to Clinical trials and evidence interpretation and Representation, generalizability, and equity by design. MALE is the exception that shows the shape of the deficit: it measured what standard endocrine therapy does to estradiol and to quality of life in men, which is a question no trial in women ever had to ask separately.

Germline BRCA2 is enriched in this population, and testing is indicated at diagnosis rather than by family history threshold Inherited susceptibility and familial breast cancer. Presentation is later and nodal involvement more frequent, which is partly biology and partly the absence of any screening pathway.

2 · Breast cancer in transgender and gender-diverse people

The tissue at risk is breast tissue, not gender. That single sentence resolves most of the clinical ambiguity, and the remaining difficulty is that health systems record gender and not anatomy.

The best incidence estimate comes from a nationwide cohort at a single gender clinic. Among 2,260 trans women followed for 33,991 person-years, 15 invasive breast cancers occurred after a median of 18 years of hormone treatment. The standardised incidence ratio was 46.7 against cisgender men, with a 95% confidence interval of 27.2 to 75.4, and 0.3 against cisgender women, with an interval of 0.2 to 0.4. Among 1,229 trans men followed for 14,883 person-years, four invasive cancers occurred. Most tumours were ductal and hormone receptor positive5.

Say what those numbers are numbers of. Forty-six-fold sounds alarming and it is a ratio against a baseline that is very close to zero. Fifteen cancers in 33,991 person-years is a low absolute rate, lower than in cisgender women. Both statements come from the same dataset and only the second is useful for counselling5.

Four practical points follow, and none of them requires new biology.

Screening should follow the tissue. A trans woman on long-term oestrogen has breast tissue. A trans man after chest masculinisation surgery retains residual breast tissue, because the procedure is not a total mastectomy. There is no trial evidence on screening in either group, so recommendations are extrapolated and should be described as such.

Record an organ inventory rather than inferring anatomy from a gender marker. The marker in a record is administrative and may have changed. The tissue has not.

Laboratory and imaging reference ranges are sex-indexed in most systems, which generates spurious flags and occasionally missed abnormalities.

Gender-affirming hormone therapy interacts with breast cancer treatment directly. Endocrine therapy for a hormone receptor positive tumour and exogenous oestrogen are working against each other. That is a real conflict and the decision belongs to the patient with the mechanism explained. Stopping a treatment central to a person's identity is not a neutral supportive care measure.

The data deficit is worth naming because it will not fix itself. Registries do not reliably record gender identity, so incidence and outcome estimates in this population rest on a small number of clinic cohorts. The access and representation arguments are developed in Disparities across the breast cancer continuum.

3 · Exogenous hormonal exposure

Three exposures recur and they behave differently. Conflating them produces most of the confusion patients arrive with.

Menopausal hormone therapy has randomised evidence, and the randomised evidence splits by formulation. In long-term follow-up of two placebo-controlled trials enrolling 27,347 postmenopausal women, conjugated equine oestrogen with medroxyprogesterone acetate, given to 16,608 women with a uterus, was associated with higher breast cancer incidence. There were 584 cases at an annualised rate of 0.45% against 447 cases at 0.36%, with a hazard ratio of 1.28 and a 95% confidence interval of 1.13 to 1.45. Breast cancer mortality did not differ significantly. Conjugated equine oestrogen alone, given to women with prior hysterectomy, was associated with lower breast cancer incidence and lower breast cancer mortality6. An individual participant meta-analysis of the observational evidence found that risk varied with the type of preparation and with the duration and timing of use7.

The divergence between the two arms is the substantive finding. Oestrogen alone and oestrogen with a progestin are not two doses of one exposure. In this trial they moved breast cancer incidence in opposite directions.

Hormonal contraception carries a small relative increase. In a nationwide prospective cohort of 1.8 million women followed on average for 10.9 years, 11,517 breast cancers occurred. Compared with never users, current and recent users had a relative risk of 1.20, with a 95% confidence interval of 1.14 to 1.26. The risk rose with duration, from 1.09 with less than a year of use to 1.38 with more than 10 years8. The baseline risk in this age range is low, so a relative risk of 1.20 corresponds to a small absolute excess. The population-level determinants that this sits inside are in Reproductive, hormonal, metabolic, and environmental determinants.

Gender-affirming hormone therapy is the third exposure and is covered in Breast cancer in transgender and gender-diverse people.

After a breast cancer diagnosis the question changes shape. Systemic menopausal hormone therapy is not offered. Low-dose vaginal oestrogen for genitourinary symptoms is the genuinely contested case, and it is taken up in Sexual health and menopausal symptoms.

