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Vasitis nodosa involves benign, reactive spindle-shaped nodular thickening of the ductal epithelium of vas deferens. We report the case of a 21-year-old male with a history of bilateral undescended testes and left orchidopexy. The patient presented with the complaint of a non-tender left inguinal swelling. The definitive diagnosis of vasitis nodosa was made based on clinical evaluation and imaging findings. We suggest that this rare entity should be considered as a differential diagnosis of inguinal swelling during the assessment of the male urogenital system.

Cholangiocarcinoma is a rare but lethal malignancy arising anywhere along the biliary ductal epithelium from the liver to the duodenum. The disease is classified based on anatomic location, and the mainstay of treatment is surgery. Complete resection is currently the only chance for cure despite significant advances in systemic and other nonsurgical therapies. In this chapter, we present a detailed evaluation of the anatomic classification of cholangiocarcinoma and preoperative evaluation, defining resectability, types of resections, and postoperative outcomes. Special attention is given to advances in the field and the future of surgery in the multidisciplinary management of cholangiocarcinoma.

Background: To investigate prostatic eosinophilic metaplasia (EM) in a large series of cases and their relationship with the basic prostate pathology in TURP-material: benign prostatic hyperplasia (BPH), National Institutes of Health category IV prostatitis (also called histologic prostatitis or HP), and prostatic adenocarcinoma (PCa). Aim: The relation between EM and basic prostate pathology: BPH, PCa, and HP. Materials and Methods: Around 61 consecutive TURP-specimens were reviewed for the presence of EM. The tissue sections were stained routinely with hematoxylin-eosin (HE), hematoxylin-phloxine-saffron (HPS), and periodic acid-Schiff's procedure. Simultaneously BPH, HP, and PCa were evaluated. Results: We found EM in 55.7% of TURP-specimens. EM is located more often in the ductal epithelium (58.8%) and is usually focal (73.5%) and in small groups (88.2%) of secretory luminal cells. They are associated with BPH and with a variable degree of HP in all cases. However, there is no association with PCa. Eosinophilic cytoplasmic granules in EM are better visualized with HPS. Zones induced by tissue electrocoagulation which mimic EM, are seen in the periphery of TURP-fragments. Conclusion: EM in prostate is presented by the presence of eosinophilic cytoplasmic granules in benign secretory epithelium. The study presents the first attempt to investigate EM in a large series of patients. Our results enrich the available information about the histoepidemiology of prostatic EM. Moreover, EM is more common in a focal lesion, found in small groups of ductal secretory epithelial cells while EM in TURP-specimens is associated with BPH and HP in all the cases.

Papillary lesions of the breast encompass a wide spectrum of benign and malignant lesions that arise from the ductal epithelium. These lesions comprise less than 10% of benign breast lesions, less than 2% of breast cancers, and less than 5% of all breast biopsies.1 It may be challenging to diagnose

Morphology plays an important role in the distinction of autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC). However, we aimed to determine the utility of immunohistochemical tumor markers to contribute in the distinction of these entities. In surgical specimens with AIP (n = 20), PDAC (n = 20) and normal pancreas (n = 20), the expression of pVHL, maspin, IMP3, S100P and Ki67 was examined. We evaluated intralobular reactive ducts / acinoductal metaplasia (ILDs) and extralobular ducts (ELDs) in AIP, neoplastic glands in PDAC, and ductal epithelium in the normal pancreas, using a five-tiered scoring system. The Ki67 hot spot index (Ki67-HSPI) was determined manually and using automated digital imaging analysis of virtual double stains of Ki67 and CK8. Besides, sequential dual-immunohistochemical staining of maspin/pVHL, maspin/IMP3 and Ki67/maspin was performed in a subset of the specimens. Strong overexpression of IMP3, maspin, S100P and Ki67 and loss of pVHL was observed in PDAC compared to AIP and normal pancreas. In AIP however, focal and weak aberrant expression was observed with the following proportions in ILDs/ELDs: pVHL in 45 %/85 %, maspin in 30 %/70 %, IMP3 in 55 %/5%, S100P in 10 %/35 % and Ki67-HSPI >20 % in 15 %/70 %. At least two markers were aberrantly expressed in ILDs/ELDs in 45 %/60 %. The aberrant expression was more pronounced in type 2 AIP compared to type 1. In conclusion, our data indicate that pVHL, maspin, IMP3, S100P and Ki67 can be focal and weak aberrantly expressed in AIP. However, when used as a panel, these markers seem to be useful for the differentiation of AIP from PC.

