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Introduction

The cancers of unknown primary (commonly named CUPs) are a heterogeneous group of tumors characterized by a difficult diagnosis, because the primary site remains occult after extensive work-up (1). The CUPs represent about 3–5% of all cancer diagnosis and the most common manifestations are metastases in the lymph nodes, lung, liver, or bone (2). In 75–85% of the cases, the metastases are disseminated (3). Considering its enigmatic features, it was discussed about the validity of CUP as a distinct cancer entity supporting the hypothesis that the diagnosis of CUP could be erroneous because the work-up may be incomplete or the syndrome may be correlated to relapses of precedent cancers (4).

Therefore, International Guidelines tried to clarify the diagnostic management (5), highlighting the importance of patients' clinical and familiar history, and on risk factors such as cancer predisposition and occupational activity. A complete physical examination should be performed with accuracy for respiratory and abdominal systems which are the most common sites of primary cancers, according to the data reported in the follow-up and autopsy of CUPs' patients, without neglecting the clinical presentation that could drive the primary tumor research (6). The initial diagnostic work-up should include basic blood analyses and relevant tumor markers. A computerized tomography (CT) of chest, abdomen and pelvis is recommended by ESMO guidelines (7) and Positron emission tomography (PET) imaging is frequently additionally employed in CUP to identify unrecognized malignant lesions (8). Only after that an extensive work-up has been performed without the detection of a primitive cancer, the possibility of CUP syndrome should be considered. The pathogenesis is controversial, but CUP condition may be created by an early metastatic dissemination, whereas the primary tumor has receded or is too small to be detected (9). The CUPs of possible breast origin represent a complex topic. ESMO Clinical Practice Guidelines recommended mammography and eventual magnetic resonance image (MRI) of the breast only for the women suspected of CUP, considering the wide spreading of breast cancer in the female sex. Breast investigation is not required routinely for men because male breast cancer (BC) is rare, representing approximately 1% of cancers that occur in males (10). Therefore, CUPs of male BC origin are rarely considered for the diagnosis and very few cases are reported in literature. Their management represents an unclear topic, characterized by an extreme variety of treatments and prognosis.

Case report

A 64 year-old male patient was admitted at the General Surgery Division of a Teaching Hospital (Luigi Vanvitelli University of Campania, Naples, Italy) for an axillary swelling with severe pain to the arm and forearm. His past medical history excluded other co-morbidities or cancer anamnesis. He was regular smoker (15 cigarettes a day for 40 years). His familiar medical history included breast cancer of one sister and ovarian cancer of the other sister. Physical examination revealed a left swelling in axilla, by the size of 2 cm, with irritated and reddened skin above. Swelling was painful and without mobility along surface and deep planes. No other signs in other districts were showed during the physical examination.

He was admitted in November 2020 and during the hospitalization (he was submitted to an axillary ultrasound (US) that revealed increased volume and thickness of many axillary lymph nodes, one of these with 2 cm of diameter and tender aspect. Magnetic Resonance Imaging (MRI) confirmed the presence of multiples oval and round homogeneous shape nodules, similar to lymph nodes, with low signal on T1 and T2. No breast lesion was identified (Fig. 1). Ultrasound guided fine needle aspiration biopsy (FNAB) was performed on the largest lymph node. Definitive pathology showed malignant cells with atypical elements like epithelioma, with clear cytoplasm, chromatin clearing nucleus and evident nucleolus. In the attempt to recognize the primary localization, a screening Total Body CT was performed and showed repetitive lung nodes and confirmed the presence of multiples axillary nodes. The largest was estimated of 4×2.3 cm in diameter. Positron emission tomography with computerized tomography (PET-CT) exam was performed in an external diagnostic center because it was not available in the hospital. The examination completed the diagnostic process, confirming the presence of numerous axillary and lung lymph nodes with elevated metabolic activity and evidencing already left thorax subcutaneous thickening and two bone lesions on D6.

