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Idiopathic gigantomastia: newer mechanistic insights implicating the paracrine milieu

  • Clinical Management of Endocrine Diseases
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Gigantomastia refers to pathological breast enlargement usually occurring in the peripubertal or peripartum period. Idiopathic gigantomastia, however, is a rare entity with hypotheses citing local expression of hormones and growth factors in causing this disease, none of which have been systemically analysed. The purpose of this study was to delve deeper into the mechanistic pathways causing this condition.

Methods

Herein, we describe three patients of idiopathic gigantomastia, all of whom had had normal puberty and uneventful pregnancies. Further, one of the patients had postmenopausal gigantomastia which is extremely rare, with only four cases described in the literature. Serum markers of autoimmunity, incriminated hormones and growth factors analysed, were normal in all the cases. Breast tissue specimens were subjected to histopathological examination and immunohistochemistry for ER, PR and Her-2-Neu. Quantitative immunofluorescence for aromatase, IGF2, EGFR, TGF-β, PDGFR-α, β, IGF1 and PTHrP was also performed.

Results

Of these, the tissue expression of aromatase, IGF2, EGFR, TGF-β, PDGFR-α and β were found to be upregulated, whereas IGF1 and PTHrP were comparable to normal breast.

Conclusion

This observation that paracrine overexpression of these factors is responsible for the pathogenesis of apparently idiopathic gigantomastia may have therapeutic ramifications in the future for patients with this debilitating condition.

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Abbreviations

PTHrP:

Parathyroid hormone related peptide

BMI:

Body mass index

E2:

Estradiol

LH:

Luteinising hormone

FSH:

Follicle stimulating hormone

IGF1:

Insulin like growth factor-1

IGF2:

Insulin like growth factor-2

GH:

Growth hormone

fT3:

Free Tri-iodo thyronine

fT4:

Free Tetra-iodo thyronine

TSH:

Thyroid stimulating hormone

HbA1c:

Glycated hemoglobin

HOMA-IR:

Homeostasis model assessment for insulin resistance

BIRADS:

Breast imaging reporting and data system

TPO:

Thyroid peroxidase

ANA:

Anti-nuclear antibodies

SMA:

Anti-smooth muscle antigen

LKM:

Anti-liver kidney muscle antibody

AMA:

Anti-mitochondrial antibody

CEA:

Carcinoembryonic antigen

α-FP:

Alpha fetoprotein

NAC:

Nipple areola complex

IHC:

Immunohistochemistry

ER:

Estrogen receptor

PR:

Progesterone receptor

Her-2-Neu:

Herceptin

IF:

Immunofluorescence

PDGFR-α:

Platelet derived growth factor-alpha

PDGFR-β:

Platelet derived growth factor-beta

VEGF:

Vascular endothelial growth factor

TGF-β:

Transforming growth factor-beta

IG:

Idiopathic gigantomastia

17-β E2:

7.6–42.6 pg/ml

Progesterone:

<1 ng/ml

LH:

2.4–12.6 mIU/ml

FSH:

3.5–12.5 mIU/ml

GH:

<1 ng/ml

Prolactin:

5–25 ng/ml

fT3:

2.3–4.2 pg/ml

T4:

0.89–1.76 ng/dl

TSH:

0.4-4.2 mIU/l

TPO:

<34 IU/ml

HbA1c:

<5.7%

CA125:

0–35

CA19-9:

0–27

CEA:

3.8–5.5

α-FP:

0–5.8

IGF1:

64–262 ng/ml

HOMA-IR:

<2—normal, 2 to 3—mild insulin resistance, 3 to 5—moderate insulin resistance, >5—severe insulin resistance

References

  1. D.C. Thew, I.M. Stewart, D penicillamine and breast enlargement. Ann. Rheum. Dis. 39(2), 200 (1980)

    Article  CAS  Google Scholar 

  2. V. Cervelli, G. Orlando, F. Giudiceandrea, M. Grimaldi, F. Pisani, F. Strati et al. Gigantomastia and breast lumps in a kidney transplant recipient. Transplant. Proc. 31, 3224–3225 (1999)

    Article  CAS  Google Scholar 

  3. E. Szymańska, E. Moszczyńska, D. Polnik, S. Szymańska, E. Jurkiewicz, M. Pyzlak et al. Virginal breast hypertrophy in a patient with Beckwith–Wiedemann syndrome. Clin. Case Rep. 6(3), 484 (2018)