Background Sialadenoma papilliferum is a benign rare condition of salivary glands showing a characteristic papillary growth of the ductal epithelium that ends up being confused with more frequent lesions of the oral cavity. Objectives: To perform a bibliometric analysis of all articles about Sialadenoma papilliferum in the oral cavity and to add a singular case report of Sialadenoma in the lower lip. Material and methods A total of 36 publications referring to Sialadenoma papilliferum in the oral cavity from the PubMed platform was reviewed. The specific data were collected, and a bibliometric analysis was performed using Microsoft Excel. The results obtained were then compared with this new case report. Results The people most affected with sialadenoma were white males at the average age of 56. The lesion was asymptomatic, usually white or red, with an average size of 1.4 cm, and the palate was by far the most affected site. The majority of the lesions were excised, and only two cases indicated recurrence. Conclusions With surgical removal, Sialadenoma papilliferum has a favorable prognosis and no further treatment is required. Due to few recorded cases of recurrence, a long follow-up period is recommended to ensure that the lesion does not redevelop. Key words:Sialadenoma papilliferum, salivary gland, oral cavity, bibliometric analysis.

Background Cysts of the salivary glands are common lesions that occur in the context of various etiologies. Although the diagnostic importance of cysts in salivary gland diseases has been well studied, molecular mechanisms that control the related pathological process remain largely unknown. IL-34 is a novel cytokine that was discovered recently as a tissue-specific ligand of colony stimulating factor-1 receptor. Since its discovery, accumulating evidence has revealed emerging roles of IL-34 in various pathological conditions and has been suggested to correlate remarkably with inflammation. In this study, we report a medical case of an inflammatory cyst within the submandibular gland, through which evaluating the possible involvement of IL-34 in salivary gland disorders. Case presentation A 37-year-old male patient suffered from a sudden swelling in the right submandibular region, started initially small and had gradually increased in size to reach 3–4 cm in 1 week, accompanied by pain and local fever. Ultrasonography and MRI imaging revealed the existence of a well-defined cystic lesion with sharp borders measuring 39.8 mm × 19.7 mm within the right submandibular gland. The cyst was removed surgically, and the diagnostic decision was determined based on histopathological observations as an inflammatory cyst in the submandibular gland. Sections were generated from different regions of the surgically resected inflammatory cyst and used to examine IL-34 expression by immunohistochemistry compared to normal salivary gland tissues. Immunohistochemical staining showed enhanced expression of IL-34 in the ductal epithelial cells and endothelial cells of blood vessels, with a tendency to be accompanied with high infiltration of immune cells, which suggests a possible involvement of IL-34 in the pathogenesis of salivary gland inflammation. Conclusions In this report, we introduce interesting findings of enhanced IL-34 expression in a case of an inflamed submandibular gland. Our findings emphasize the pathological roles of IL-34 as an inflammation amplifier and angiogenic enhancer in inflammatory conditions, such as in salivary gland disorders. Electronic supplementary material The online version of this article (10.1186/s41232-018-0069-6) contains supplementary material, which is available to authorized users.

Case summary Mammary fibroadenomatous hyperplasia (MFH) is a benign pathology characterised by extensive proliferation of the ductal epithelium and mammary stroma. It typically occurs in young female cats, and seems to result from hypersensitivity to progesterone. A 2-year-old entire male European Shorthair cat presented to the veterinary clinic with enlargement of several mammary glands, which had developed within the previous 10 days. There was no prior administration of progestin in the cat’s medical history. Diagnostic tests were performed to assess the basal progesterone concentration and the concentration after stimulation with gonadotropin-releasing hormone, which ruled out the presence of functional ovarian tissue. Histological examination of the testes excluded hormone-secreting testicular tumours. Histological examination of the mammary gland confirmed the diagnosis of MFH. Treatment was started with aglepristone, a selective competitor for progesterone receptors, administered subcutaneously at 15 mg/kg at days 1, 2, 8 and 15. A reduction in the size of the mammary glands was evident 6 days after the first administration, with complete remission observed after 4 weeks. Relevance and novel information To the best of our knowledge, this is the first full report of MFH in a male cat. Although the origin of the progestins responsible for MFH in this case could not be confirmed, in the light of the diagnostic tests performed and the results obtained, accidental contact with hormone-like substances seems to be the only plausible explanation for the cat’s clinical signs. Inhibitor therapy was successful.

