{"paper_id":"f6b05b7d-95fa-4447-9c7b-54e9b413107d","body_text":"Scholarly Research In Progress  •  Vol. 5, November 2021\nBattling Trainee Biases and Reconstructing Perceptions in Global Neurology \nPrimary Ectopic Breast Carcinoma of the Vulva: A Case Report\nYoungeun C. Armbuster1† , Paula Ronjon2, Cletus Baidoo3, and Waqarun N. Rashid4\n¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509\n²Hematology and Oncology, Geisinger, Danville, PA 17822\n³Pathology, Geisinger, Danville, PA 17822\n4Obstetrics and Gynecology, Geisinger, Danville, PA 17822\n† Doctor of Medicine Program\nCorrespondence: yarmbuster@som.geisinger.edu\nAbstract\nA 64-year-old woman presented to the Emergency Department \nwith acute vomiting and moderate, sharp, diffused abdominal \npain, and weakness. She reported chronic Bartholin’s cyst for \n1 year, which prompted gynecology consult. Investigations \nhad revealed a primary breast carcinoma of the vulva. \nSurgical excision was performed, and pathology of the mass \ndemonstrated estrogen receptor weakly positive (20%), \nprogesterone receptor negative (<1%), and HER2 oncoprotein \npositive (3+). PET/CT showed metastatic disease involving \nretroperitoneal, bilateral iliac chain and pelvic lymph nodes \nand the left T12 lamina. Mammogram showed no evidence of \ndisease, and all her prior mammograms were negative. Due \nto the lack of standard treatment guidelines, the patient was \nmanaged utilizing the established breast cancer treatment \nguidelines. The purpose of this case report is to highlight the \nrarity of the diagnosis of primary breast carcinoma of the vulva \nand the importance of including this diagnosis in differential \nwhen evaluating patients with mass lesions of the vulva.\nIntroduction\nEctopic breast tissue is a common congenital condition found \nin 2% to 6% of women and 1% to 3% of males, which may \ndevelop along the embryologic mammary lines extending \nbilaterally from the axilla through the breast to the mons pubis \n(1, 2). The term ectopic breast tissue is used for \nboth supernumerary and aberrant breast tissue. \nSupernumerary breasts have nipples, areolae or \nboth with varied composition of glandular tissue, \nwhereas an aberrant or accessory breast tissue \nhas no organized secretory system and does \nnot communicate with the overlying skin. The \nmost common location for the accessory breast \ntissue is the axilla while other uncommon sites \nare infraclavicular, subscapular, epigastric and \nvulva (3). An accessory breast tissue is hormonally \nsensitive and may enlarge in response to pregnancy \nor exogenous hormones, and these tissues \nmay also develop breast pathologies, including \nfibroadenoma, phyllodes tumor, Paget disease, \nand invasive adenocarcinoma (1, 2). Ectopic breast \ncarcinoma is often not detected, or diagnosis is \ndelayed until significant clinical symptoms due \nto lack of screening. We report herein a case of \nprimary ectopic breast carcinoma of the vulva with \ndistant metastasis to bones and lymph nodes in a \npostmenopausal woman.\nCase Presentation\nA 64-year-old obese, postmenopausal woman, gravida 1 para \n1-0-0-1, presented to the Emergency Department with acute \nvomiting and moderate, sharp, diffused abdominal pain, and \nweakness. On physical exam, patient was febrile and tachycardic \nwith diffuse abdominal tenderness. Her complete blood count \nwith differential revealed neutrophilic leukocytosis. Blood \nculture grew group B Streptococcus. Computed tomography \nof abdomen and pelvis revealed several enlarged lymph nodes \nwithin the inguinal regions and iliac chains within the pelvis \nbilaterally (Figure 1). The patient was admitted for evaluation \nand management of her presenting symptoms.