Figure 1. Bilateral breast magnetic resonance imaging. No breast lesion was identified.

The patient underwent a lymphadenectomy of the first and second axillary levels. A drain was placed. The post-operative course was regular, and no complications occurred. A total of 3 days after admission he was discharged from the hospital with no symptoms or pain and the drain was removed the fifth postoperative day. Histological exam showed adenocarcinoma with multiples nodes, oxyphilic and apocrine aspect, sclerosis stromal and multifocal coagulative and colliquative areas into the tumor. It was described local perineural neoplastic infiltration without neoplastic embolus. Immunohistochemistry was performed automatically on BenchMark Ultra platform (Ventana Medical Systems), according to the manufacturer's instructions, as previously described (11). Immunohistochemistry (IHC) (Fig. 2) analysis was positive for cytokeratin (CK) AE1/AE3, CK7, GATA3, Gross cystic disease fluid protein (GCDFP)-15, androgen receptor (AR), human epidermal growth factor receptor 2 (HER 2), low and focal positive for mammaglobin. The lesion did not show CK20, transcriptional thyroid factor (TTF) 1, Napsin A, Estrogen Receptor (ER), Progesterone Receptor (PgR). The expression rate of proliferation marker Ki67 was 40%. The final diagnosis was moderate differentiation grade 2 (G2) apocrine carcinoma, inter-medial differentiation sec. Elston-Ellis score 7: tubules formation, nuclear pleomorphism score 2, mitosis score 3. The histological findings correlated with IHC were no sufficient to make a differential diagnosis between cutaneous annexes histogenesis and breast origin. Considering ER and mammaglobin expression, we performed Mammography and breast US searching a rare male BC, without identifying any breast lesions (Fig. 3). MRI revealed presence of focal areas on D5 and D10 (maximum diameter was 11 mm), micro nodular areas on D2, D12 and L1 and Multiples Bone lesions on pelvic region (diameter maximum of 15 mm). Dermatology visit excluded cutaneous histogenesis and the case was treated like man CUP syndrome of possible breast origin. The patients signed a written consensus and agreed the publication of his clinical case.

Figure 2. Histological and immunohistochemical findings. (A) Histology showing malignant epithelial neoplasm constituted by atypical cells with oxyphilic cytoplasm arranged in cribriform and glandular pattern (hematoxylin and eosin stain, original magnification 200×). By immunohistochemistry, the neoplasm expressed (B) CK AE1/AE3, (C) CK7, (D) GATA3, (E) androgen receptor, (F) GCDFP-15 and (G) HER2; (H) Ki67-positive expression was ~40%; the neoplasm did not express (I) estrogen receptor, (J) progesterone receptor, (K) TTF1 and (L) Napsin A (immunohistochemical stains, original magnification ×200).

Figure 3. Bilateral mammography. No breast lesion was identified.

Discussion

CUPs are a group of neoplasms characterized by the diagnosis of metastasis in the absence of a detectable primitivity, after a complete clinical work-up (12,13). The CUPs represent about 3–5% of all cancer diagnosis with an overall age-standardized incidence ranges between 4 and 9 cases per 100.000 people annually worldwide (3). It is recognized as the fifth most common cause of cancer death (14). CUPs accounts for up to 1% of all breast cancers and the involvement of axillary is the most common presentation in these cases. It is known, in fact, that in over 50% of the cases of axillary lymphadenopathy, the primary originates from the breast (15–17). Therefore, mammography and axillary-breast US should be included in the instrumental work-up in all CUPs with axillary repetitions (18–20). Breast Magnetic Resonance Imaging (MRI) is also recommended by international guidelines because it can improve the detection of an occult primary breast cancer in a wide range of cases (from 35 to 100%) (21–23).

BC is common in women and innovative technologies for very accurate diagnosis and treatments were established (24–26) while male breast cancer is rare, and CUP of male breast origin is anecdotal. Moreover, there is no consensus in literature about a specific panel of IHC due to their rarity (27).