Background. The majority of the benign and malignant lesions in the breast arise from the ductal epithelium and terminal ductlobular unit. A minimally invasive procedure called ductoscopy is able to visualize these lesions as it inspects the ductal epithelium using a small micro-endoscope. Unfortunately, it is currently challenging to obtain a tissue sample during ductoscopy and reach the most distal duct. Methods. In this study we have, therefore, developed a novel miniature (∅1.2 mm) biopsy needle that can be used during ductoscopy. This biopsy needle consists of two coaxial counter-rotating hollow blades with a distal cutout to resect lesions from the ductal wall. Three cutouts were manufactured resulting in a beveled, straight, and reverse-beveled blade. The blades were actuated using a novel mechanism containing two helical paths that allows for the counter-rotating motion of the blades at different velocities. In a proof-of-principle experiment, the performance of the biopsy needle was evaluated using a polymeric duct model and gelatin tissue phantom. Results. During the experiment, the straight and reverse-beveled blades were able to obtain a sufficiently large tissue sample for histopathological examination. Based on these promising results, a second experiment was performed in which the micro-endoscope was integrated in the needle and we were able to take a biopsy from a chicken breast. Conclusions. In a future clinical instrument, the biopsy needle will be miniaturized and optimized to allow for an efficient, safe, and effective intraductal biopsy procedure without the need for an invasive excisional biopsy procedure.

Breast diseases are combined with the pathology of other organs in 77% of cases. The primary multiplicity of tumors is now defined as the independent occurrence and development of two or more neoplasms in the body of one patient. In this case, not only different organs of different systems but also paired organs (mammary glands, lungs, etc.) can be affected. Multicentric lesions of one organ can occur as well. Combination of two tumors predominates in the structure of polyneoplasias. The cases of triple localization occur in 5–8% of cases. The risk of developing tumors in patients already having neoplasms is approximately 1.3 times higher than in those who did not previously have neoplasms. The risk of breast cancer depends on the intensity of the proliferation of the lobular and/or ductal epithelium and increases by 3–5 times at preexisting benign breast diseases, especially in combination with diseases of reproductive organs. Metastatic lesions in mammary glands can occur in cases of primary tumors of various localizations. These cases are rare and are often associated with poor prognosis.

Solid papillary carcinoma of breast is a low-grade tumour originating in the ductal epithelium. It is commonly seen in post-menopausal women and account for

We have developed an efficient simulation of breast anatomy over a range of spatial scales, covering tissue details seen in both radiology and pathology images. The simulation is based on recursive partitioning using octrees, and is performed in two stages. First, the macro- and meso-scale anatomical features are simulated: breast outline, skin, and the matrix of tissue compartments and subcompartments, outlined by Cooper's ligaments. These compartments are labeled as adipose or fibroglandular, according to the desired overall glandularity and the realistic distribution of dense tissue. Second, pathology images are generated to match selected region within the breast, by filling the region with simulated cells adipocytes, ductal epithelium and myoepithelium, lymphocytes, and fibroblasts and collagen fibers. Matched synthetic images can support discovery and virtual trials of image-based biomarkers for specific pathology findings. Our proof-of-concept is presented and further optimizations of the simulation discussed.

