Prognostic Role of Prolactin-Induced Protein (PIP) in Breast Cancer.

Prolactin-inducible protein (PIP), also referred to as gross cystic disease fluid protein 15 (GCDFP-15), has been a trending topic in recent years due to its potential role as a specific marker in breast cancer. PIP binds to aquaporin-5 (AQP5), CD4, actin, fibrinogen, ß-tubulin, serum albumin, hydroxyapatite, zinc α2-glycoprotein, and the Fc fragment of IgGs, and the expression of PIP has been demonstrated to be modulated by various cytokines, including IL4/13, IL1, and IL6. PIP gene expression has been extensively studied due to its captivating nature. It is influenced by various factors, with androgens, progesterone, glucocorticosteroids, prolactin, and growth hormone enhancing its expression while estrogens suppress it. The regulatory mechanisms involve important proteins such as STAT5A, STAT5B, Runx2, and androgen receptor, which collaborate to enhance PIP gene transcription and protein production. The expression level of PIP in breast cancer is dependent on the tumor stage and subtype. Higher expression is observed in early-stage tumors of the luminal A subtype, while lower expression is associated with luminal B, basal-like, and triple-negative subtypes, which have a poorer prognosis. PIP expression is also correlated with apocrine differentiation, hormone receptor positivity, and longer metastasis-free survival. PIP plays a role in supporting the immune system's antitumor response during the early stages of breast cancer development. However, as cancer progresses, the protective role of PIP may become less effective or diminished. In this work, we summarized the clinical significance of the PIP molecule in breast cancer and its potential role as a new candidate for cell-based therapies.

Gross Cystic Disease Fluid Protein-15 (GCDFP-15) Expression Characterizes Breast Mucinous Carcinomas in Older Women.

The predominant histological subtype of breast mucinous carcinoma in older women is type B (hypercellular type), and, in younger women, it is type A (hypocellular type). The characteristics of mucinous carcinomas of the same histological subtype may differ between older and younger women. This study aims to systematically clarify the pathological/immunohistochemical features of mucinous carcinomas. A total of 21 surgical cases of mucinous carcinoma (type A/B: 9/12 cases) in the older group (≥65 years) and 16 cases (type A/B: 14/2 cases) in the younger group (≤55 years) (n = 37) were included. Gross cystic disease fluid protein-15 (GCDFP-15) and eight other markers were used for immunostaining. The GCDFP-15-positive rate in the older group was high regardless of the histological subtype (type A, 77.8%; type B, 91.7%). The GCDFP-15 positivity in the older group was significantly higher than that in the younger group (p < 0.001 for Allred score). Among type A, GCDFP-15 positivity was significantly higher in the older group than in the younger group (p = 0.042 for the Allred score and p = 0.007 for the positivity rate). The present results suggest that GCDFP-15 expression characterizes mucinous carcinomas in older women.

A Case Report on Apocrine Encapsulated Papillary Carcinoma of the Breast with Frank Invasion: A Diagnostic Quandary.

Encapsulated papillary carcinoma is a special type of breast cancer defined in the fifth edition of the World Health Organization breast tumor classification guidelines. Apocrine encapsulated papillary carcinoma is extremely rare, and only 10 cases have been described previously. We encountered a case of apocrine encapsulated papillary carcinoma with frank invasion. The patient was a 77-year-old woman with a painless mass in her right breast. Core needle biopsy revealed that the tumor cells had voluminous eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli. We diagnosed this lesion as carcinoma with apocrine differentiation and suggested the possibility of an encapsulated papillary carcinoma. The patient underwent a right-sided mastectomy. Gross examination of the resected specimen revealed a multilobulated tumor. Microscopically, the tumor cells, which had voluminous eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli, proliferated in papillary fashion with fibrous stalks in the cystic space. Myoepithelial cells were not observed around the cystic space. Frank invasion was also observed around the encapsulated papillary carcinoma. Immunohistochemistry analysis revealed that the tumor cells were negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and positive for androgen receptor and gross cys-tic disease fluid protein 15. Based on these findings, we diagnosed this lesion as an apocrine encapsulated papillary carcinoma with frank invasion.

α-Methylacyl-CoA racemase: a useful immunohistochemical marker of breast carcinoma with apocrine differentiation.