Using the PubMed database, a systematic review of the current literature was carried out, up to March 2023. The final article was realized in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (28). The MeSH (Medical Subject Headings) search terms used were ‘breast’, ‘cancer of unknown primary’, ‘occult breast cancer’. The Authors observed that male breast cancer of unknown primary was an extremely rare neoplasm. The keywords ‘male breast cancer’, ‘occult male breast cancer’, ‘male breast cancer of unknown primary’ were used for the research. Several combinations of the keywords and MeSH terms were utilized, and the various terms were substituted during the search. References of the more relevant articles were manually searched. The last research was concluded on March 21, 2022.

Twelve articles published from 2008 to 2020 and reporting cases of CUP of breast cancer origin were identified (27,29–39) (Table I). The mean age of the patients was 59,23 years (range 29 to 83). Three men were smokers (35,38,39) and two of them (35,38) referred a familiarity for gastric cancer: in a case the father, and in the other the mother was affected. In 12 cases reported the first presentation was an axillary mass; in one case the tumor was located on the anterior chest wall (29) while in another case, a vertebral painful lesion was diagnosed in the same moment of the axillary nodule (39). Seven men was affected by comorbidities: four of them showed dermatologic disease such as eczema, reddish skin, dermatomyositis, and erythema (27,29,34–35). A patient had a benign thyroid nodule (35), one presented gynecomastia (37), and another found out a renal cystic (39).

Table I. Reported cases of occult male breast cancers.

Table I.

Reported cases of occult male breast cancers.