4 · Occult primary and unusual presentations

Occult primary breast cancer is axillary nodal adenocarcinoma with a compatible immunophenotype and no primary identified on examination, mammography, or ultrasound. It is a radiological category rather than a biological one, which is why its incidence fell when magnetic resonance imaging became available.

The diagnostic sequence is fixed. Core biopsy of the node with receptor testing comes first. Receptor studies on the axillary metastasis can point to the breast as the origin and may be the only chance to learn the tumour's receptor status9. Breast magnetic resonance imaging follows, and it identifies a primary in a substantial proportion of cases. A systematic review of eight retrospective studies found an otherwise occult cancer in more than two thirds of patients10. In 55 patients with stage II disease, suspicious lesions were seen in 76%, and 62% of those were the primary11. Case series and reviews established the approach12,13,14. Systemic staging excludes an extramammary source, and the immunoprofile should be reviewed against alternatives before the breast is accepted as the origin.

Treatment follows the principle that this is node-positive breast cancer of the corresponding stage. Systemic therapy is selected by receptor status exactly as it would be with a visible primary. Local management of the breast is either mastectomy or whole-breast irradiation, and irradiation is the option that preserves the breast without leaving the presumed primary untreated. A primary found on MRI can make breast conservation possible, and a negative MRI predicts a low yield of tumour at mastectomy15. In one series, breast conservation with radiation alone was followed by no recurrence at a median of 57 months16. Axillary management follows nodal burden.

Other unusual presentations share one feature, which is that they disturb the staging workflow rather than the treatment logic. Paget disease of the nipple requires a search for an underlying carcinoma. It is almost always associated with one. Among patients without a palpable mass, 29% in one institutional series had a peripheral cancer rather than one beneath the nipple17. Negative mammography does not exclude it, and MRI found otherwise occult disease18,19. Breast conservation, removing the nipple-areola complex with the underlying disease and irradiating the whole breast, is an accepted alternative to mastectomy. A prospective EORTC study and retrospective series support it20,21,22,23,24. Mastectomy remains the operation when a mass or a mammographic abnormality is present25,26. Sentinel node biopsy is appropriate when invasive disease is found or mastectomy is planned27. In 39 patients, invasive carcinoma was found in 27% of those with Paget disease alone, and positive sentinel nodes in 11%28. Metastasis-first presentation, where disease is found at a distant site before the breast, requires receptor testing on the accessible lesion and a decision about whether the primary needs local treatment at all Local intervention in the metastatic setting. Inflammatory presentation is a clinical diagnosis and belongs to Locally advanced and inflammatory breast cancer.

In practice

Test receptors on the nodal core before anything else. The whole systemic plan follows from that result, and the node is the only tissue you have.

Order breast magnetic resonance imaging before committing to a local plan. Finding the primary converts an unusual problem into an ordinary one.

Review the immunoprofile against non-breast origins explicitly. An axillary node is a plausible destination for several primaries, and accepting the breast by default is the error here.

Treat by stage, not by the fact that the primary is invisible. This is node-positive breast cancer, and the systemic algorithms in Part IX apply unchanged.

5 · Bilateral and multiple primary cancers

Bilateral disease is synchronous or metachronous by an arbitrary interval, usually three to six months. The interval is a reporting convention. Its clinical value is that it separates two cancers being staged together from a second cancer arising in a treated patient.

The long-term risk is quantified in a population cohort of 476,373 women with breast cancer as their first invasive cancer. By 20 years, 5.6% had developed a contralateral breast cancer, which was 3.1 percentage points more than expected in the general population. The absolute excess was greater in younger women. Endocrine therapy was associated with reduced contralateral risk and radiotherapy with increased risk29.

The harder problem is distinguishing a second primary from a metastasis to the contralateral breast, because the treatment intent differs completely. Features supporting an independent primary are an in situ component, a different histological type, a different grade, and a location in a separate quadrant. Features supporting metastasis are absence of an in situ component and involvement of skin or lymphatics.

Caution

Receptor discordance between the two tumours is frequently used as evidence of independence. It is weak evidence. Receptor status changes between a primary and its own metastases often enough that discordance alone cannot establish clonal independence, which is the argument in Receptor discordance and conversion. Sequencing can address the question directly and is rarely performed for this indication.

Bilateral disease at presentation, and any second breast primary, raises the germline testing threshold Inherited susceptibility and familial breast cancer. A confirmed pathogenic variant then changes the contralateral risk estimate and with it the risk-reducing surgery discussion in Risk-reducing surgery and the decision calculus.

6 · Rare breast malignancies and the boundaries of this book

Everything in Parts VIII to X assumes an invasive carcinoma of the breast. The lesions in this section are not that, and applying those algorithms to them is the characteristic error.

