National Academy of Medical Sciences
Prof Sandeep Kumar MS FRCS PhD MMSc received a national award of the Academy of Medical Sciences for the year 2015. This award is called Col Sangham Lal Oration award and is generally given by Vice President of India
Modern concept of Benign Breast Disorders and its Endocrinological Background & Treatment
Theme Breast pain or mastalgia often associated with non-discrete lumpiness of the breast was erroneously interpreted as a histo-morphological disease for several decades1. A sounding board article in New England Journal of Medicine declared fibrocystic breast disease a non-disease2. Prof Sandeep Kumars contribution in the development of the modern concept of Benign Breast Disorders3 and its endocrinological background turns a full circle. He first described the natural history of breast pain4 then the clinical classification of benign breast disorder5, a subtle endocrinological aetio-pathogenesis was described in several experiments6-14 conducted by him. This was followed by population based epidemiology of breast pain and nodularity15, development of a clinical objective tool for assessment of breast pain and nodularity16 and a double blind randomized placebo controlled clinical trial to successfully treat predominant breast pain and nodularity17 are some of the contributions made by the proposer.
Histo-morphology Breasts are composed of epithelial system of ducts and lobulo-alveolar secretary units embedded in adipose tissue with interspersed fibrous septae derived from mesenchymal tissue. The growth and morpho-genesis of these tissues occur in various stages associated with concurrent hormonal changes in the female body. Such changes are also affected by genetic constitution and mutation. Breast growth secretion and involution are affected by systemic hormones, the sensitivity of its glandular and stromal tissue to the circulating hormones and the milieu interior of its paracrine effects of locally derived factors affecting the epithelium and stromal relationship. This forms the major basis of benign breast disorders mainly breast pain and nodularity. Its histo-pathogenesis was erroneously described by previous authors1
Natural history Untreated cyclical breast pain cohort of 258 patients was followed for up to 7 years and the natural history was described for first time. Two distinct pain patterns were identified i.e. cyclical pronounced mastalgia (CPM) and non cyclical mastalgia (NCM). Two populations emerged; one experience relief after a mean of 3 years and in another the pain was persistent for up to 2 decades. The cyclical pain generally related to a hormonal event, started early in life and usually abated at menopause spontaneously. This study indicated that type of pain and age at onset may allow some prediction of the course of disease and choice of therapy.
Epidemiology With social, economical, educational and information evolution increasing number of women solicit medical opinion for pain and nodularity in breasts but unfortunately majority are poorly managed and unnecessary biopsies and cancer phobia is commonly generated. If it is mild it can be regarded as normal. This condition was described as ANDI or Aberration of Normal Development and Involution. It has no histological basis. Breast nodularity is a physiologic, hormonally mediated change characterized by lumpiness of the breast and varying degrees of pain and tenderness. Its prevalence in the community and hospital based population was described.
Aetiology of Mastalgia and Nodularity – ANDI In the past, benign breast disease for most doctors has been regarded as synonymous with “fibroadenosis” or “fibrocystic disease”. These terms were used for the syndrome of premenstrual pain and nodularity. This concept arose from the unfortunate fact that early workers described histological changes of fibrosis, adenosis, cyst formation and apocrine metaplasia and assumed a causative association. Subsequently, it was well established that these histological changes were normal features of the breast microanatomy and ubiquitous in nature. Three main theories have thus emerged regarding the aetiology of painful nodular breasts: 1. Increased oestrogen secretion from the ovary. 2. Deficient progesterone production (or ‘relative hyper-oestrogenism’) and 3. Hyper-prolactinaemia. In summary, pulsatile secretion of prolactin and / or gonadotropins are abnormal in painful nodular breasts. Levels of oestrogen, the administration of which is known to cause symptoms of painful nodularity, does not seem to be abnormal in CPM patients. Progesterone deficiency due to inadequate corpus luteal function is unlikely to be present. Ironically, a defect in the tissue response or an end organ abnormality has not been investigated so far.
Assessment – Lucknow Cardiff breast nodularity scale was developed Breast nodularity scale is a 5-point ordinal scale depicting increasing order of nodularity in the outer quadrants of the breasts. Clinically breast nodularity is especially and most commonly noticeable in the upper outer quadrant of the breast that has the maximum amount of breast tissue hence the depiction of a scheme mostly shown in the upper outer quadrants of the breasts. An extrapolation can be charted for other quadrants of the breast in the index picture. Grade – 0 depicts a smooth textured breast with extreme extent of normalcy and grade – 4 the maximum nodularity. In the present scale, the five figures are cue for the examining doctor to chart the nodularity in the index breast. The examining clinician or nurse is taught to make a holistic interpretation of breast nodularity as a sum of area or quadrants involved and the coarseness of nodularity. Approximately, 2/3rd normal women have some grade of nodularity.
