{"paper_id":"b969001c-29f8-45ad-b70c-07e36bac074d","body_text":"BioMed Central\nPage 1 of 6\n(page number not for citation purposes)\nBMC Cancer\nOpen AccessCase report\nSmall primary adenocarcinoma in adenomyosis with nodal \nmetastasis: a case report\nGiacomo Puppa1, Makio Shozu2, Tiziana Perin1, Kazuhito Nomura3, \nAnnunziata Gloghini4, Elio Campagnutta5 and Vincenzo Canzonieri*1\nAddress: 1Division of Pathology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori – IRCCS, Via Pedemontana Occidentale 12, 33081 \nAviano PN, Italy, 2Graduate School of Chiba University, Reproductive Medicine, Chuo-ku, Chiba, Japan, 3Department of Obstetrics and \nGynecology, Kanazawa University School of Medicine, Takara-machi, Kanazawa, Japan, 4Diagnostic Immunohistochemistry and Molecular \nPathology Unit, Istituto Nazionale Tumori – IRCCS, Aviano PN, Italy and 5Division of Gynecologic Oncology, Centro di Riferimento Oncologico, \nIstituto Nazionale Tumori – IRCCS, Aviano PN, Italy\nEmail: Giacomo Puppa - gpuppa@yahoo.com; Makio Shozu - shozu@faculty.chiba-u.jp; Tiziana Perin - tperin@cro.it; \nKazuhito Nomura - nomura@med.kanazawa-u.ac.jp; Annunziata Gloghini - agloghini@cro.it; Elio Campagnutta - ecampagnutta@cro.it; \nVincenzo Canzonieri* - vcanzonieri@cro.it\n* Corresponding author    \nAbstract\nBackground: Malignant transformation of adenomyosis is a very rare event. Only about 30 cases\nof this occurrence have been documented till now.\nCase presentation: The patient was a 57-year-old woman with a slightly enlarged uterus, who\nunderwent total hysterectomy and unilateral adne xectomy. On gross inspection, the uterine wall\ndisplayed a single nodule measuring 5 cm and several small gelatinous lesions. Microscopic\nexamination revealed a common leiomyoma and multiple adenomyotic foci. A few of these glands\nwere transformed into a mode rately differentiated adenocarcinoma. The endometrium was\ncompletely examined and tumor free. The carc inoma was, therefore, considered to be an\nendometrioid adenocarcinoma arising from adenom yosis. Four months late r, an ultrasound scan\nrevealed enlarged pelvic lymph nodes: a cytologi cal diagnosis of metastat ic adenocarcinoma was\nmade.\nImmunohistochemical studies showed an enhanced positivity of the tumor site together with the\nneighbouring adenomyotic foci fo r estrogen receptors, aromat ase, p53 and COX-2 expression\nwhen compared to the distant adenomyotic glands and the endometrium. We therefore postulate\nthat the neoplastic transformation of adenomyosis implies an early carcinogenic event involving p53\nand COX-2; further tumor growth is sustained by an autocrine-paracrine loop, based on a\nmodulation of hormone receptors as well as aromatase and COX-2 local expression.\nConclusion: Adenocarcinoma in adenomyosis may be affected by local hormonal influence and,\ndespite its small size, may metastasize.\nPublished: 20 June 2007\nBMC Cancer 2007, 7:103 doi:10.1186/1471-2407-7-103\nReceived: 18 November 2006\nAccepted: 20 June 2007\nThis article is available from: http://www.biomedcentral.com/1471-2407/7/103\n© 2007 Puppa et al; licensee BioMed Central Ltd. \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), \nwhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nBMC Cancer 2007, 7:103 http://www.biomedcen tral.com/1471-2407/7/103\nPage 2 of 6\n(page number not for citation purposes)\nBackground\nLeiomyoma and adenomyosis are both commonly\nencountered in hysterectomy surgical specimens, often as\nincidental findings. A frequent association of adenomyo-\nsis with other hormone-dependent uterine lesions, both\nbenign and malignant, such as endometrial hyperplasia,\nendometrial carcinoma and leiomyoma has already been\ndescribed in the literature [1,2]. However, the develop-\nment of cancer from adenomyosis is a relatively rare\noccurrence. In all cases, the following Sampson's criteria\nshould be fulfilled to confirm the malignant transforma-\ntion:\n1) evidence of pre-existing endometriosis at the site of the\nsupposed malignant lesion;\n2) exclusion of the possibility of the carcinoma represent-\ning an invasion or metastasis from another location;\n3) evidence of transitions between the benign and malig-\nnant glandular structures; and\n4) both glands and stroma must be present to constitute\ngenuine adenomyosis [3].