Carcinoma with apocrine differentiation is an androgen receptor (AR)-positive subset of triple-negative breast carcinomas. In addition to carcinoma with apocrine differentiation, other AR-positive triple-negative breast carcinomas occur, albeit less frequently. We found that α-methylacyl-CoA racemase (AMACR), also known as P504S, is overexpressed in carcinoma with apocrine differentiation and non-neoplastic apocrine metaplasia. We aimed to evaluate AMACR as a possible marker of carcinoma with apocrine differentiation. We immunohistochemically examined the expression of AMACR in carcinoma with apocrine differentiation and nonapocrine carcinomas and compared it with that of gross cystic disease fluid protein-15 (GCDFP-15). In total, 212 breast carcinomas were evaluated: 39 carcinomas with apocrine differentiation, 28 ductal carcinomas in situ with apocrine morphology (ADCIS), and 145 nonapocrine breast carcinomas. AMACR was expressed in 38 of 39 (97.4%) carcinomas with apocrine differentiation and in 27 of 28 (96.4%) ADCIS, consistent with the expression of GCDFP-15. However, in nonapocrine carcinomas, AMACR expression was observed in 32 of 145 (22.0%) lesions, whereas GCDFP-15 expression was observed in 91 of 145 (62.7%) lesions. For carcinoma with apocrine differentiation, AMACR was as sensitive as GCDFP-15 (both 97.1%) but more specific (77.9% versus 37.2%). In selected cases, AMACR messenger RNA (mRNA) levels were quantitatively determined relative to that of TATA-binding protein mRNA, and they comprised 5.23, 1.33, and 0.60 for carcinomas with apocrine differentiation, nonapocrine carcinomas, and normal breast tissue, respectively. CONCLUSION: Our findings demonstrate that AMACR expression may be used for differentiating carcinoma with apocrine differentiation from nonapocrine carcinomas and indicate that AMACR is a more sensitive carcinoma with apocrine differentiation marker than GCDFP-15.

A Very Rare Reason for Gastric Perforation, Caused by Gastric Metastasis of Breast Cancer: Case Presentation.

Breast cancer is the mostly seen malignancy of women. Breast cancer causes lung, bone, liver and brain metastasis. On the other hand, gastric metastasis of breast cancer is a rarely seen metastasis. For this reason, it may be misdiagnosed or diagnosed after its morbid or mortal complications occurred. This may also result as a delay of breast cancers primary treatment. If occurred the best tool is immunohistochemical panels especially gross cystic disease fluid protein 15 (GCDFP-15) for exact diagnosis. In our case, a gastric metastasis of breast cancer is presented which was admitted with the acute abdominal findings caused by its result as gastric perforation and diagnosed by GCDFP-15 immunohistochemical panel.

Prolactin-induced protein (PIP)-characterization and role in breast cancer progression.

Prolactin-induced protein (PIP) is a small secreted glycoprotein carrying several N-linked carbohydrate chains. The expression of PIP is generally restricted to cells with apocrine properties. It was found in apocrine glands of the axilla, vulva, eyelid, ear canal, and seminal vesicle. Being a secretory protein, PIP is present in seminal plasma, saliva, lacrimal fluid, tears, sweat gland secretion. Little is known about the biological role of PIP. It binds to numerous proteins, however, in most cases the biological role of such interactions is poorly understood. A notable exception is its binding to CD4 receptors present on the surface of T lymphocytes, macrophages, and spermatozoa. The available data suggest that PIP can have immunomodulatory functions and plays an important role in cell-mediate adoptive immunity. PIP binds to bacteria from several genera, which suggests that this glycoprotein may participate also in innate immunity and protection of hosts against microbial infections. Increased levels of PIP were found in several types of human cancer (prostate, sweat and salivary gland cancers). It is especially common in breast cancer, however, data on the expression of PIP in normal and cancerous breast cancer tissues are to some degree conflicting. In early studies, it was shown that PIP is absent or its expression is very low in normal breast epithelium, whereas in breast cancers PIP is frequently expressed and present in large amounts. On the other hand, later study showed that expression of PIP is lower in advanced apocrine carcinomas and invasive carcinomas than in, respectively, in situ carcinomas and adjacent normal tissue. The most recent study revealed that PIP gene expression decreased gradually along with higher stage and grade of breast cancer. In agreement with these data, it was shown that that low levels or the lack of PIP expression are associated with a worse response of breast cancer cells to chemotherapy. It was proposed that PIP plays important role in the development and progression of breast cancer. However, its role in these processes is both unclear and controversial. In this review, the role of PIP in both physiological processes and carcinogenesis is discussed.

Expression of hormone receptors, adipophilin, and GCDFP-15 in mucinous carcinoma of the skin.