\nUpon further investigation of unclear etiology of inguinal \nlymphadenopathy and bacteremia, patient reported chronic \nBartholin’s cyst for 1 year, which prompted gynecology consult. \nExternal examination of genitalia showed 3 cm x 4 cm firm left \nvulvar mass with irregular border superiorly with erythema. \nThere was no fluctuance or drainage. On her hospital stay day \n3, she was taken to the operating room for simple excision of \nvulvar mass for management of sepsis as suspected source of \ninfection. Firm, non-mobile, non-necrotic, 3.5 cm x 4.5 cm vulvar \nmass on left labia majora was excised for biopsy. \nHistopathologic evaluation reveals a 2.7 cm poorly \ndifferentiated infiltrative mass invading subcutaneous tissue, \nepidermis, and dermis with skin ulceration. Deep surgical \nFigure 1. Computed tomography shows several enlarged lymph nodes within the \ninguinal regions and iliac chains within the pelvis bilaterally.\n          49\n\n\nFigure 2. Hematoxylin \nand eosin stain of \nulcerated skin with \ninvasive tumor x20 \nmagnification (left) and \nx200 magnification \n(right).\nFigure 3. CK7 \nimmunostain (top left), \nestrogen receptor \nimmunostain (top \nright), GATA-3 \nimmunostain (bottom \nleft), and GCDFP-15 \nimmunostain (bottom \nright) of invasive tumor \nx40 magnification.\nFigure 4. PET/CT scan \nshows multiple FDG \navid bilateral iliac chain \nand pelvic lymph nodes \n(left) and left T12 \nlamina (right).\nPrimary Ectopic Breast Carcinoma of the Vulva: A Case Report\n50\n\n\nPrimary Ectopic Breast Carcinoma of the Vulva: A Case Report\nmargins were involved, and the mass comprises infiltrative \nsheets and clusters of malignant ductal epithelial cells with \ncomedo-type necrosis. The tumor cells show markedly enlarged \npleomorphic nuclei with vesicular chromatin and a distinct-to-\nprominent nucleoli (Figure 2). Myoepithelial cell layer is absent. \nThe tumor shows the following immunophenotypic profile: \nCK7 and GATA-3 diffuse positivity; GCDFP-15 and estrogen \nreceptor (ER) patchy positivity; BNC5 immunostain confirms \na clonal ductal proliferation with loss of the myoepithelial cell \nlayer; CK20, p40, CK5/6, uroplakin-II, mammaglobin, CD56, \nsynaptophysin, and S100 immunostains are all negative; and \np16 immunostain shows equivocal patchy staining. Therefore, \nusual markers of breast origin (CK7, GATA-3, GCDFP-15, \nand ER) are positive, while usual markers of melanocytic, \nneuroendocrine, and urothelial primaries are negative (Figure \n3). Hence, the diagnosis of a primary ectopic breast carcinoma \nof the vulva, histologic grade 3 (poorly differentiated). The \npathologic staging for this case is a pT1b pNX (for lesions more \nthan 2 cm or any size with stromal invasion more than 1.0 mm, \nconfined to the vulva and/or perineum; and regional lymph \nnodes cannot be assessed). Prognostic markers revealed: ER is \nweakly positive (20%), progesterone receptor (PR) is negative \n(<1%), and HER2 oncoprotein is positive (3+).\nThe tumor cells show the usual profile of an invasive ductal \ncarcinoma of breast origin. Evaluation of receptor protein \nexpression is performed by visual analysis of formalin-fixed \nparaffin-embedded immunostaining of the invasive tumor using \nFDA-cleared antibodies and protocols with estrogen receptor \nprotein (Ventana SP1 antibody), progesterone receptor protein \n(1E2 antibody) and FDA approved HER2 oncoprotein (Ventana \n4B5 antibody). ER protein expression is weakly positive \nwith 20% nuclear positivity and 2+ average intensity score \n(range 0 to 3+). PR protein expression is negative with <1% \nnuclear positivity. Assay external control immunoreactivity is \nappropriate. No internal control was present in the analyzed \ntissue. False negative results may occur when no internal \ncontrol ducts are present in tissue with negative reactivity in \nFigure 5. Mammography from 2019 (top) and 2020 (bottom).