\nAt present, only about 30 cases of adenocarcinoma arising\nfrom adenomyosis without endometrial malignancy have\nbeen reported in the English literature [4-12]. In all these\ncases, the immunohistochemical studies were of limited\nextent and the few cases reported with immunohisto-\nchemistry were all negative for ER [6,9,12].\nWe report on the clinico-pathological and immunohisto-\nchemical findings of a small endometrioid adenocarci-\nnoma arising from adenomyosis, incidentally discovered\naround a leiomyoma after extensive sampling. To the best\nof our knowledge, this is the single smallest reported\ninstance of such an occurrence with a distinct immunohis-\ntochemical profile. The possible connection between\nmalignant transformation of adenomyosis and benign,\nhormone-dependent disease is discussed.\nCase presentation\nClinical summary\nThe patient was a 57-year-old nulliparous, asymptomatic\nwoman of normal weight. She was in follow-up for a\nfibromatous uterus. On palpation, a uterine softening was\nnoted. An ultrasound scan displayed the enlargement of a\npre-existent leiomyomatous nodule and multiple minute\nfocal lesions throughout the uterine wall, diagnosed as a\nlikely adenomyosis. Menopause had commenced at the\nage of 54. Her past medical history was significant for pap-\nillary serous cystoadenoma of the left ovary which was\nremoved when she was 33 years of age. For the last few\nyears, the patient was being treated with an antihyperten-\nsive therapy, while, nine years previously, for a period of\ntwo years, she had taken symptomatic therapy for peri-\nmenopausal symptoms including progesterone, and, dur-\ning the last year, a non-hormonal therapy with a\nhyperprolactinemic effect to reduce hot flushes.\nBecause of the recent appearance of focal lesions in the\nuterine corpus in an already enlarged uterus (as seen on\nthe ultrasound scan), a total hysterectomy and unilateral\nadnexectomy were performed. Four months later, an\nultrasound scan revealed an enlargement of the left exter-\nnal iliac chain nodes and a thickening of the lateral pelvic\nwall up to the inguinal ring. A second-look surgical\ninspection as well as an extensive clinical work-up, which\nincluded a thoraco-abdominal CT scan, excluded the pres-\nence of other primary tumors.\nMethods\nThe tissues were fixed in Bouin solution and embedded in\nparaffin for histologic processing. Tissue sections were\nstained with hematoxylin and eosin for conventional his-\ntology.\nImmunohistochemical stainings were performed using a\ncombination of the avidin-biotin complex peroxidase\nmethod (ABC kit; Vector Laboratories, Burlingham, CA,\nUSA) and microwave antigen retrieval with the following\nantibodies: ER (Clone 6F11, Novocastra, Newcastle, UK);\nPR (Clone Pgr636 Dakocytomation, Glostrup, Denmark);\nC-erb B2 (Clone A0485, polyclonal antibody Dakocyto-\nmation, Glostrup, Denmark); Cyclooxygenase-2 (COX-2)\n(clone 4H12, Novocastra, Newcastle, UK); p53 (Clone\nDO-7, Novocastra, Newcastle, UK) and CA125 (Clone\nOv185:1, Novocastra, Newcastle, UK).\nThe sections were also stained for aromatase as follows:\nsections were dewaxed in xylene and taken through a\ngraded series of ethanol. Epitope retrieval was performed\nby enzymatic digestion with trypsin for 20 minutes at\n37°C (TRYPSIN Tablets; Sigma, St. Louis, MO, USA). After\nincubation with 0.3% hydrogen and protein block solu-\ntion (DAKO) for 5 minutes, the sections were treated with\npolyclonal antiaromatase antibody (provided by Dr.\nNobuhiro Harada, Ph.D., Fujita Health University,\nNagoya, Japan) for 15 minutes at room temperature fol-\nlowing dilution to 1:1,000 in buffer. After incubation with\nthe primary antibody, streptavidin-biotin complex and\nstreptavidin-peroxidase complex were applied for 15 min-\nutes each at room temperature. Colour was developed by\nincubation with 3,3-diaminobenzidine-tetrahydrochlo-\nride for 1 min, followed by counterstaining with hematox-\nylin.\nNegative controls included sections incubated with nor-\nmal rabbit serum instead of the primary antibody. In\n\nBMC Cancer 2007, 7:103 http://www.biomedcen tral.com/1471-2407/7/103\nPage 3 of 6\n(page number not for citation purposes)\naddition, an immunoabsorption test was done as follows:\na complex of 1 μl of anti-aromatase antibody and 1.5 μl of\nmicrosome (at a concentration of 4 μg/μl), extracted from\nplacental tissue, was stirred in phosphate buffer saline\ncontaining 1% bovine serum albumin for 12 hours at\n4°C, and the resulting precipitate was then centrifuged\n(10,000 g for 1 hour). Instead of the primary antibody,\nthe supernatant was used for immunostaining.