Is Immunohistochemical Sex Hormone Binding Globulin Expression Important in the Differential Diagnosis of Adenocarcinomas?

  • Bulut, Gulay (Department of Pathology, Faculty of Medicine, Yuzuncu Yil University) ;
  • Kosem, Mustafa (Department of Pathology, Sakarya University) ;
  • Bulut, Mehmet Deniz (Department of Radiology, Faculty of Medicine, Yuzuncu Yil University) ;
  • Erten, Remzi (Department of Pathology, Faculty of Medicine, Yuzuncu Yil University) ;
  • Bayram, Irfan (Department of Pathology, Faculty of Medicine, Yuzuncu Yil University)
  • Published : 2016.01.11


Adenocarcinomas (AC) are the most frequently encountered carcinomas. It may be quite challenging to detect the primary origin when those carcinomas metastasize and the first finding is a metastatic tumor. This study evaluated the role of sex hormone binding globulin (SHBG) positivity in tumor cells in the subclassification and detection of the original organ of adenocarcinomas. Between 1994 and 2008, 64 sections of normal tissue belonging to ten organs, and 116 cases diagnosed as adenoid cystic carcinoma and mucoepidermoid carcinoma of the salivary gland, lung adenocarcinoma, invasive ductal carcinoma of the breast, adenocarcinoma of stomach, colon, gallbladder, pancreas and prostate, endometrial adenocarcinoma and serous adenocarcinoma and mucinous adenocarcinoma of the ovary, were sent to the laboratory at the Department of Pathology at the Yuzuncu Yil University School of Medicine, where they were stained immunohistochemically, using antibodies against SHBG. The SHBG immunoreactivity in both the tumor cells and normal cells, together with the type, diffuseness and intensity of the staining were then evaluated. In the differential diagnosis of the adenocarcinomas of the organs, including the glandular structures, impressively valuable results are encountered in the tumor cells, whether the SHBG immunopositivity is evaluated alone or together with other IHC markers. Further extensive research with a larger number of cases, including instances of cholangiocarcinoma and cervix uteri AC [which we could not include in the study for technical reasons] should be performed, in order to appropriately evaluate the role of SHBG in the differential diagnosis of AC.


SHGB;adenocarcinoma;differential diagnosis


  1. Austin H, Austin JM, Partridge EE, et al (1991). Endometrial cancer, obesity and body fat distribution. Cancer Res, 51, 568-72.
  2. Avvakumov GV, Grishkovskaya I, Muller YA, et al (2001). Resolution of the human sex hormone-binding globulin dimer interface and evidence for two steroid-binding sites per homodimer. J Biol Chem, 276, 34453-57.
  3. Aygen E M, Ozcelik B, Basbug M. (2003). The effect of cyclic and continuous estrogen replacement therapy on sex hormone binding globulins and androgen levels. Erciyes Med J, 25, 11-5.
  4. Barrett-Connor E, Garland C, McPhillips JB, et al (1990). A prospective, population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Res, 50, 169-73.
  5. Bobe J, Mahe S, Nguyen T, et al (2008). A novel, functional, and highly divergent sex hormone-binding globulin that may participate in the local control of ovarian functions in salmonids. Endocrinol, 149, 2980-89.
  6. Cousin P, Dechaud H, Grenot C, et al (1998). Human variant sex hormone-binding globulin (SHBG) with an additional carbohydrate chain has a reduced clearance rate in rabbit. J Clin Endocrinol Metab, 83, 235-40.
  7. Dechaud H, Goujon R, Claustrat F, et al (1995). In vitro influence of plasma steroid-binding proteins on androgen metabolism in human leukocytes. Steroids, 60, 226-33.
  8. Dorgan JF, Albanes D, Virtamo J, et al (1998). Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiol Biomarkers Prev, 7, 1069-74.
