As per the reports of the International Agency For Research On Cancer (IARC) 2026, globally one in five people develops cancer in their lifetime. In 2025, there were approximately 20 million new cancer cases with over 10 million deaths world-wide.⁽¹⁾ Multiple primary malignancies are becoming common in cancer patients, with risk factors such as genetics, viral infection, smoking, betel nut chewing, and environmental or treatment-related factors. These multiple malignancies may be synchronous if they get detected within 6 months duration of the first primary tumour. The frequency of multiple primary tumours as synchronous tumours is rare though metachronous tumours appear to be common these days. The exact statistical data on the prevalence of synchronous tumours is not available and the existing data in publications worldwide is based on a study in 2010 by A. Irimie, etal.⁽²⁾ But a study from AIIMS Jodhpur by Nishtha Choudhary etal in 2025 on 51 cases of dual primary cancers showed that 12 of them were synchronous tumours amounting to 23.53% of dual tumour population in individuals.⁽³⁾ With the availability of high-end technologically sophisticated diagnostic and imaging facilities, the rate of detection of multiple primary cancers is also increasing. We are reporting an extremely rare set of synchronous tumours, a Secretory type of Breast carcinoma which in itself is a very rare variant (0.15%) among all breast cancers existing with a Squamous Cell Carcinoma of the buccal mucosa. With the available literature, there is no evidence of coexistence of both these tumours in a single patient till date.

ABOUT THE CASE

A 58 years old female presented in the month of December 2025 to the surgery OP of SVRRGGH Tirupathi with a painless lump in the right breast. Core biopsy was reported on 8^th Dec 2025 as Duct cell Carcinoma Breast.

Figure 1.  Clinical picture of the Right breast mass

Figure 2 Clinical picture of the Nonhealing ulcer in buccal mucosa

She has a history of betel nut chewing and history of injury to buccal mucosa on the left side due to sharp teeth and she developed an ulcer on her left buccal mucosa which was not responding to symptomatic treatments and punch biopsy was conducted and reported on 27^th Dec 2025 as Moderately differentiated Squamous cell carcinoma.

Later she was registered as an inpatient and investigated as per the standard operating procedures and surgery was done for both the lesions on 20^th January 2026 as per her convenience. Modified Radical Mastectomy was done for the right breast and Left Mandibulectomy was conducted simultaneously in one sitting. Both the specimens were sent to the Department of Pathology, S.V. Medical College, Tirupathi, for Histopathological evaluation.

                           Figure 3. Gross specimen of breast                Figure 4. Cross section of breast specimen showing mucin

Grossly breast lesion was measuring 9.5 x 7 x 4cms. Cut surface showed massive areas of mucin. After due processing it was reported as Secretory carcinoma (Grade 2 CAP PROTOCOL) by Histopathology examination which is a very rare entity under breast cancers.

Figure 5. Low power 10x

Figure 6. Low power 10x

Figure 5 & 6 Atypical ductal epithelial cells arranged as follicles with secretions mimicking thyroid tissue

Figure 7 High power 40x

Figure 8 High power 40x

Figure 7 & 8 Tumour cells are round to oval with mild pleomorphism and vesicular nuclei and eosinophilic cytoplasm

On Immunohistochemical Examination, ER positivity was seen in 10% of tumour cells while PR and HER2 were negative.15% of Tumour cells showed positivity for KI67.

Figure 9 10% of Tumour cells showing positivity for ER indicating moderate positivity

Figure 10 Tumour cells negative for PR

Figure 11 Tumour cells negative for HER2

Figure 12. 15% of Tumour cells positive for KI67

Grossly buccal mucosa lesion/left mandibulectomy specimen was measuring 3 x 2 x 1cms. It was reported as Well Differentiated Squamous cell carcinoma (Grade 1 CAP PROTOCOL) on histopathology.