BACKGROUND: Primary cutaneous mucinous carcinoma (PCMC) is a rare epithelial tumor with unclear histogenesis. METHODS: We evaluated the immunohistochemical expression of the estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) in six cases of PCMC. The immunoreactivity of adipophilin and gross cystic disease fluid protein (GCDFP)-15 was investigated to determine the origin of the tumor. RESULTS: The study included five males and one female aged 50 to 69 years who presented with a cutaneous mass in the face. Immunoreactivity for ER, PR, and AR was observed in all cases, and all cases were negative for adipophilin but positive for GCDFP-15. CONCLUSIONS: This report is the first to show AR expression in PCMC. All of followed cases manifested indolent clinical course, and the prognostic significance of hormone receptors in PCMC remains unclear. The negative immunoreactivity of PCMC for adipophilin and positivity for GCDFP-15 suggests a more likely relationship to apocrine than to sebaceous glands.

Metastasis of cervical cancer to breast: A case report and review of literature.

Metastasis to the breast from an extra-mammary malignancy has been documented in literature, however cervical cancer metastasis to the breast is very rare. Thirty-eight cases of metastatic deposit to the breast from cervical cancer have been reported in literature. Though most patients present with a breast lump, it is very difficult to clinically distinguish a primary breast malignancy from a metastatic deposit. Histopathology of the tissue, aided with immune-histochemical staining pattern provides a definitive diagnosis. Our patient, a 51-year old woman presented with breast lump and history of post-menopausal bleeding. Upon further workup, the patient was diagnosed with cervical cancer. The mammogram and ultrasound of the breast showed multiple lumps within the breast. Histopathology of the breast mass showed metastatic deposit in the breast from cervical cancer. The patient was treated with radiation therapy to the cervix along with concurrent chemotherapy for local control of pain. After completion of local treatment, she started systemic chemotherapy, however she developed health-care associated pneumonia and subdural hematoma leading to deterioration in her performance status. The patient opted for hospice care and died 2 months later. In this report, we will review the presentation of the 38 cases reported in literature and the imaging and histopathologic findings of metastatic deposits to the breast.

Cells in 3D-reconstitutued eccrine sweat gland cell spheroids differentiate into gross cystic disease fluid protein 15-expressing dark secretory cells and carbonic anhydrase II-expressing clear secretory cells.

Secretory coils of eccrine sweat glands are composed of myoepithelial cells, dark secretory cells and clear secretory cells. The two types of cells play important roles in sweat secretion. In our previous study, we demonstrated that the 3D-reconstituted eccrine sweat gland cell spheroids differentiate into secretory coil-like structures. However, whether the secretory coil-like structures further differentiate into dark secretory cells and clear secretory cells were is still unknown. In this study, we detected the differentiation of clear and dark secretory cells in the 3D-reconstituted eccrine sweat gland cell spheroids using the dark secretory cell-specific marker, GCDFP-15, and clear secretory cell-specific marker, CAII by immunofluorescence staining. Results showed that there were both GCDFP-15- and CAII-expressing cells in 12-week-old 3D spheroids, similar to native eccrine sweat glands, indicating that the spheroids possess a cellular structure capable of sweat secretion. We conclude that the 12-week 3D spheroids may have secretory capability.

A microanatomic abnormality of the lacrimal gland associated with Goldenhar syndrome.

A 12-month-old male infant, noted from birth to have a diffuse right temporal epibulbar thickening that encroached on the limbus inferotemporally, was found to manifest stigmata of Goldenhar syndrome, including a limbal dermoid with vellus hairs, esotropia, astigmatism, fullness and ectropion of the lower eyelid, preauricular skin tag, agenesis of the right kidney, and a supernumerary rib. In the excised epibulbar specimen, in addition to a solid dermoid, lobules of lacrimal gland tissue were interpreted as a portion of the palpebral or orbital lobes. This tissue displayed a unique histopathologic finding. Within some of the lobules were cuffs of eosinophilic squamous (epidermoid) cells that surrounded the intralobular ductules and made variable incursions into, with replacement of, the acinar units. Immunohistochemistry disclosed that the normal acinar and lumen-forming ductular cells were intermediate weight cytokeratin7-positive. The acinar cells were additionally gross cystic disease fluid protein-15 positive. The cells of the squamous cuffs were heavy weight cytokeratin 5/6-positive. The outermost basal cells of the cuffs were cytokeratin 14-positive, in common with the myoepithelial cells of the acini. The intraacinar squamous cells were negative for smooth muscle actin and gross cystic disease fluid protein-15. These findings suggest, but do not prove, that the source of the periductular and acinar squamous metaplasia was the germinal transitional cells where the acinar myoepithelium interfaces and imperceptibly converts into ductular basal cells. The foregoing findings are evaluated in the context of the panoply of ocular, facial, and visceral anomalies manifested in Goldenhar spectrum.