First author, year	Age, years	Risk factors	Clinical presentation	Examinations	H&E histopathological examination	Immunohistochemical staining	Surgery	Neoadjuvant therapy	Adjuvant CT	RT	Follow up	(Refs.)
Gu, 2008	72	N/A	Painless and	MX, breast and	Breast	ER (−), PgR (−),	ALNB,	No	No	No	After 18 months:	(36)
			enlarged	axillary US	infiltrating	P53 (+), PCNA (+),	mastectomy,				The lesion
			lymph node		ductal	BCL 2 oncoprotein	ALND				disappeared
					carcinoma	(+), Nm 23 (+), HER2
						score 3+, MPR (+)
Gu, 2009	72	No	Painless	MX, breast and	Infiltrating	ER (−), PgR (−),	ALNB,	No	No	No	After 24 months:	(31)
			enlarged	axillary US	breast ductal	P53 (+), PCNA (+),	mastectomy				The lesion
			axillary		carcinoma	BCL 2 oncoprotein					disappeared
			lymph node			(+), Nm 23 (+), HER2
						score 3+, MPR (+)
Takeyama,	58	N/A	1 cm right,	Chest CT, MX,	Metastatic	ER 40%, PgR 30%,	ALNB,	Cisplatin,	Anthracycline,	No	N/A	(27)
2010			non-mobile,	breast and axillary	adenocarcinoma	mammaglobulin	resection,	paclitaxel	taxane,
			hard axillary	US, breast MRI,	from an unknown	70–80%, HER2 (−),	ALND		tamoxifen
			mass	head, lung, upper	primary	P53 (−)
				and lower
				gastrointestinal
				system endoscopy
Hur, 2012	59	Smoking;	Palpable	MX, breast and	Metastatic poor	ER (+), PgR (+),	ALNB,	No	Doxorubicin,		After 10 years:	(35)
		gastric	mass in	axillary US, breast	differentiated	HER2 (score 1+),	skin sparing		cyclophospha-		The lesion
		cancer	right axilla	MRI, chest CT,	adenocarcinoma	BRST-2 (+), S-100 (−)	mastectomy,		mide, docetaxel,		disappeared
		familiarity		abdominal US,	likely of breast		ALND		tamoxifen
		(father)		EGDS,	origin
				colonoscopy
				AFP, CEA, PSA,
				CA 19-9, CA 15-3
Hur, 2012	45	No	Palpable	MX, breast and	Adenocarcinoma	TTF-1 (−), CK 20 (−),	ALND	No	Doxorubicin,	Yes	After 24 months:	(35)
			mass in		axillary US, breast	CEA (+), ER (+),			cyclophospha-		The lesion
			left axilla		MRI, PET, chest	PgR (+), HER2 (−),			mide, docetaxel,		disappeared
					CT, abdominal	Ki-67 (+), EGFR (−),			tamoxifen
					CT, EGDS; CEA,	BRST-2 (+)
					PSA, CA 19-9,
					CA 15-3,
					Calcitonin blood
					test
Wang,	58	N/A	Left armpit	Breast and axillary	Glandular cancer	After neoadjuvant CT:	ALNB,	Paclitaxel,	Doxorubicin	Yes	After 12 months:	(32)
2014			painful	US, MX, PET-CT;	with high	E-cadherin (+),	mastectomy	oxaliplatin			The lesion
			0.8×0.6 cm	CA-125, CEA	possibility of	P120 (+), CK7 (+),		with partial			disappeared
			mass	blood test	primary mammary	ER 90%, PgR 85%		response;
					tumor			docetaxel,
								lobaplatin
								with no
								response
He, 2015	40	No	Left axillary	Breast and axillary	Moderately	CK 20 (−),	ALNB,	No	Trastuzumab,	No	After 9 months:	(37)
			palpable	US, total body	differentiated	mammaglobin (−),	mastectomy,		paclitaxel,		Newly increased
			2.2 cm	CT, abdominal	adenocarcinoma	TTF-1 (−), ER (−),	ALND		carboplatin		uptake on left
			nodule	US, thyroid US,	with solid nests	GCDPF 15 (−),					supraclavicular
				genitourinary US,	and cord-like	PgR (+), HER2					region detected
				breast MRI, PET;	arrangements of	(score 2+)					on PET/CT;
				CEA, PSA, CA	cancer cells						after 3 years
				19-9, CA 15-3,							Stable disease
				Calcitonin, AFP
				blood test
Rigakos,	54	Smoking	Painful	Lumbar spinal	Metastatic low	CK AE1/3 (+),	ALNB,		Capecitabine,		After 33 months:	(39)
2016			vertebral	MRI, PSA, total	grade carcinoma	CAM 5.2 (+),	ALND		trastuzumab,		Stable bone
			mass, right	body CT, PET-CT	of epithelial origin	epithelial membrane			vinorelbine,		disease
			axillary		origin	antigen (+),			tamoxifen,
			mass, bone			E-cadherin (+),			letrozole
			lesions			melan A (+),
						synaptophysin (+),
						placental alkaline
						phosphatase (+),
						NSE (+), CD (1),
						human melanoma
						black 45 (+), renal
						cell (−), inhibin (−),
						TTF-1 (−), CK5/6 (−),
						GCDPF 15 (−),
						vimentin (−),
						CD 117 (−), PSA (−);
						after Micro-RNA:
						ER (+), PgR (+),
						HER2 (+)
Zhang,	84	No	Palpable	Total body CT	Metastatic poor	ER (−), PgR (−),	Core needle	No	Paclitaxel,	No	After 24 months:	(34)
2017			3.9 cm		differentiated	PSA (−), GCDPF 15	biopsy,		cyclophospha-		The lesion
			nodule		adenocarcinoma	(+), AE1/AE3 (+),	ALND		mide		disappeared
			in right		likely of breast	CK 7 (+), CK 20 (+),
			axilla		origin	HER2 (−)
Kuninaka,	67	N/A	3 cm left	CT	Metastatic	ER (+), PgR (<1%),	ALNB	No	Trastuzumab	No	After 18 months:	(29)
2017			anterior		adenocarcinoma	HER2 score 3+,					The lesion
			chest wall		from an unknown	CK 7 (+), CK 20 (−),					disappeared
			tumor		primary	GCDPF 15 (+)
Xu, 2017	29	Smoking,	Left axillary	Chest CT, PET-CT,	Infiltrating ductal	CK 5/6 (+), CK 7 (+),	ALND	No	Adriamycin,	Yes	After 9 months:	(38)
		gastric	palpable	breast and axillary	carcinoma	CDX-2 (+), P63 (+),			docetaxel		The lesion
		cancer	4.3×2.3 cm	US, MX (rejected);		TTF-1 (+),					disappeared
		familiarity	nodule	CEA, PSA, CA		synaptophysin (+),
		(mother)		19-9, CA 15-3,		chromogranin A (+),
				CA 72-4, NSE,		S 100 (+), GCDPF
				Cyfra 21-1,		15 (−), HER2
				Calcitonin, AFP		(score 2+), FISH (−),
				blood test		ER (−), PgR (−),
						EMA (+), GATA-3 (−),
						CK 20 (−),
						mammaglobin (−)
Wang,	49	N/A	Painless	US PET-TC,	Metastatic	ER (+), PgR (+),	ALNB,	No	Paclitaxel,	Yes	After 4 years:	(33)
2018			4×3 cm side	MX (rejected)	adenocarcinoma	GCDPF 15 (+),	mastectomy		phosphamide,		The lesion
			mass in left		from an unknown	HER2 (−), CK 7 (−),	(rejected),		pharmorubicin,		disappeared
			axilla		primary	CK 20 (−), TTF-1 (+)	ALNB		tamoxifen
Sood,	83	N/A	10×6 cm	Mammography	Metastatic	ER (+), PgR (+),	ALNB,	No	Yes	No	N/A	(30)
2020			right		adenocarcinoma	GCDPF 15 (+),	ALND
			axillary		from an unknown	androgen receptor (+),
			mass		primary	E-cadherin (+),
						calponin (−), P53 (−),
						HER2 (−), NSE (+),
						synaptophysin (+)