Phyllodes tumours are fibroepithelial neoplasms graded benign, borderline, or malignant. They are a surgical disease. Wide local excision with clear margins is the treatment, axillary staging is not indicated because spread is haematogenous, and neither endocrine therapy nor conventional breast cancer chemotherapy has a role. Malignant phyllodes behaves as a sarcoma. Wide excision with a margin of about 1 cm is definitive primary treatment, mastectomy is reserved for large lesions, and enucleation is inadequate30,31,32. Stromal overgrowth, particularly in tumours larger than 5 cm, predicted distant failure33. Adjuvant radiotherapy appeared to improve disease-free survival in one series of malignant tumours34. Hormone receptor expression in the epithelial component falls as grade rises, which is one reason endocrine therapy has no role35. Phyllodes tumour is one of the cancers most increased in carriers of germline TP53 variants, which makes a family history worth taking36.

Angiosarcoma occurs as a primary tumour and as a late complication of breast irradiation. In a multicentre series of radiation-associated angiosarcoma after breast cancer, recurrence was frequent and survival poor despite complete surgical resection37. It presents as cutaneous discolouration that is easily mistaken for radiation change or infection, and the diagnosis is made by biopsying skin that a clinician was inclined to observe.

Primary breast lymphoma is managed as lymphoma of its histological subtype. Breast implant associated anaplastic large cell lymphoma arises in the capsule around a textured implant rather than in breast parenchyma, and presents most often as a late seroma. Its management is capsulectomy and implant removal, not breast cancer treatment.

Metaplastic carcinoma is an invasive carcinoma and behaves unlike the rest of them. It is usually triple-negative, frequently chemoresistant, and is discussed with the phenotypic spectrum in Triple-negative and other biologically diverse phenotypes. Secretory carcinoma carries the ETV6-NTRK3 fusion, which makes it one of the few breast tumours with a tumour-agnostic targeted option38, and the general form of that argument is in Rare actionable mutations and fusions and Tumor-agnostic biomarkers.

The boundary statement is simple and worth making explicitly. These entities are treated by histology-specific principles drawn from sarcoma, lymphoma, and rare tumour practice. When a pathology report names one of them, the correct next step is to leave this book's algorithms rather than adapt them.