\nthe tumor cells. Therefore, the results \nfrom specimens that are negative must be \nevaluated accordingly. HER2 oncoprotein \nexpression is positive with 3+ average \nmembranous intensity.\nPositron emission tomography/computed \ntomography (PET/CT) scan was performed \nwhich showed multiple enlarged \nand fluorodeoxyglucose (FDG) avid \nretroperitoneal, bilateral iliac chain and \npelvic lymph nodes most consistent with \nmetastatic disease. Several indeterminate \nsubcentimeter, mildly FDG avid bilateral \nsubpectoral lymph nodes were visualized \nas well. Hypermetabolic osseous lesion \ninvolving the left T12 lamina is consistent \nwith metastatic disease (Figure 4). There \nis an indeterminate 8 mm left upper lobe \nnodule with no abnormal FDG activity \nseen on CT, likely too small to be seen on \nPET. Mammogram showed no evidence of malignancy (BI-\nRADS Category 1), and past mammography from 2019, 2018, \n2016 and 2014 were all negative (Figure 5). The patient has a \nhistory of hypertension, diabetes mellitus Type 2, dyslipidemia, \niron deficiency anemia, osteoarthritis, rheumatoid arthritis, \nsleep apnea, chronic diarrhea, and nausea. Past surgical history \nincludes Cesarean section, dilation and curettage, fluorescein \nangioscopy, bevacizumab injection, and retina treatment \n(photocoagulation). There is no significant family history  \nof cancer. \nThe patient is being managed by a hematology oncology \nprovider. A biopsy of lymph nodes or bone was requested \nbut was not feasible. Initial treatment options were followed: \nchemotherapy with paclitaxel, trastuzumab and pertuzumab. A \ncycle is every 21 days with close monitoring of heart function. \nEchocardiogram was obtained prior to initiating the treatment \nto assess the baseline cardiac function which was within normal \nlimits. Denosumab is given to prevent skeletal events with the \nplan for restaging every three to four cycles. Following the \ninitiation of the treatment, T axol was changed to Abraxane due \nto allergic reaction, even with oral high dose dexamethasone. \nA cycle is 21 days: 2 weeks on and 1 week off. The patient \nreported severe depression and anxiety, and she was referred \nto palliative care and support group. The patient also reported \na new onset headache, which prompted CT scan of brain which \nwas within normal limits. The patient declined MRI due to \nclaustrophobia. \nDiscussion\nAt the fifth or sixth week of fetal development, an ectodermic \nthickening starts to form the mammary ridges, which extends \nbilaterally from the axilla to the groin along the milk lines. These \nridges are not prominent in the human embryo and disappear \nover the following months, except for small portions that may \npersist in the pectoral region (5, 6). Ectopic breast tissue is \npersistent epidermal thickenings along milk line from axilla to \nperineum or vulva due to clusters of primordial breast cells \nthat fail to involute. Ectopic breast tissue may be combinations \nof breast glandular tissue and nipple, and it occurs in 2% to 6% \n        \n  51\n\nPrimary Ectopic Breast Carcinoma of the Vulva: A Case Report\nof females and 1% to 3% of males. Almost any type of known \nbreast pathology can occur in such ectopic breast tissue, and \nprimary breast carcinoma arising from accessory breast tissue \nhas been reported in 60% to 70% of all forms of ectopic breast \ntumor (4). \nPrimary carcinoma of the ectopic breast is relatively common at \nthe axilla, while primary carcinoma arising from ectopic breast \ntissue in the vulva is extremely rare with an incidence of 4%. \nThe predominant pathology is that of invasive ductal carcinoma, \nhowever, ductal carcinoma in situ, lobular carcinoma, mucinous \nadenocarcinoma, phyllodes tumors, and fibroadenomas have \nalso been reported in ectopic breast tissue (7). Multiple cases of \nthis rare malignancy have been reported in the English-language \nclinical literature; however, ectopic breast carcinoma is difficult \nto diagnose due to the late expression of pathologic symptoms.