  9. Ergun A, Dilek S, Kansiz L, et al (1995). The Value Of Shbg As A High Risk Factor In Endometrial Cancers. Turkiye Klinikleri J Gynecol Obst, 5, 64-7.
  10. Forges T, Gerard A, Hess K, et al (2004). Expression of sex hormone-binding globulin (SHBG) in human granulosalutein cells. Mol Cell Endocrinol, 219, 61-8.
  11. Fortunati N, Catalano MG, Boccuzzi G, et al (2010). Sex Hormone-Bindin Globulin (SHBG), estradiol and breast cancer. Mol Cell Endocrinol, 316, 86-92.
  12. Gann PH, Hennekens CH, Stampfer MJ (1996). Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst, 88, 1118-26.
  13. Garcia-Closas M, Brinton LA, Lissowska J, et al (2007). Ovarian cancer risk and common variation in the sex hormonebinding globulin gene: a population-based case-control study. BMC Cancer, 7, 60.
  14. Grasso M, Buonaguidi A, Mondina R, et al (1990). Plasma sex hormone binding globulin in patients with prostatic carcinoma. Cancer, 66, 354-7.<354::AID-CNCR2820660225>3.0.CO;2-N
  15. Grishkovskaya I, Avvakumov GV, Sklenar G, et al (2000). Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain. EMBO J, 19, 504-12.
  16. Guess HA, Friedman G, Sadler MC, et al (1997). 5 alphareductase activity and prostate cancer: A case-control study using stored sera. Cancer Epidemiol Biomarkers Prev, 6, 21-4.
  17. Hagen FS, Arguelles C, Sui LM, et al (1992). Mammalian expression of the human sex steroid-binding protein of plasma (SBP or SHBG) and testis (ABP). Characterization of the recombinant protein. FEBS Lett, 299, 23-7.
  18. Hammond GL (1995). Potential functions of plasma steroidbinding proteins. Trends Endocrinol Metab, 6, 298-04.
  19. Herbert Z, Gothe S, Caldwell JD, et al (2005). Identification of sex hormone-binding globulin in the human hypothalamus. Neuroendocrinol, 81, 287-93.
  20. Hryb DJ, Nakhla AM, Kahn SM, et al (2002). Sex hormonebinding globulin in the human prostate is locally synthesized and may act as an autocrine/paracrine effector. J Biol Chem, 277, 26618-22.
  21. Joseph DR, Sullivan PM, Wang YM, et al (1991). Complex structure and regulation of the ABP/SHBG gene. J Steroid Biochem Mol Biol, 40, 771-5.
  22. Kahn SM, Li YH, Hryb DJ, et al (2008). Sex hormone-binding globulin influences gene expression of LNCaP and MCF-7 cells in response to androgen and estrogen treatment. Adv Exp Med Biol, 617, 557-64.
  23. Langdon SP, Faratian D, Harrison DJ (2009). The importance of growth factors and steroid hormones in ovarian cancer. Onkologie, 32, 623-4.
  24. Larrea F, Diaz L, Carino C, et al (1993). Evidence that human placenta is a site of sex hormone-binding globulin gene expression. J Steroid Biochem Mol Biol, 46, 497-05.
  25. Lee SE, Chung JS, Han BK, et al (2008). Preoperative serum sex hormone-binding globulin as a predictive marker for extraprostatic extension of tumor in patients with clinically localized prostate cancer. Eur Urol, 54, 1324-32.
  26. Lindstedt G, Lundberg PA, Lapidus L, et al (1991). Low hormone-binding globulin concentration as independent risk factor for development of Nll 12-year follow-up of population study of women in Gothenburg, Sweden. Diabetes, 40, 123-8.
  27. Mahlck CG, Backstrom T, Kjellgren O (1989). Significance of initial plasma steroid concentrations in the prognosis of 'nonendocrine' malignant ovarian tumors. Gynecol Obstet Invest, 28, 41-6.