References

All 38 references
  1. Cardoso F, Bartlett JMS, Slaets L, et al. Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Ann Oncol 2018 29:405-417. PMID 29092024
  2. Hassett MJ, Somerfield MR, Baker ER, et al. Management of Male Breast Cancer: ASCO Guideline. J Clin Oncol 2020 38:1849-1863. PMID 32058842
  3. Eggemann H, Altmann U, Costa SD, et al. Survival benefit of tamoxifen and aromatase inhibitor in male and female breast cancer. J Cancer Res Clin Oncol 2018 144:337-341. PMID 29098396
  4. Eggemann H, Brucker C, Schrauder M, et al. Survival benefit of tamoxifen in male breast cancer: prospective cohort analysis. Br J Cancer 2020 123:33-37. PMID 32367072
  5. de Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ 2019 365:l1652. PMID 31088823
  6. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials. JAMA 2020 324:369-380. PMID 32721007
  7. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019 394:1159-1168. PMID 31474332
  8. Mørch LS, Skovlund CW, Hannaford PC, et al. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med 2017 377:2228-2239. PMID 29211679
  9. Bhatia SK, Saclarides TJ, Witt TR, Bonomi PD, Anderson KM, Economou SG. Hormone receptor studies in axillary metastases from occult breast cancers. Cancer 1987 59:1170-2. PMID 3815292
  10. de Bresser J, de Vos B, van der Ent F, Hulsewé K. Breast MRI in clinically and mammographically occult breast cancer presenting with an axillary metastasis: a systematic review. Eur J Surg Oncol 2010 36:114-9. PMID 19822403
  11. Buchanan CL, Morris EA, Dorn PL, Borgen PI, Van Zee KJ. Utility of breast magnetic resonance imaging in patients with occult primary breast cancer. Ann Surg Oncol 2005 12:1045-53. PMID 16244803
  12. Stomper PC, Waddell BE, Edge SB, Klippenstein DL. Breast MRI in the Evaluation of Patients with Occult Primary Breast Carcinoma. Breast J 1999 5:230-234. PMID 11348292
  13. Schelfout K, Kersschot E, Van Goethem M, et al. Breast MR imaging in a patient with unilateral axillary lymphadenopathy and unknown primary malignancy. Eur Radiol 2003 13:2128-32. PMID 12928964
  14. Bleicher RJ, Morrow M. MRI and breast cancer: role in detection, diagnosis, and staging. Oncology (Williston Park) 2007 21:1521-8, 1530; discussion 1530, 1532-3. PMID 18077995
  15. Olson JA, Morris EA, Van Zee KJ, Linehan DC, Borgen PI. Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol 2000 7:411-5. PMID 10894136
  16. Varadarajan R, Edge SB, Yu J, Watroba N, Janarthanan BR. Prognosis of occult breast carcinoma presenting as isolated axillary nodal metastasis. Oncology 2007 71:456-9. PMID 17690561
  17. Kollmorgen DR, Varanasi JS, Edge SB, Carson WE. Paget's disease of the breast: a 33-year experience. J Am Coll Surg 1998 187:171-7. PMID 9704964
  18. Morrogh M, Morris EA, Liberman L, Van Zee K, Cody HS, King TA. MRI identifies otherwise occult disease in select patients with Paget disease of the nipple. J Am Coll Surg 2008 206:316-21. PMID 18222386
  19. Frei KA, Bonel HM, Pelte MF, Hylton NM, Kinkel K. Paget disease of the breast: findings at magnetic resonance imaging and histopathologic correlation. Invest Radiol 2005 40:363-7. PMID 15905723
  20. Bijker N, Rutgers EJ, Duchateau L, Peterse JL, Julien JP, Cataliotti L. Breast-conserving therapy for Paget disease of the nipple: a prospective European Organization for Research and Treatment of Cancer study of 61 patients. Cancer 2001 91:472-7. PMID 11169928
  21. Kawase K, Dimaio DJ, Tucker SL, et al. Paget's disease of the breast: there is a role for breast-conserving therapy. Ann Surg Oncol 2005 12:391-7. PMID 15915373
  22. Marshall JK, Griffith KA, Haffty BG, et al. Conservative management of Paget disease of the breast with radiotherapy: 10- and 15-year results. Cancer 2003 97:2142-9. PMID 12712465
  23. Pierce LJ, Haffty BG, Solin LJ, et al. The conservative management of Paget's disease of the breast with radiotherapy. Cancer 1997 80:1065-72. PMID 9305706
  24. Singh A, Sutton RJ, Baker CB, Sacks NP. Is mastectomy overtreatment for Paget's disease of the nipple?. Breast 1999 8:191-4. PMID 14731439
  25. Marcus E. The management of Paget's disease of the breast. Curr Treat Options Oncol 2004 5:153-60. PMID 14990209
  26. Sakorafas GH, Blanchard K, Sarr MG, Farley DR. Paget's disease of the breast. Cancer Treat Rev 2001 27:9-18. PMID 11237774
  27. Laronga C, Hasson D, Hoover S, et al. Paget's disease in the era of sentinel lymph node biopsy. Am J Surg 2006 192:481-3. PMID 16978954
  28. Sukumvanich P, Bentrem DJ, Cody HS, et al. The role of sentinel lymph node biopsy in Paget's disease of the breast. Ann Surg Oncol 2007 14:1020-3. PMID 17195914
  29. McGale P, Dodwell D, Challenger A, et al. Second cancers in 475 000 women with early invasive breast cancer diagnosed in England during 1993-2016: population based observational cohort study. BMJ 2025 390:e083975. PMID 40865997
  30. Salvadori B, Cusumano F, Del Bo R, et al. Surgical treatment of phyllodes tumors of the breast. Cancer 1989 63:2532-6. PMID 2541890
  31. Mangi AA, Smith BL, Gadd MA, Tanabe KK, Ott MJ, Souba WW. Surgical management of phyllodes tumors. Arch Surg 1999 134:487-92; discussion 492-3. PMID 10323420
  32. Telli ML, Horst KC, Guardino AE, Dirbas FM, Carlson RW. Phyllodes tumors of the breast: natural history, diagnosis, and treatment. J Natl Compr Canc Netw 2007 5:324-30. PMID 17439760
  33. Chaney AW, Pollack A, McNeese MD, et al. Primary treatment of cystosarcoma phyllodes of the breast. Cancer 2000 89:1502-11. PMID 11013364
  34. Pandey M, Mathew A, Kattoor J, et al. Malignant phyllodes tumor. Breast J 2001 7:411-6. PMID 11843853
  35. Tse GM, Lee CS, Kung FY, et al. Hormonal receptors expression in epithelial cells of mammary phyllodes tumors correlates with pathologic grade of the tumor: a multicenter study of 143 cases. Am J Clin Pathol 2002 118:522-6. PMID 12375638
  36. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 2001 20:4621-8. PMID 11498785
  37. Seinen JM, Styring E, Verstappen V, et al. Radiation-associated angiosarcoma after breast cancer: high recurrence rate and poor survival despite surgical treatment with R0 resection. Ann Surg Oncol 2012 19:2700-6. PMID 22466664
  38. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018 378:731-739. PMID 29466156