    Article  Google Scholar 

  4. A. Sood, R.K. Garg, R. Saily, R.J. Dash, A patient with congenital hypertrichosis, gum hyperplasia and macromastia. J. Pediatr. Endocrinol. Metab. 13(5), 561–564 (2000)

    Article  CAS  Google Scholar 

  5. A. Dancey, M. Khan, J. Dawson, F. Peart, Gigantomastia–a classification and review of the literature. J. Plast. Reconstr. Aesthetic Surg. 61(5), 493–502 (2008). https://doi.org/10.1016/j.bjps.2007.10.041

    Article  Google Scholar 

  6. H. Dafydd, K.R. Roehl, L.G. Phillips, A. Dancey, F. Peart, K. Shokrollahi, Redefining gigantomastia. J. Plast. Reconstr. Aesthet. Surg. 64(2), 160–163 (2011). https://doi.org/10.1016/j.bjps.2010.04.043

    Article  CAS  PubMed  Google Scholar 

  7. P. Touraine, N. Youssef, M.A. Alyanakian, X. Lechat, C. Balleyguier, C. Duflos, A. Dib, A. May, J.C. Carel, K. Laborde, B. Sigal-Zafrani, Breast inflammatory gigantomastia in a context of immune-mediated diseases. J. Clin. Endocrinol. Metab. 90(9), 5287–5294 (2005). https://doi.org/10.1210/jc.2005-0642

    Article  CAS  PubMed  Google Scholar 

  8. L.K. Kalliainen, ASPS clinical practice guideline summary on reduction mammaplasty. Plast. Reconstr. Surg. 130(4), 785–789 (2012). https://doi.org/10.1097/PRS.0b013e318262f0c0. ASPS Health Policy Committee

    Article  CAS  PubMed  Google Scholar 

  9. R. Subramani, S.B. Nandy, D.A. Pedroza, R. Lakshmanaswamy, Role of growth hormone in breast cancer. Endocrinology 158(6), 1543–1555 (2017). https://doi.org/10.1210/en.2016-1928

    Article  PubMed  Google Scholar 

  10. M.D. Sternlicht, Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis. Breast Cancer Res. 8(1), 201 (2005). https://doi.org/10.1186/bcr1368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. W.E. Ruan, V.E. Catanese, R.O. Wieczorek, M.A. Feldman, D.L. Kleinberg, Estradiol enhances the stimulatory effect of insulin-like growth factor-I (IGF-I) on mammary development and growth hormone-induced IGF-I messenger ribonucleic acid. Endocrinology. 136(3), 1296–1302 (1995). https://doi.org/10.1210/endo.136.3.7867584

    Article  CAS  Google Scholar 

  12. J.Y. Li, D.L. Mu, L.H. Mu, M.Q. Xin, L. Jie, Functional annotation of the microRNA-mediated network in gigantomastia by integrating microRNA and mRNA expression profiling. Chin. Med. J. 126(4), 740–746 (2013)

    CAS  PubMed  Google Scholar 

  13. C. Mishima, N. Kagara, T. Tanei, Y. Naoi, M. Shimoda, A. Shimomura, K. Shimazu, S.J. Kim, S. Noguchi, Loss of imprinting of IGF2 in fibroadenomas and phyllodes tumors of the breast. Oncol. Rep. 35(3), 1511–1518 (2016). https://doi.org/10.3892/or.2015.4489

    Article  CAS  PubMed  Google Scholar 

  14. M. Hiremath, J. Wysolmerski, Parathyroid hormone-related protein specifies the mammary mesenchyme and regulates embryonic mammary development. J. Mammary Gland Biol. Neoplasia 18(2), 171–177 (2013). https://doi.org/10.1007/s10911-013-9283-7

    Article  PubMed  PubMed Central  Google Scholar 

  15. S. Khosla, J.A. Van Heerden, H. Gharib, I.T. Jackson, J. Danks, J.A. Hayman et al. Parathyroid hormone-related protein and hypercalcemia secondary to massive mammary hyperplasia. New Engl. J. Med. 322(16), 1157 (1990). https://doi.org/10.1056/NEJM199004193221613

    Article  CAS  PubMed  Google Scholar 

  16. T. Modarressi, M.A. Levine, J. Tchou, A.N. Khan, Gestational gigantomastia complicated by PTHrP-mediated hypercalcemia. J. Clin. Endocrinol. Metab. 103(9), 3124–3130 (2018). https://doi.org/10.1210/jc.2018-01181