\nPathological findings\nOn gross examination, the uterus measured 7 × 4 × 9 cm\nand the right ovary measured 3 cm. On cut section, the\nmyometrium of the fundus presented a subserosal\nwhorled leiomyomatous nodule which measured 5 cm,\nwas well circumscribed, solid and surrounded by gelati-\nnous foci. The endometrium appeared thinned with no\nsuperficial irregularities. It was totally examined, and only\natrophic-cystic changes with focal proliferative activity\nwere seen. There were several adenomyotic foci in the\ninner half of the myometrium, while some others, in the\nouter half, were pushed out by the leiomyoma and were\nlocated proximally to the serosa and parametrium. A clus-\nter of these glands harboured a focal malignant transfor-\nmation of the epithelial component, diagnosed as\nmoderately differentiated endometrioid adenocarcinoma\nmeasuring 0,8 cm (Figures 1A and 1B) associated with\natypical hyperplasia. The tumor was considered invasive\nbecause of the presence of solid areas with the confluence\nof neoplastic glands uninterrupted by stroma.\nThe enlarged iliac lymph nodes, detected 4 months after\nsurgery, were biopsied by fine-needle aspiration during a\nsecond-look procedure, and were diagnosed as metastatic\nadenocarcinoma (Figure 1C).\nImmunohistochemically, the primary tumor displayed\nstrong positivity for ER, PR, COX-2, CA125 and focal pos-\nitivity for p53 and aromatase (Figures 2A–F). The leiomy-\noma was positive for ER, PR, weakly positive for COX-2\nand negative for p53 and CA125. The primary tumor was\nnegative for C-erb B2. In both the eutopic and ectopic\nendometrial glands, the positivity for PR was diffuse,\nwhereas an alternation of positive and negative foci were\nnoted for ER, aromatase and p53 (Figures 3A–D). In par-\nticular, we noted a tendency of the endometrial glands to\nbe negative for ER in the atrophic areas and positive in the\nproliferative component (Figure 3A). The cell block cytol-\nogy of the lymph node metastasis was positive for Cytok-\neratins AE1/AE3, ER, PR, CA125, p53 and COX-2 (Figure\n1D, only CA125 shown).\nConclusion\nThe case that we present is a single, small, moderately dif-\nferentiated endometrioid adenocarcinoma which devel-\noped into adenomyosis with subsequent metastatic\nspread to the iliac lymph nodes. The primary tumor was\npositive for ER, PR, COX-2, CA125, p53 and focally weak-\npositive for aromatase. Malignant transformation of ade-\nnomyotic foci is per se a rare event, but the development\nof metastatic lymph nodal deposits from a very small pri-\nmary adenomyotic adenocarcinoma is quite exceptional.\nThe diagnosis of malignant tumors in adenomyosis is\nusually made in an advanced stage of disease when the\nneoplasm has grown in nodules within the uterine wall or\nhas involved the endometrium causing abnormal uterine\nbleeding and/or has spread out of the uterus [5,7-9,12].\nIn 1925, Sampson introduced the histological criteria to\ndefine an adenocarcinoma arising in external endometri-\nosis, which can be adapted to adenomyosis [3].\nIn the literature, the clinico-pathological findings of 8\ncases of adenocarcinoma arising in adenomyosis were\npresented by Hernandez and Woodruff in 1980, but these\nwere all associated with endometrial adenocarcinomas.\nThey also evaluated 16 cases previously reported by other\nauthors in the literature, and found that only 8 of these\nwere not associated with endometrial adenocarcinomas\n[5]. In the few cases described as small or microscopic\ntumors, the pathology report did not include the number\nor the diameter of the largest tumor, mentioning only that\nthe inner or the outer part of the uterine wall was involved\n[5,11].\nIt is well known that gynaecological malignancies, includ-\ning breast, ovarian and uterine carcinomas, are influenced\n(A) The tumor arises from the confluence of transformed fociFigure 1\n(A) The tumor arises from the confluence of transformed \nfoci. (B) Higher power magnification of the tumor. (C) Cell \nblock cytology of the lymph node metastasis. (D) Immunocy-\ntochemical staining of the metastasis for CA125.