Markers of metastatic carcinoma of breast origin.

This review summarizes the three major breast-associated markers that can be of assistance in evaluating metastatic carcinomas for which a breast primary diagnosis is entertained. These markers include gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, and GATA3. The first two are cytoplasmic markers that show comparable sensitivities for breast cancer, although relatively few of the published studies have employed the same antibodies against the target molecule, making direct comparisons challenging. GATA3 is a nuclear transcription factor that shows superior sensitivity to GCDFP-15 and mammaglobin. However, the specificity of GATA3 can pose challenges, inasmuch as carcinomas of the bladder and other sites can show significant levels of positivity. Determination of the optimal panel of antibodies employed in a given clinical setting will thus depend on the non-breast tumours included in the differential diagnosis.

Heat shock protein 27 and gross cystic disease fluid protein 15 play critical roles in molecular apocrine breast cancer.

Molecular apocrine breast cancer (MABC) has a distinct hormonal profile, being estrogen receptor (ER) and progesterone receptor (PR) negative but androgen receptor (AR) positive. The clinical significance of MABC and its relative variables have not been absolutely clarified and remain to be determined. Five hundred cases of invasive breast carcinoma were randomly selected in this study, including 158 MABC cases and 342 nonMABC cases. Expression of ER, PR, epidermal growth factor receptor 2 (HER2), Ki67, AR, gross cystic disease fluid protein 15 (GCDFP15), and heat shock protein 27 (HSP27) were analyzed by immunohistochemistry. Differences of continuous variables between MABC and nonMABC subgroups were evaluated by the chi-square test. The Kaplan-Meier method was performed to evaluate disease-free survival (DFS) and overall survival (OS). The MABC subgroup had higher histological grade, bigger tumor size, more lymph node metastasis, and higher pTNM stage than the nonMABC subgroup (P < 0.05), and patients with MABC had poorer prognosis than those of the nonMABC subgroup (P < 0.05). Both GCDFP15 and HSP27 were expressed differently in the MABC and nonMABC subgroups (P < 0.05). Furthermore, in the MABC subgroup, positive HSP27 expression indicated higher risk of recurrence (P < 0.05) and positive GCDFP15 expression was also a poor marker for patient outcome (P < 0.05). MABC patients with HSP27 and GCDFP15 co-expression had worse outcome (P < 0.05). Our data suggested that MABC had a high risk of recurrence. Positive expression of both GCDFP15 and HSP27 were correlated with MABC malignancy. Targeting AR and HSP27 at the same time might offer a useful strategy to MABC.

Evaluation of androgen receptor and GATA binding protein 3 as immunohistochemical markers in the diagnosis of metastatic breast carcinoma to the lung.

Differentiating metastatic breast carcinoma in the lungs from primary lung tumors and mesotheliomas is important for determining prognosis and treatment. We evaluated novel breast specific markers, androgen receptor (AR) and GATA binding protein 3 (GATA3) immunohistostaining, for this differential, and compare to other traditional markers. The specimens comprised 33 metastatic breast carcinomas to the lung, 566 primary lung tumors (170 adenocarcinomas, 157 squamous cell carcinomas, 31 pleomorphic carcinomas, 115 large cell neuroendocrine carcinomas, 43 small cell carcinomas, and 49 typical carcinoids) and 42 malignant mesotheliomas. They were analyzed by immunohistochemistry using antibodies to AR, GATA3, estrogen receptor (ER), progesterone receptor (PgR), mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15). Of the metastatic breast carcinomas, immunohistostaining of AR, GATA3, ER, PgR, mammaglobin, GCDFP-15 were positive in 27 cases (81.8%), 24 cases (72.7%), 26 cases (78.8%), 13 cases (39.4%), 12 cases (36.4%), 9 cases (27.3%), respectively. Of primary lung tumors and mesotheliomas, staining of AR, GATA3, ER, PgR, mammaglobin, GCDFP-15 were positive in 18 cases (3%), 3 cases (0.5%), 4 cases (0.7%), 2 cases (0.3%), 0 case (0%), 2 cases (0.3%), respectively. Immunohistochemistry of AR and GATA3 are reliable for differentiating metastatic breast carcinoma from primary lung tumors and mesotheliomas.