                        Figure 13. Gross Specimen of Mandibulectomy      Figure 14. Cross section of Mandibulectomy specimen

Figure 15 Scanner view 4x

Figure 16 Low Power 10x

Figure 17 Low power 10x

Figures 15,16 & 17 Keratinising stratified squamous epithelium with dysplastic changes transcending into the stroma, arranged as sheets nests and clusters with intercellular bridging with focal keratin pearl formation.

Figure18 High Power 40x

Figure 18 Tumour cells are large round to polygonal with increased N:C ratio, prominent nucleoli and scant eosinophilic cytoplasm

Further molecular evaluation using next-generation sequencing, performed at Onquest Laboratories, New Delhi, identified the presence of an ETV6–NTRK3 fusion gene, specifically involving exon 5 of ETV6 and exon 15 of NTRK3. This gain-of-function fusion protein is characteristic of secretory breast carcinoma and supports the histopathological diagnosis.

DISCUSSION:

By definition synchronous tumours are those tumours occurring simultaneously or within 6 months of the diagnosis of the first primary tumour ⁽⁴⁾. Billroth was the first person to introduce Multiple Primary Malignant Tumours (MPMTs) into the literature. ⁽⁵⁾

Subsequently, Warren and Gates in their research in 1932 set-up certain criteria ⁽⁶⁾ which should be fulfilled before stating that multiple co-occurring neoplasia are MPMTs.

1. Both tumours should be histopathologically dissimilar.
2. The possibility of co-occurrence is due to metastases should be excluded.
3. Vivid characteristics of malignant transformation should be present.

Our case fully satisfies these criteria.

Later Gluckman defined “Synchronous malignancy” as any malignant tumours either presenting simultaneously or within the first 6 months of the time of diagnosis of the first primary malignancy. Any time beyond those 6 months milestone, those tumours would be considered “Metachronous malignancy” ⁽⁷⁾.

In our case both the tumours were diagnosed incidentally at the same time upon our patient's clinical presentation.

Based on the sites of occurrences, tumours can be categorized into four different types ⁽⁸⁾.

1. The multicentric type, if two histopathological different malignancies originate from the same organ.
2. The systemic type if both the malignancies originate from functionally or anatomically related organ tissues of the same organ system (i.e., rectal and colon neoplasia).
3. The paired organ neoplasia, as in the bilateral breast tissues.
4. The random type if the distinct malignancies are found incidentally in functionally and anatomically unrelated organs.

Our case is of the random type (4^th type) because the Secretary carcinoma is in breast while the Squamous cell carcinoma originated in the buccal mucosa, two unrelated organ sites and histopathologically entirely indistinct from one another but arising almost in the same period of time.

The right breast showed Secretary Carcinoma which is a very rare variant whose incidence is less than 0.15% of all breast cancers ⁽⁹⁾ and the buccal mucosa showed Well differentiated squamous cell carcinoma whose incidence is 31.7% in all the oral cancers. ⁽¹⁰⁾

Secretory Breast Carcinoma is usually negative for estrogen and progesterone receptor and negative HER-2 (triple-negative breast cancer). Yet it has a good prognosis.⁽¹¹⁾ Lijaun Li et al reported 21 ER-positive cases out of 44 total cases of SBC.¹² Our case is also of intermediate ER positivity with 10% of cells with nuclear positivity and 15% of cells positive for KI67. On the other hand the squamous cell carcinoma of the buccal mucosa has a poor prognosis ⁽¹³⁾.

On Histopathology, Secretory carcinoma of breast is a circumscribed lesion with pushing borders but may be infiltrative at periphery with microcystic, solid or tubular or admixture of all 3 patterns or sometimes can display peripheral papillary architecture with a Low grade cytologic atypia, bland uniform nuclei, low mitotic rate with vacuolated, foamy cytoplasm and abundant intracellular and extracellular pale blue to dense pink secretions, which are periodic acid Schiff (PAS) positive and diastase resistant.