\n\n\nBMC Cancer 2007, 7:103 http://www.biomedcen tral.com/1471-2407/7/103\nPage 4 of 6\n(page number not for citation purposes)\nby hormonal stimulation. In the uterus, a peculiar hormo-\nnal microenvironment may explain different pathologic\nconditions, both benign and malignant. The complex\ninter-relationships between adenomyosis, endometriosis,\nleiomyomata, endometrial hyperplasia and carcinoma\narising in the endometrium or in adenomyosis have been\nillustrated together with their hormonal dependency\n[1,2,13], and factors like obesity and hormonal replace-\nment therapy have been considered as relevant risk factors\n[13,14].\nIn postmenopausal women, estrogen formation is\nensured by extraglandular tissues, namely adipose tissue\nand skin. Endometriosis and leiomyomas constitute two\nadded sources of aberrant estrogen biosynthesis, prima-\nrily by aromatase enzymatic activity, promoting their self-\nstimulation [15,16]. Aromatase detection has already\nbeen proposed as a test for endometriosis in endometrial\nbiopsies because aromatase cytochrome P450 is expressed\nin the eutopic endometrium of patients with endometrio-\nsis but not in those of disease-free women [17].\nIn endometriosis, aromatase activity is stimulated by\nprostaglandin E(2) wich, in turn, is up-regulated by\nincreased levels of the enzyme cyclo-oxygenase-2 (COX-\n2) [18].\nFinally, besides aberrant aromatase expression, a local\nestrogen overproduction in endometriosis may also be a\nresult of a deficiency of 17 β-hydroxysteroid dehydroge-\nnase, resulting in failure to metabolize 17β-Estradiol [19].\nIn three studies, adenocarcinomas in adenomyosis were\nreported as all negative for ER and fairly negative for PR\n[6,9,12]. The reported cases in these small series were\nrather advanced. Therefore, the hormone receptor and C-\nerb B2 status in our case of moderately differentiated ade-\nnocarcinoma is indicative of early tumor development,\nsimilar to that observed in correspondent neoplasms\narisen in the eutopic endometrium where hormonal\nreceptor positivity and C-erb B2 negativity are most often\nassociated with low grade and early-stage tumors [20,21].\nA peculiar observation in our case is the alternation of\npositive and negative areas for ER, aromatase and COX-2\nin both the normal and the pathological tissues, including\nthe endometrium and the adenomyotic foci. This heterog-\nenous, \"checker-board-like\" expression of steroid recep-\ntors and enzymes involved in steroidogenesis suggests\n(A) Diffuse strong positivity for ER of the tumorFigure 2\n(A) Diffuse strong positivity for ER of the tumor. (B) Patchy positivity for PR of the tumor. (C) Aromatase positivity of benign \nadenomyotic foci (arrows). Most neoplastic cells are negative for aromatase (asterisk) except for some glands (insert). (D) \nCOX-2 positivity of the tumor and adenomyosis. (E) CA125 positivity of the tumor and of the adenomyotic epithelium. (F) \nFocal positivity for p53 of the tumor.\n\n\nBMC Cancer 2007, 7:103 http://www.biomedcen tral.com/1471-2407/7/103\nPage 5 of 6\n(page number not for citation purposes)\nfirstly that there are different fields of hormonal respon-\nsiveness, and secondly, that the endometriosis derives\nfrom, and is in phase with, the endometrium [22].\nCOX-2 overexpression has been described in ectopic\nendometriosis implants when compared with eutopic\nendometrium [23], in endometrial carcinoma where it is\nassociated with several parameters of tumor aggressive-\nness [24,25], and in endometriosis-associated ovarian car-\ncinoma [26].\nMoreover, COX-2 has been suggested to be involved in\nmultiple steps in endometrial cancer: besides tumor pro-\ngression, the enzyme has been implicated in the earlier\nphases of neoplastic transformation, in endometrial\nhyperplasia [27] and in endometrial carcinomas arising in\nendometrial polyps [28].\nAccordingly, we found an enhanced positivity for COX-2\nboth in the tumor and in the neighbouring adenomyotic\nfoci, when compared to the distant adenomyosis and the\nendometrium.\nP53 has been showed to be expressed in endometrial car-\ncinoma with and without adenomyosis [29], in other\ncases of adenocarcinoma arising from uterine adenomyo-\nsis without endometrial malignancy [6,9], but also in\nhyperplastic and atypical epithelia of carcinoma-associ-\nated adenomyosis [29] and in endometrial carcinoma\nwithout myometrial invasion [30]. Therefore, an early\ninvolvement of p53 in endometrial carcinoma and in the\nmalignant transformation of adenomyosis has been sug-\ngested [29, 30]. In the case we present here, p53 positivity\nwas observed in the benign adenomyotic glands, in the\natypical hyperplasia and in the neoplasm itself, lending\nsupport to the proposed model of carcinogenesis in aden-\nomyosis.