    Article  PubMed  Google Scholar 

  17. A. Shimatsu, N. Hattori, Macroprolactinemia: diagnostic, clinical, and pathogenic significance. Clin. Dev. Immunol. (2012). https://doi.org/10.1155/2012/167132

    Article  Google Scholar 

  18. S.A. Emami, R. Sobhani, Impact of reduction mammaplasty on sexuality in patients with macromastia and their partners. J. Plast. Reconstr. Aesthet. Surg. 69(10), 1335–1339 (2016). https://doi.org/10.1016/j.bjps.2016.07.018

    Article  PubMed  Google Scholar 

  19. K.E. Koger, D. Sunde, B.H. Press, L.M. Hovey, Reduction mammaplasty for gigantomastia using inferiorly based pedicle and free nipple transplantation. Ann. Plast. Surg. 33(5), 561–564 (1994)

    Article  CAS  Google Scholar 

  20. J. Skillman, N. Beechey-Newman, H. Hamed, Gigantomastia unrelated to pregnancy or puberty: a case report. Breast 11(2), 179–180 (2002). https://doi.org/10.1054/brst.2001.0406

    Article  CAS  PubMed  Google Scholar 

  21. W. Chromiński, B. Madej, R. Maciejewski, K. Torres, R. Ciechanek, F. Burdan, A developmental anomaly of the mammary glands-gigantomastia. A case report. Folia Morphol. 62(4), 517–518 (2003)

    Google Scholar 

  22. D. Kulkarni, N. Beechey-Newman, H. Hamed, I.S. Fentiman, Gigantomastia: a problem of local recurrence. Breast 15(1), 100–102 (2006). https://doi.org/10.1016/j.breast.2005.03.002

    Article  PubMed  Google Scholar 

  23. M.J. Cho, J.H. Yang, H.G. Choi, W.S. Kim, Y.B. Yu, K.S. Park, An idiopathic gigantomastia. Ann. Surg. Treat. Res. 88(3), 166–169 (2015). https://doi.org/10.4174/astr.2015.88.3.166

    Article  PubMed  PubMed Central  Google Scholar 

  24. M. Roy, J. Lee, S. Aldekhayel, T. Dionisopoulos. Pseudoangiomatous stromal hyperplasia: a rare cause of idiopathic gigantomastia. Plast. Reconstr. Surg. Global Open 3(9), (2015). https://doi.org/10.1097/GOX.0000000000000468

    Article  Google Scholar 

  25. Oppenheimer A. J., Oppenheimer D. C., Fiala T. G., Noori S. Pseudoangiomatous stromal hyperplasia: a rare cause of idiopathic gigantomastia. Plast. Reconstr. Surg. Global Open 4(1), (2016). https://doi.org/10.1097/GOX.0000000000000572

    Article  Google Scholar 

  26. A.J. Barragan-Morteo, M.A. Martinez-Jimenez, Massive Idiopathic prepubertal Gigantomastia. Indian Paediatr. 53(1), 77 (2016)

    Google Scholar 

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Acknowledgements

We would like to thank Prof. Ashley Grossman for his constructive comments.

Author contribution

L.D. drafted the manuscript and interpreted observations. A.R. was involved in histopathology interpretation and manuscript writing. K.V. was involved in histopathology interpretation and manuscript editing. A.G. assisted surgery of the first case. S.M. assisted surgery of the first case. A.B. edited the manuscript. P.D. conceived the idea and was involved in manuscript writing as well as editing. S.S.T. operated the case and was involved in manuscript editing.

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Author notes

  1. These authors contributed equally: Liza Das, Ashutosh Rai

Authors and Affiliations

  1. Department of Endocrinology, PGIMER, Chandigarh, India

    Liza Das, Anil Bhansali & Pinaki Dutta

  2. Department of Translational and Regenerative Medicine, PGIMER, Chandigarh, India

    Ashutosh Rai

  3. Department of Pathology, PGIMER, Chandigarh, India

    Kim Vaiphei

  4. Department of Plastic surgery, PGIMER, Chandigarh, India

    Akhil Garg, Subair Mohsina & Satyaswarup Tripathy

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  1. Liza Das
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Correspondence to Pinaki Dutta or Satyaswarup Tripathy.

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All procedures performed involving human participants/patients were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Das, L., Rai, A., Vaiphei, K. et al. Idiopathic gigantomastia: newer mechanistic insights implicating the paracrine milieu. Endocrine 66, 166–177 (2019). https://doi.org/10.1007/s12020-019-02065-x

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