Gynecomastia is the most common abnormality in the male breast and has been associated with male breast cancer, but whether there is an etiological role remains unknown. In the present study we conducted an immunohistochemical investigation to further characterize gynecomastia. A total of 46 cases of gynecomastia were immunohistochemically stained on tissue microarrays for estrogen receptor (ER), progesterone receptor, HER2, androgen receptor, cytokeratins (CK5, CK14, CK7, and CK8/18), p63, E-cadherin, BRST2, cyclin D1, Bcl-2, p53, p16, p21, and Ki67. In addition, 8 cases of male ductal carcinoma in situ and normal breast tissue obtained from autopsies (n=10) and adjacent to male breast cancer (n=5) were studied. Normal ductal male breast epithelial cells were very often ER and Bcl-2 positive (69%), and progesterone receptor and androgen receptor expression was also common (39%). Gynecomastia showed a consistent 3-layered pattern: 1 myoepithelial and 2 epithelial cell layers with a distinctive immunohistochemical staining pattern. The intermediate luminal layer, consisting of vertically oriented cuboidal-to-columnar cells, is hormone receptor positive and expresses Bcl-2 and cyclin D1. The inner luminal layer is composed of smaller cells expressing CK5 and often CK14 but is usually negative for hormone receptors and Bcl-2. Male ductal carcinoma in situ was consistently ER positive and CK5/CK14 negative. In conclusion, for the first time we describe the 3-layered ductal epithelium in gynecomastia, which has a distinctive immunohistochemical profile. These results indicate that different cellular compartments exist in gynecomastia, and therefore gynecomastia does not seem to be an obligate precursor lesion of male breast cancer.

Sclerosing polycystic adenosis (SPA) was first described in 1996 by Smith et al. and was characterized by resemblance to epithelial proliferative lesions of the breast such as fibrocystic disease and sclerosing adenosis. Etiopathogenetically, it is generally believed to represent a nonneoplastic sclerosing and inflammatory process. The age range is broad (typically fourth decade), with a slight female predilection. The vast majority are parotid lesions, with very few in minor salivary glands. As of 2017, not more than 60 cases have been reported worldwide. Microscopically, it is characterized by a well-circumscribed to partially circumscribed tubulocystic proliferation of a gland within a sclerotic-fibrous stroma. Ductal epithelium showing variations such as foamy, mucous and apocrine are seen. We report a case of SPA of lower lip in a 70-year-old male.

Obstructive dysfunction of the meibomian glands (MGD) is surprisingly frequent in the general population and increases with age. Clinically, the focus is mainly on the consequences at the ocular surface in the sense of an evaporative dry eye syndrome. However, in addition, chronic obstruction of the meibomian glands also leads to degeneration of the secretory gland tissue which can result in a secondary hyposecretion even if the primary obstruction is later resolved by therapeutic approaches.Important influencing factors in the pathogenesis of obstructive MGDs and their interaction during the progression of the disease are systematically analyzed and displayed in a flow diagram. Age, hormonal disturbances and environmental influences, such as contact lenses, as well as qualitative alterations in the composition of the meibomian oil (meibum) lead to hyperkeratinization of the ductal epithelium and increased viscosity of the meibum which result, either alone or in combination, in obstruction of the duct and orifice. This leads to a lack of meibum on the lid margin and tear film with downstream hyperevaporative dry eye syndrome. At the same time, obstruction leads to a stasis of meibum inside the meibomian gland with increased pressure and resulting dilatation of the ducts and in atrophy of the acini with rarefaction of the secretory meibocytes and gland dropout. Stasis can also increase the growth of commensal bacteria, their production of oil degrading enzymes (lipases) and release of toxic mediators. These factors can, in return, act as self-enforcing feedback loops in the sense of vicious circles that aggravate the primary hyperkeratinization and compositional disturbance of meibum and can hence lead to a progressive MGD.