\nOur case is quite peculiar for the early metastatic spread to\nthe iliac lymph nodes, confirmed by cytological fine-nee-\ndle aspiration performed during the second-look surgical\ninspection and by an extensive clinical work-up to exclude\nother sites of primaries. The origin of the metastasis from\nadenocarcinoma in adenomyosis was also confirmed by\nits immunocytochemical profile. A possible explanation\nfor such early metastatic spreading is that this tumor arose\nin the outer myometrium, near to the richly vascularized\nparametrium.\nIn conclusion, considering that no evidence of systemic\nexogenous or endogenous hyperestrogenism are on\nrecord in our case, it is arguable that the presence of a lei-\nomyoma, close to a pool of adenomyotic foci, along with\nthe overexpression of estrogen receptors and enzymes\ninvolved in steroidogenesis, represent a hyperestrogenic\nmicroenvironment with converging sources of estrogen\nbiosynthesis. Therefore, the same local estrogen excess,\nbesides sustaining adenomyosis and leiomyoma persist-\nence, may also promote growth in tumors having ade-\nquate ER/PR expression. This local hormonal\noverproduction most likely interacts with other events,\nsuch as p53 mutations and COX-2 increased activity, in\nthe pathogenesis of adenocarcinoma in adenomyosis.\nAbbreviations\nER: estrogen receptors; PR: progesterone receptors.\nCompeting interests\nThe author(s) declare that they have no competing inter-\nests.\nAuthors' contributions\nGP conceived and coordinated the study and drafted the\nmanuscript. MS was responsible for the immunohisto-\nchemical staining with aromatase and revised the manu-\nscript for important intellectual content. TP was\nresponsible for the sampling of the surgical specimen. KN\nwas responsible for the immunohistochemical staining\nwith aromatase. AG was responsible for the immunohis-\ntochemical staining with ER, PR, C-erb B2 and COX-2. EC\nwas responsible for performeance of all the surgical inter-\nventions. VC participated in the coordination of the study\nand revised the manuscript for important intellectual con-\ntent. All the authors approved the final manuscript.\n(A) The atrophic and proliferative component in the endometrium, respectively negative and positive for ERFigure 3\n(A) The atrophic and proliferative component in the \nendometrium, respectively negative and positive for ER. (B) \nAromatase positivity in the superficial layer of a part of the \nendometrium. (C) The adenomyotic glands throughout the \nuterus: aromatase expressed by some glands (left), whereas \nother glands are negative (right) (D) p53 positivity in some \nadenomyotic glands.\n\n\nPublish with BioMed Central   and  every \nscientist can read your work free of charge\n\"BioMed Central will be the most significant development for \ndisseminating the results of biomedical research in our lifetime.\"\nSir Paul Nurse, Cancer Research UK\nYour research papers will be:\navailable free of charge to the entire biomedical community\npeer reviewed and published immediately upon acceptance\ncited in PubMed and archived on PubMed Central \nyours — you keep the copyright\nSubmit your manuscript here:\nhttp://www.biomedcentral.com/info/publishing_adv.asp\nBioMedcentral\nBMC Cancer 2007, 7:103 http://www.biomedcen tral.com/1471-2407/7/103\nPage 6 of 6\n(page number not for citation purposes)\nAcknowledgements\nThe authors gratefully thank Mrs. Anna Maria Colussi for her assistance \nwith the editing of the text.\nWritten consent was obtained from the patient for publication of the study.\nReferences\n1. 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Koshiyama M, Konishi I, Wang DP, Mandai M, Komatsu T, Yamamoto\nS, Nanbu K, Naito MF, Mori T: Immunohistochemical analysis of\np53 protein over-expression in endometrial carcinomas:\ninverse correlation with sex steroid receptor status.  Virchows\nArch A Pathol Anat Histopathol 1993, 423:265-271.\nPre-publication history\nThe pre-publication history for this paper can be accessed\nhere:\nhttp://www.biomedcentral.com/1471-2407/7/103/pre\npub","source_license":"CC0","license_restricted":false}