On the other hand, Well differentiated squamous cell carcinoma has an entirely different histopathological picture. It appears as dysplastic stratified squamous epithelium extending through the basement membrane into the underlying fibrous connective tissue and is arranged as islands, nests, cords or dispersed individual cells without attachment to the surface. The malignant epithelial cells show hyperchromatic nuclei, pleomorphism, mitotic activity, individual cell keratinization, intercellular bridging and eosinophilic cytoplasm. Round, eosinophilic, concentric layers of keratin fancily called Keratin pearls are a feature of well differentiated squamous cell carcinoma.

Genetics: Apart from the regular etiological risk factors for all cancers, the pathogenesis of Secretory carcinoma breast is attributed to a specific genetic alteration, a t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 fusion gene in both the in situ and invasive components ^(14,15,16). By RNA analysis, the most frequent fusion breakpoints are between exon 5 of ETV6 and exon 15 of NTRK3⁽¹⁷⁾. The pathogenesis of squamous cell carcinoma of buccal mucosa is multifactorial with accumulation of genetic alterations such as Loss of function of TP53 mutations and CDKN2A inactivation.⁽¹⁸⁾

While breast cancer as primary tumour is the most common source of metastasis to the oral cavity in women, metastasis to the buccal mucosa is uncommon.⁽¹⁹⁾ This present case of Buccal mucosal Squamous cell Carcinoma cannot be considered at any stage as a metastasis from the secretory breast carcinoma as both are morphologically different variants. With the available literature, there is no evidence of coexistence of both these tumours in a single patient.

Treatment: The increased incidence of multiple malignant tumours is a real challenge to the clinician and clinical attention should be made to avoid a misdiagnosis. Synchronous cancers that required no modification of the treatment, the prognosis was better and the survival rate was 28%⁽²⁰⁾.  Treatment modality should be carefully made and tailored on the individual patient suffering from this disease⁽²¹⁾. Despite favourable Disease Specific Survival outcomes in early-stage oropharyngeal and hypopharyngeal cancers, Overall Survival remains compromised due to secondary malignancies⁽²²⁾.

Secretory Ca of Breast being a very rare tumour in spite of being Triple negative phenotype yet carries good prognosis⁽²³⁾. It is a relatively indolent tumour with an excellent overall prognosis. Despite a 30% incidence of axillary lymph node metastases, the 5-year survival rate is almost 100%. Surgery, whether conservative or radical, is the preferred treatment. The prognosis remains good. Simple mastectomy cures in most cases and axillary dissection to be done in LN+ on imaging or clinical positive nodes. The benefits of chemotherapy and radiotherapy remain debatable. Management is not codified, given the rarity of this subtype, so further studies are needed in order to establish appropriate management ⁽²²⁾.

As our case has synchronous Squamous cell Carcinoma of oral cavity, this poses a complex scenario to navigate. Firstly, MRM breast surgery followed by Mandibulectomy was done. Neoadjuvant chemo with 6 cycles of Pacli Carbo was suggested for both breast and oral cavity lesions. Opinion for Radiation is required for both the tumours.

CONCLUSION:

The occurrences of synchronous tumours is an alarming situation to the patients and their attendants and must drive the medical fraternity into finding new regimens and methods in treating these cases without any significant side effects or toxicity to the patients while treating both the tumours simultaneously. To the best of our knowledge and based on the currently available literature, this combination has not been previously reported. This rarity emphasizes the importance of thorough clinical evaluation and a high index of suspicion for additional primary malignancies.

The motive behind presenting this case report is only to bring to light that a very rare tumour secretory carcinoma of breast is coexisting with squamous cell carcinoma of the buccal mucosa. With the available literature, there is no evidence of these two tumours coexisting in a single patient and probably we are the first to report this combination.  This poses a challenge for the treating clinician in planning the best treatment. Hence, more case studies must be reported in the future to evaluate the association between secretory carcinoma of breast and squamous cell carcinoma of the buccal mucosa to develop proper treatment protocols.

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Ethics statement by all authors

As this is a case report without identifiers, approval from Institutional Review Board is not required.

Data Access Statement: All relevant data are within the paper and its supporting information files.