We previously demonstrated that Fibroblast Growth Factor 10 (FGF10) and its receptor FGFR2b play a key role in controlling the very early stages of mammary gland development during embryogenesis [Mailleux, A.A., Spencer-Dene, B., Dillon, C., Ndiaye, D., Savona-Baron, C., Itoh, N., Kato, S., Dickson, C., Thiery, J.P., and Bellusci, S. (2002). Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 129, 53–60. Veltmaat, J. M., Relaix, F., Le, L.T., Kratochwil, K., Sala, F.G., van Veelen, W., Rice, R., Spencer-Dene, B., Mailleux, A.A., Rice, D.P., Thiery, J.P., and Bellusci, S. (2006). Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 133, 2325–35.]. However, the role of FGFR2b signaling in postnatal mammary gland development is still elusive. We show that FGF10 is expressed at high level throughout the adipose tissue in the mammary gland of young virgin female mice whereas its main receptor FGFR2 is found mostly in the epithelium. Using a rtTA transactivator/tetracycline promoter approach allowing inducible and reversible attenuation of the FGFR2b signaling throughout the adult mouse, we are now reporting that FGFR2b signaling is also critical during postnatal mammary gland development. Ubiquitous attenuation of FGFR2b signaling in the postnatal mouse for 6 weeks starting immediately after birth is not lethal and leads to minor defects in the animal. Upon dissection of the mammary glands, a 40% reduction in size compared to the WT control is observed. Further examination shows a rudimentary mammary epithelial tree with completely absent terminal end buds (TEBs), compared to a well-branched structure observed in wild type. Transplantation of mammary gland explants into cleared fat pad of wild type mouse recipients indicates that the observed abnormal branching results from defective FGFR2b signaling in the epithelium. We also demonstrate that this rudimentary tree reforms TEBs and resumes branching upon removal of doxycycline suggesting that the regenerative capacities of the mammary epithelial progenitor cells were still functional despite long-term inactivation of the FGFR2b pathway. At the cellular level, upon FGFR2b attenuation, we show an increase in apoptosis associated with a decrease in the proliferation of the mammary luminal epithelium. We conclude that during puberty, there is a differential requirement for FGFR2b signaling in ductal vs. TEBs epithelium. FGFR2b signaling is crucial for the survival and proliferation of the mammary luminal epithelial cells, but does not affect the regenerative potential of the mammary epithelial progenitor cells.

Intraductal papillomas (IP) are benign papillary lesions caused by proliferation of mammary ductal epithelium. IP occurs in the breast tissue. Prolapse of IP from nipple can be rarely seen. IPs are generally treated with total excision. A 31-year-old female patient was admitted to our clinic because of a protruded lesion from the nipple of her right breast. On her breast examination, an 8 mm- prolapsed mass was seen on the areola of her right breast. Breast ultrasonography showed no other lesions in the breast. The patient was operated with initial diagnosis of IP. The prolapsed mass, the overlying nipple skin and related ductus were totally excised under local anesthesia. Histopathological examination of the specimen revealed intraductal papilloma without atypical dysplasia. Herein, we are presenting a rarely encountered case of IP prolapsed from the nipple of a female patient.

A number of findings suggest that cyclooxygenase-2 (COX-2) is overexpressed in breast tumours. However, there is a lack of consensus in the literature regarding the pattern of expression of this protein in invasive breast ductal carcinoma and in the adjacent non-tumour ductal epithelium. This study compares the expression of COX-2 mRNA and protein in breast ductal carcinoma relative to non-tumour breast tissue. We analysed the expression of COX-2 mRNA by quantitative PCR, and COX-2 protein by immunohistochemistry in invasive ductal carcinoma as well as in non-tumour adjacent ductal epithelium from 54 breast biopsies diagnosed as being invasive ductal carcinoma. As control, we analysed expression of COX-2 protein by immunohistochemistry in surgically-resected benign breast lesions. Our results show that COX-2 mRNA and protein are overexpressed in non-tumour ductal epithelium compared with invasive ductal carcinoma. However, the pattern of the protein expression is different in tumour and non-tumour tissue: COX-2 protein is expressed predominantly in the membrane of the non-tumour ductal epithelium (including in benign breast lesions) while, in invasive ductal carcinoma cells, it is localised in the cytoplasm. The non-tumour ductal epithelium adjacent to invasive ductal carcinoma shows a higher COX-2 expression than does the invasive ductal carcinoma. However, the different localisation of the immunohistochemically-detected protein suggests a possible post-translational regulation of the protein.

We report a rare case of a papillary cystadenoma arising from the upper lip. This tumor was not distinctly encapsulated and had proliferated replacing the ductal epithelium. Mast cells were found not only in the stroma but also in the oncocytic epithelial layer. There was a strong immunoreaction with mitochondrial antibody in the epithelial layer. Only one case (0.9%) of papillary cystadenoma has occurred among the 110 benign intraoral salivary gland tumors seen in our hospital from 1966 through September 2003.