Treatment There was a need to find a drug for mastalgia which is effective and safe drug is reflected from the review of literature. Several agents have been tried. The two broad categories used are hormonal and non hormonal. Hormonal manipulation is done by danazol, tamoxifen, bromocriptine, progesterone, oral contraceptive pill and more recently LHRH analogue or goserelin or GLA – gamma linolic acid. Non hormonal agents include analgesics (oral/ topical), plant extracts like fructus-agni-casti, evening primrose oil and GLA. Double blind randomized placebo controlled clinical trial of oral centchroman 30 mg (ormeloxifene); a SERM or placebo twice a week for 3 months in women (20-50 yrs) with pronounced breast pain with or without lumpiness were recruited after excluding discrete benign lump or cancer. Serial assessments of pain on a visual analogue scale and nodularity grade on a 5-point ordinal Lucknow-Cardiff scale were done. A total of 151 patients were randomly allocated to two interventions using blocks of size four. Participants and physicians were blinded to randomization. Of the 151 patients, 121 (active=57, placebo=64) were available for efficacy analysis. The mean pain level showed a systematic downward trend over five visits (F=105.23, p<0.0001), that significantly reduced in active group compared to placebo (F=18.66, p<0.0001). The patterns of variation in pain over time for the individual groups differ from the overall mean pattern for two groups and thus from one another (F=44.43, p<0.0001). Cumulative frequencies of breast nodularity grades during the successive visits showed significant improvement (p=0.001) compared to placebo at the end of third month. The effect of active drug persisted till the completion (6 months) of the treatment (p < 0.001). At the last visit, 93.3% subjects in active group had grade 2 or lower nodularity as compared to 71.05% in the placebo. Oligomenorrhea alone was reported in 12 subjects. Centchroman showed significant efficacy for treating breast pain and nodularity.
- Foote FW, Stewart FW. Comparative studies of cancerous versus non-cancerous breasts. Ann Surg 1945; 6 : 121
- Love SM, Gelman RS, Silen W. Fibrocystic disease of the breast – A non-disease. New Eng J Med 1982; 307 : 1010-1014
- Hughes LE. Benign Breast Disorders – Introduction. Fibrocystic Disease ? Nondisease ? or ANDI ? World J Surg 1989; 13 : 667 – 668
- Natural history of breast pain. Wisbey JR, Kumar Sandeep, Mansel RE, Preece PE, Pye JK, Hughes LE. Lancet 1983; ii: 672‑74 Impact Factor : 36.427 Citations : 54
- Kumar Sandeep Studies on the role of Prolactin in the aetiology of breast disease. University of Wales College of Medicine PhD Thesis 1984
- Kumar Sandeep, Mansel RE, Scanlon MF, Hughes LE, Edward CA, Woodhead JS, Newcombe RG. Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone gonadotrophin releasing hormone stimulation in cyclical mastalgia. Br J Surg 1984; 71 : 870 – 873 Impact Factor : 4.839
- Secretory response of prolactin and TSH in benign breast disease before and after TRH stimulation. Kumar Sandeep, Mansel RE, Hughes LE. Br J Surg (abstract) 1983; 70: 293 Impact Factor : 4.839
- Prolactin response to Thyrotropin ‑ Releasing Hormone stimulation and dopaminergic inhibition in benign breast disease. Kumar Sandeep, Mansel RE, Hughes LE, Woodhead JS, Edwards CA, Scanlon MF, Newcombe RG. Cancer 1984; 53:1311‑15 Impact Factor : 5.201 Citations : 39
- Prolactin and antiemetics for adjuvant chemotherapy of breast cancer. Kumar Sandeep, Mansel RE. Br Med J 1984; 288: 760 Impact Factor : 17.215
- Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/ gonadotrophin releasing hormone stimulation in cyclical mastalgia. Kumar Sandeep, Mansel RE, Scanlon MF, Hughes LE, Edwards CA, Woodhead JS and Newcombe RG. Br J Surg 1984; 71:870‑73 Impact Factor : 4.839 Citations : 28
- Prediction of response to endocrine therapy in pronounced cyclical mastalgia using dynamic tests of Prolactin release. Kumar Sandeep, Mansel RE, Hughes LE, Edwards CA and Scanlon MF. Clin Endocrinal (Oxford) 1985; 23: 699‑704 Impact Factor : 3.4 Citations : 16
- Daily salivary progesterone levels in cyclical mastalgia patients and their controls. Kumar Sandeep, Mansel RE, Read GF, Truran PL, Wilson DW and Hughes LE. Br J Surg 1986; 73: 260 – 263Impact Factor : 4.839 Citations : 9
- Presence and possible significance of immunohistochemically demonstrable prolactin in breast apocrine metaplasia. Kumar Sandeep, Mansel RE, Jasani B. Br J Cancer 1987; 55: 307‑309 Impact Factor : 5.082 Citations : 8
- Highly specific sites of Prolactin binding in benign and malignant breast tissue. Agarwal PK, Tandon S, Agarwal AK, Kumar Sandeep, Ind J Exp Biol 1989; 27: 1035‑1038 Impact Factor: 1.195
- Benign Breast Disorders in Nonwestern Populations: Part II Benign Breast Disorders in India. Shukla HS, Kumar Sandeep. World J Surg 1989; 13: 747 Impact Factor : 2.228 Citations : 12
- Visual analogue scale for assessing breast nodularity in non discrete lumpy breasts: The Lucknow Cardiff breast nodularity scale. Kumar Sandeep, Rai R, Das V, Dwivedi V, Kumar S, Agrawal GG. The Breast 2010; 19 : 238 – 242 Impact Factor : 1.967
- A Randomised Double Blind Placebo Controlled Clinical Trial of Centchroman (Ormeloxifene) in Breast Pain and Nodularity (Benign Breast Disorder). Kumar Sandeep, Rai R, Agarwal GG, Dwivedi V, Kumar S, Das V. Nat Med J India 2013; 26: 69-74 Impact Factor: .626
- A Systematic Review of Current Understanding and Management of Mastalgia. Kamal Kataria, Anita Dhar, Anurag Srivastava, Kumar Sandeep, Amit Goyal. Indian J Surg 2013; 75: 1-6 (DOI 10.1007/s12262-013-0813-8) Impact Factor: 0.092