[i] MX, mammography; US, ultrasound; ALNB, axillary lymph node biopsy; ALND, axillary lymph node dissection; H&E, hematoxylin and eosin; CT, chemotherapy; RT, radiotherapy; ER, estrogen receptors; PgR, progesterone receptors; P, protein; PCNA, proliferating cell nuclear antigen; BCL, B-cell lymphoma 2; Nm 23, non metastasis 23; HER2, human epidermal growth factor receptor 2; MPR, mannose phosphate receptor; MRI, magnetic resonance imaging; EGDS, esopahgo-gastro-duodenoscopy; TTF-1, thyroid transcription factor-1; CK, creatine kinase; CEA, carcino-embryonic antigen; BRST-2, Gross Cystic Disease Fluid Protein 15; PSA, prostate specific antigen; CA, carbohydrate antigen; PET, positron emission tomography; CAM 5.2, cell adhesion molecule; NSE, neuronal specific enolase; CD, cluster of differentiation; GCDPF, anti-human gross cystic disease fluid protein; AFP, α fetal protein; FISH, fluorescent in situ hybridization; EMA, anti-endomysium protein; N/A, not available.

Despite mammography is considered the gold standard for the breast cancer diagnosis, in four cases it was not recommended by the surgeons (29,34,37,39) and in another two studies the patient rejected it (32,38). US was performed in 9 out of 13 cases (27,31–33,35–38), while breast MRI was planned for only 4 patients (27,35,37). A complete work-up with the association of US, mammography and breast MRI has been realized in only three case reports (27–35). Therefore, it is possible to assume that more accurate and diagnostic process would be desirable to define a diagnosis of CUP. In fact, a patient underwent to an incomplete diagnostic work-up is not suitable to receive this kind of diagnosis. In the present case, despite the complete preoperative diagnostic work-up with mammography, US, MRI, Total Body CT and 18 FDG PET-CT was not possible to clearly identify a primary origin conuring a ‘real’ CUP. The clinical suspicious was driven only by the familiarity for breast and ovarian cancers of the sisters, and for the IHC on the resected specimen. Moreover, the diagnostic trouble appears even more relevant considering that even after the definitive pathology was not possible to certainly distinguish between the breast and the cutaneous annexes histogenesis. Only the dermatological counselling, after an accurate clinical examination was able to exclude the cutaneous annexes origin.