Two related techniques of breast epithelial sampling have emerged in the past several years: ductal lavage, in which fluid-yielding nipple ducts are cannulated at their orifices and lavaged with saline while the breast is intermittently massaged; and ductoscopy, in which discharging or fluid-yielding duct orifices are dilated, intubated with a microendoscope, and the lumen directly visualized. Both of these techniques have significant potential in terms of allowing the repeated sampling of ductal epithelium over time and, as such, have generated considerable enthusiasm. However, data regarding the impact of these techniques on the detection of significant breast disease is very scant. It is important at the outset of the assessment of this new technology that breast cancer clinicians and clinical researchers think carefully about the standards of evidence that need to be met regarding the benefits of these procedures before they are widely adopted. In this review of the rationale and early results of these procedures, we attempt to define some of these evidentiary requirements.

Changes in bile ducts in cholestasis are characterized by activation of proliferation and hypertrophy of cholangiocytes and degenerative and necrobiotic changes in ductal epithelium. Long-term cholestasis led to massive necrosis of cholangiocytes. Inflammatory changes in the choledochal mucosa were most pronounced in patients with choledocholithiasis.

300 Background: Ampullary adenocarcinoma (AA) is a rare entity. AA can originate from either intestinal or pancreaticobiliary ductal epithelium, and patients are often managed as those with pancreaticobiliary carcinomas. The study objectives were the genetic profiling of AA and the identification of specific molecular profiles according to these 2 pathological types. Methods: AA patients included in the AGEO retrospective multicenter cohort who underwent surgical resection of their tumor between 1999 and 2010 were selected. Formalin-fixed, paraffin-embedded (FFPE) archival tissue blocks were collected. Next generation sequencing (NGS) using a 50 gene panel (Ion AmpliSeq Cancer panel) on tumor DNA, and immunohistochemistry (IHC) panel including CK7, CK20, MUC1, MUC2 and CDX2, on tumor sections, were performed. Results: NGS was performed on 101 tumors from 6 hospitals, with 1 technical failure. In total, the most frequent gene mutations were: KRAS (45%), TP53 (40%), APC (15%), PIK3CA (12%), SMAD4 (9%), BRAF (8%), CDKN2A (6%). No mutation was found in 21% of tumors. According to IHC, the most common histological type was intestinal (51%), followed by pancreaticobiliary type (42%) and undetermined (7%). BRAF mutation was significantly associated with intestinal type (8 vs 0, p = 0.017). According to Cosmic database, similarities of molecular profiles exist between AA with intestinal type and colorectal adenocarcinoma, and between AA with pancreaticobiliary type and pancreas adenocarcinoma, respectively. Conclusions: This study shows that AA is a heterogeneous entity and that a large proportion of AA presents a molecular profile that is more similar to that of colorectal adenocarcinoma, compared to pancreatic adenocarcinoma. This important information could be interesting to guide treatment decision in patients with this rare disease.

George F. Laidlaw first described a pancreatic abnormality now known to be the most common cause of persistent hyperinsulinemic hypoglycemia in infants in 1938 (1, 2). The term he coined, nesidioblastosis, is derived from the Greek words for “islets” (nesidia) and “germ” (blastos) (3). It accurately describes the characteristic feature of nesidioblastosis, islet cells differentiating and budding from ductal epithelium. In adults, hyperinsulinemic hypoglycemia is rarely caused by nesidioblastosis and is usually caused by insulinoma or exogenous insulin treatment (4, 5). The first case series of adult nesidioblastosis was reported by Harness et al in 1981 (6). Since this case series of six patients, there have been only sporadic literature reports of adult nesidioblastosis, documenting fewer than 20 cases of adult nesidioblastosis over the past 15 years (3, 7-10). This paper presents an adult patient with hyperinsulinemic hypoglycemia due to nesidioblastosis and provides a guide to the diagnosis and treatment of this rare disorder in the adult population.

The localization of IgA, IgG, and IgM was investigated immunohistochemically in the mucosal surface of the main excretory duct of the human submandibular gland in order to verify the possible antimicrobial properties of this duct. Only secretory IgA-immunoreactivity was recognized in the epithelial cells of the duct. An intense immunoreactivity was observed in the cytoplasm of some cells and at the luminal surface of most of the cells. Clusters of IgA-positive immuno-competent cells were also recognizable in the subepithelial layers. No reactivity for IgG and IgM was noticed. The results suggest that the ductal epithelium may actively be involved in the release of secretory IgA, which could play a prominent role in the local defense mechanism of the duct.

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90% of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.