A comparative immunohistochemistry study of diagnostic tools in salivary gland tumors: usefulness of mammaglobin, gross cystic disease fluid protein 15, and p63 cytoplasmic staining for the diagnosis of mammary analog secretory carcinoma?

BACKGROUND: Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. METHODS: A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. RESULTS: Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. CONCLUSION: Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement.

Perianal Paget's Disease Co-Associated with Anorectal Adenocarcinoma: Primary or Secondary Disease?

Perianal Paget's disease (PPD) represents a skin neoplasm which can be either primary or secondary to carcinoma from an adjacent internal organ. PPD with underlying colorectal adenocarcinoma is usually looked upon as a secondary disease. We report a rare case of co-associated PPD and anorectal adenocarcinoma. The PPD was found to be located near the anorectal adenocarcinoma with normal tissues between them. Immunohistochemical stains demonstrated that the Paget's cells were CK7+/GCDFP-15-/CK20-/MUC2-/CDX2-, whereas the anorectal adenocarcinoma was shown to be CK7+/GCDFP-15-/CK20+/MUC2+/CDX2+. This immunological phenotypic profile supported the notion that PPD and anorectal adenocarcinoma were of different origins, but could not define the exact origins of PPD. In our determination, this case was a primary PPD with anorectal adenocarcinoma. PPD remains a heterogeneous and complex pathology, and additional studies are required to differentiate between the various possible origins.

Papillary hidradenoma of the eyelid margin: clinical and immunohistochemical observations further supporting an apocrine rather than an eccrine origin.

A 46-year-old woman was evaluated for a "recurring papilloma" of the left medial upper eyelid margin. Beneath the papillary lesion medial to the punctum was a 5-mm diameter cutaneous mass thought to be cystic. After excisional biopsy, histopathologic analysis documented the presence of an epidermal keratinizing squamous papilloma surmounting a circumscribed dermal papillary hidradenoma composed of deeply eosinophilic columnar cells. Additionally, there was intraductal proliferation of tumor extending toward a subclinical poral opening through the epidermis. Immunohistochemistry proved the apocrine nature of the benign, non-cystic lesion by virtue of its nuclear androgen receptor and cytoplasmic gross-cystic disease fluid protein-15 positivity, along with its smooth muscle actin-positive myoepithelial layer. This and prior cases establish that apocrine tumors, both benign and malignant, are strictly localized at or near the eyelid margin where only apocrine glands are found. These tumors are more often papillary than solid adenomas, and most exceptionally can be malignant. We review the differential diagnosis of simulating eccrine eyelid tumors. We recommend wide local excision for benign lesions, in view of possible intraductal extension that can be eccentric to the main tumor and the miniscule potential for malignant transformation.

Use of GCDFP-15 (BRST-2) as a Specific Immunocytochemical Marker for Diagnosis of Gastric Metastasis of Breast Carcinoma.

Metastasis of breast cancer to the stomach is relatively uncommon and typically occurs in patients with disseminated diseases. This may cause difficulty in differentiating it from primary gastric carcinoma. The correct diagnosis of the primary source is important, since the treatment and prognosis of metastatic breast cancer is quite different from those of metastatic gastric cancer. Immunohistochemical staining with GCDFP-15 (gross cystic disease fluid protein-15) can be used to differentiate primary gastric carcinoma and gastric metastasis from breast cancer. We report two cases of gastric metastasis of breast cancer by describing their clinical course, illustrating the histologic findings, and showing the results of immunohistochemical staining with GCDFP-15.

Use of GCDFP-15 (BRST-2) as a Specific Immunocytochemical Marker for Diagnosis of Gastric Metastasis of Breast Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

Metastasis of breast cancer to the stomach is relatively uncommon and typically occurs in patients with disseminated diseases. This may cause difficulty in differentiating it from primary gastric carcinoma. The correct diagnosis of the primary source is important, since the treatment and prognosis of metastatic breast cancer is quite different from those of metastatic gastric cancer. Immunohistochemical staining with GCDFP-15 (gross cystic disease fluid protein-15) can be used to differentiate primary gastric carcinoma and gastric metastasis from breast cancer. We report two cases of gastric metastasis of breast cancer by describing their clinical course, illustrating the histologic findings, and showing the results of immunohistochemical staining with GCDFP-15.