The most important method for the individuation and characterization of the breast origin of a CUP was the immunochemistry (IHC) performed on the biopsied specimen, pointing out the preeminence of the surgical approach. Only Zhang et al (34) obtained the diagnosis performing an IHC analysis on a core needle biopsy. Noteworthy, the necessity of the surgery in the diagnostic process reduces the opportunities for the neoadjuvant approach and this fact could negatively influence the prognosis. The conventional histological diagnosis with eosin and hematoxylin (H&E) staining was able to reach the diagnosis only in 5 cases on 13 (38,5%) (31,32,34–36); three patients was affected by infiltrating ductal carcinoma (31,32,36), while for the other two case the diagnosis was less accurate (34–35). Considering the c-erbB-2 mutation, three tumors were Her2 positive with score 3+ (29,31,36); some authors reported a positive determination for Her2 with lower score while He et al (37), referred about a Her2 positivity with score 2+ but the florescent in situ hybridization (FISH) test was not reported. Wang et al (33) had not mentioned Her2 verify and Rigakos et al (39) had not detailed the Her2 positivity. Lack of the FISH analysis and Her2 determination has precluded any possible adjuvant treatment with Trastuzumab. Luminal forms were the most diagnosed (6 out of 13 cases, 46.2%) (27,29,33,35,37,39). Only one patient was candidate to neoadjuvant treatment (27), after an incisional biopsy. Taxane drugs were indicated for 7 patients on 13 (27,33–35,37,38). Only four patients underwent to irradiation during the neoadjuvant phase (32,33,35,38). Two studies did not reported data about the follow up (27,30). The other papers referred that the patients were alive until the last follow up. The mean period of observation was 22,4 months (range 9–48).

Rigakos et al (39) performed the microRNA Rosetta Cancer Origin test to find out the primitivity after the failure of PET-TC, Total body CT and MRI. Many studies have demonstrated that microRNA profiling may be useful for the CUPs' work up, with agreement to final diagnosis for microRNA testing ranging from 84 to 92% (40–42). MicroRNAs are small, non-coding RNAs of 17–25 nucleotides involved in a regulatory function in protein translation and expression. Since their discovery, they are becoming important as cancer biomarker. However, it is not clear if this technique was necessary in the diagnostic process, because it was performed before the axillary surgery and the HIC test.

Despite CUP of male BC origin is very rare, this review highlighted the heterogeneity of the diagnostic methods and the therapeutic strategies. In any suspicious cases of CUP, a strict and accurate diagnostic work-up appears mandatory to exclude any possible primary origin of the tumor. This aspect seems even more important since the scarce experience with this pathology and the absence of guidelines could influence the treatment and the prognosis of the CUP patients. Larger comparative studies about the diagnostic methods and therapeutic approach are needed to address this issue.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors' contributions

SP was responsible for collecting clinical, imaging and pathological data of the patient, and was responsible for the conception, design, content and writing of the manuscript. FF, FI, MLV, GC, FMM and LB collected data. CG, RR, ST, LD and FSL contributed to the conception and revisions of the manuscript. RA contributed to the writing of the manuscript, the conception of the study and the collection of pathological images. All authors agreed on the journal to which the article has been submitted and agreed to be accountable for all aspects of the work. All authors read and approved the final manuscript. SP and CG confirm the authenticity of the raw data.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent was obtained from the patient for publication of this case report and the accompanying images.

Competing interests

The authors declare that they have no competing interests.

References