  28. Mahlck CG, Grankvist K, Backstrom T, et al (1986). Testosterone, SHBG and albumin in patients with ovarian carcinoma. Acta Obstet Gynecol Scand, 65, 533-8.
  29. Mahlck CG, Grankvist K, Backstrom T, et al (1986). Testosterone, SHBG and albumin in patients with ovarian carcinoma. Acta Obstet Gynecol Scand, 65, 533-38.
  30. Maliqueo M, Bacallao K, Quezada S, et al (2007). Sex hormonebinding globulin expression in the endometria of women with polycystic ovary syndrome. Fertil Steril, 87, 321-8.
  31. Meyer S, Brumm C, Stegner HE, et al (1994). Intracellular sex hormone-binding globulin (SHBG) in normal and neoplastic breast tissue--an additional marker for hormone dependency? Exp Clin Endocrinol, 102, 334-40.
  32. Mikkola AK, Aro JL, Rannikko SA, et al (1999). Pretreatment plasma testosterone and estradiol levels in patients with locally advanced or metastasized prostatic cancer. Prostate, 39, 175-81.<175::AID-PROS5>3.0.CO;2-E
  33. Misao R, Hori M, Ichigo S, et al (1995). Levels of sex hormonebinding globulin (SHBG) and corticosteroid-binding globulin (CBG) messenger ribonucleic acid (mRNAs) in ovarian endometriosis. Reprod Nutr Dev, 35, 155-65.
  34. Misao R, Nakanishi Y, Fujimoto J, et al (1995). Expression of sex hormone-binding globulin mRNA in uterine leiomyoma, myometrium and endometrium of human subjects. Gynecol Endocrinol, 9, 317-23.
  35. Misao R, Nakanishi Y, Fujimoto J, et al (1995). Expression of sex hormone-binding globulin mRNA in human ovarian cancers. Eur J Endocrinol, 133, 327-34.
  36. Misao R, Nakanishi Y, Ichigo S, et al (1995). Expression of sex hormone-binding globulin mRNA in human endometrial cancers. J Steroid Biochem Mol Biol, 52, 517-22.
  37. Nisker JA, Hammond GL, Davidson BJ, et al (1980). Serum sex-hormon binding globulin capacity and the percentage of free estradiol in postmenopausal women with or without endometrial cancer. Am J Obstet Gynecol, 138, 637-42.
  38. Pasquali R, Vicennati V, Bertazzo D, et al (1997). Determinants of sex hormone-binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status. Metabolism, 46, 5-9.
  39. Potischman N, Hoover RN, Brinton LA, et al (1996). Casecontrol study of endogenous steroid hormones and endometrial cancer. J Natl Cancer Inst, 88, 1127-35.
  40. Selby C (1990). Sex hormone binding globulin: origin, function and clinical significance. Ann Clin Biochem, 27, 532-41.
  41. Selva DM, Hammond GL (2006). Human sex hormone-binding globulin is expressed in testicular germ cells and not in sertoli cells. Horm Metab Res, 38, 230-5.
  42. Sinnecker G, Hiort O, Kwan PW, et al (1990). Immunohistochemical localization of sex hormone-binding globulin in normal and neoplastic breast tissue. Horm Metab Res, 22, 47-50.
  43. Sulkes A, Fuks Z, Gordon A, et al (1984). Sex hormone binding globulin (SHBG) in breast cancer: a correlation with obesity but not with estrogen receptor status. Eur J Cancer Clin Oncol, 20, 19-23.
  44. Teruel M, Bolufer P, Rodriguez A, et al (1989). Plasma sex steroids and SHBG in patients with breast cancer and their relation to tumor oestrogen-dependency. Exp Clin Endocrinol, 93, 37-44.
  45. Westphal U (1986). Steroid-protein interactions II, springer-verlag, berlin, heidelberg (1986), 198-264.
  46. Zeleniuch-Jacquotte A, Akhmedkhanov A, Kato I, et al (2001). Postmenopausal endogenous estrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer, 84, 975-81.