\nIn the absence of concurrent breast carcinoma, the lesion of \nprimary vulvar origin can be categorized by the following:  a \nmorphologic pattern consistent with breast carcinoma, the \npresence of estrogen and progesterone receptors, and/or \npositivity for common breast cancer markers such as epithelial \nmembrane antigen, carcinoembryonic antigen, and glandular \nkeratins (8). For a diagnosis of this disease, a thorough \nmetastatic workup is necessary including, but not limited to \nhistory, physical examination, and radiologic examination of the \nbreasts, to confirm that the vulvar lesion is the primary site as \nopposed to a metastasis from a primary breast cancer. Although \nprimary breast cancer of the vulva tends to metastasize early \nand to have a poor prognosis, definitive treatment guidelines \nhave been unavailable. Currently, this type of cancer is stage \nand treated according to current tumor, node, metastasis \n(TNM)-based classification applicable to primary breast cancer. \nThe treatment should consist of individualized combination of \nsurgery, chemotherapy, monoclonal antibody therapy, radiation, \nand adjuvant endocrine therapy, as appropriate.\nConclusion\nPrimary breast carcinoma, arising from embryonic mammary \nridge remnants, is an extremely rare histologic subtype of \nvulvar cancer; however, this should be included in differential \ndiagnosis when evaluating patients with mass lesions of \nthe vulva. Obtaining adequate tissue biopsy is essential in \nestablishing a morphologic diagnosis, since diagnosis rests on \nthe pathologic findings, with recognition of the characteristic \nhistologic features and the presence of estrogen, progesterone \nand/or HER2 receptors and the extent of disease. Therapy \nshould consist of an individualized combination of surgery, \nradiotherapy, chemotherapy, antiestrogen therapy, and \nmonoclonal antibody therapy, like cancer of the orthotopic \nbreast of similar stage. Owing to the rarity of this lesion, clinical \ntrials to determine optimum treatment are not available, and \nmanagement guidelines will rely on small series or case studies.\nAcknowledgments\nWe thank the patient for allowing us to share her details and \nthank John S. Farrell, MD, Department of Radiology, Geisinger, \nfor radiologic image acquisition. \nDisclosures\nYoungeun C. Armbuster, Paula Ronjon, Cletus Baidoo,  \nand Waqarun N. Rashid declare that they have no conflict  \nof interest.\nReferences\n1. Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, \nCorton MM, Schaffer JI. Benign Disorders of the Lower \nReproductive Tract. Williams Gynecology, 4e. McGraw-\nHill; [cited 2020 Oct 24]. Available from: https://\naccessmedicine-mhmedical-com.gcsom.idm.oclc.org/\ncontent.aspx?bookid=2658&sectionid=219458833\n2. Patel PP , Ibrahim AM, Zhang J, Nguyen JT, Lin SJ, Lee BT. \nAccessory breast tissue. Eplasty. 2012;12:ic5.\n3. Husain M, Khan S, Bhat A, Hajini F. Accessory breast \ntissue mimicking pedunculated lipoma. BMJ Case Rep. \n2014;2014:bcr2014204990. Published 2014 Jul 8. \ndoi:10.1136/bcr-2014-204990\n4. Lee J, Jung JH, Kim WW, et al. Ductal carcinoma arising \nfrom ectopic breast tissue following microcalcification \nobserved on screening mammography: a case report and \nreview of the literature. J Breast Cancer. 2014;17(4):393-\n396. doi:10.4048/jbc.2014.17.4.393\n5. C. 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