ACKNOWLEDGEMENTS: Dr. P. Chandra Sekhar Vice Chancellor of Dr NTR University of Health Sciences, for his support

Onquest Laboratories New Delhi

REFERENCES:

1. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16. PMID: 39817679; PMCID: PMC11745215.
2. Irimie, P. Achimas-Cadariu, C. Burz, E. Puscas, Multiple primary malignancies - epidemiological analysis at a single tertiary institution, J. Gastrointestin. Liver Dis. 19 (2010) 69–73. PMID: 20361078.
3. Nishitha Choudary etal. Optimizing treatment strategies for synchronous malignancies: Integrating overlapping regimens for improved outcomes. 2025 American Society of Clinical Oncology.
4. Coyte A, Morrison DS, McLoone P. Second primary cancer risk—the impact of applying different definitions of multiple primaries: Results from a retrospective population-based cancer registry study. BMC Cancer. 2014;14:272. doi: 10.1186/1471-2407-14-272. 
5. Billroth, G. Reimer, in: Die allgemeine chirurgische pathologie und therapie. 51 Vorlesungen-Ein Handbuch fur Studierende und Artze, 14 Auflage, Berlin, 1889, p. 908.
6. Warren, O. Gates, Multiple primary malignant tumors: a survey of the literature and a statistical study, Am. J. Cancer 16 (1932) 1358–1414.
7. L. Gluckman, J.D. Crissman, J.O. Donegan, Multicentric squamous-cell carcinoma of the upper aerodigestive tract, Head Neck Surg. 3 (1980) 90–96, https://doi.org/10.1002/hed.2890030203.
8. G. Moertel, Multiple primary malignant neoplasms: historical perspectives, Cancer 40 (4 Suppl) (1977) 1786–1792, https://doi.org/10.1002/1097-0142 (197710)40:4+%3C1786::aid-cncr2820400803%3E3.0.co;2-2.
9. Margoum S, Berhili S, Bouabid M, Moukhlissi M, Loubna M. Secretory Carcinoma of the Breast: A Rare Entity With Favorable Prognosis. Cureus. 2024 May 16;16(5):e60430. doi: 10.7759/cureus.60430. PMID: 38883124; PMCID: PMC11179585.
10. Tandon P, Dadhich A, Saluja H, Bawane S, Sachdeva S. The prevalence of squamous cell carcinoma in different sites of oral cavity at our Rural Health Care Centre in Loni, Maharashtra - a retrospective 10-year study. Contemp Oncol (Pozn). 2017;21(2):178-183. doi: 10.5114/wo.2017.68628. Epub 2017 Jun 30. PMID: 28947890; PMCID: PMC5611509.
11. Z. Liang et al. Characteristics of secretory breast carcinoma with extensive in situ carcinoma components: Clinical and histopathologic analysis. Human Pathology Reports 37 (2024) 300755
12. Li L, Wu N, Li F, et al. Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma. Cancer Biol Med 2019;16:139–46.
13. Gayathri PS, M B, Ramani P, J M, Jeyakumaran S, Raman P. Oral Squamous Cell Carcinoma of the Right Buccal Mucosa: A Case Report. Cureus. 2024 May 3;16(5):e59571. doi: 10.7759/cureus.59571. PMID: 38826907; PMCID: PMC11144300.
14. P. Horowitz, C.S. Sharma, E. Connolly, D. Gidea-Addeo, I. Deutsch Secretory carcinoma of the breast: results from the survival, epidemiology and end results database Breast, 21 (3) (2012), pp. 350-353, 10.1016/j.breast.2012.02.013
15. Del Castillo, F. Chibon, L. Arnould, et al.Secretory breast carcinoma: a histopathologic and genomic spectrum characterized by a joint specific ETV6-NTRK3 gene fusion Am. J. Surg. Pathol., 39 (11) (2015), pp. 1458-1467,
16. Krings, N.M. Joseph, G.R. Bean, et al. Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas Mod. Pathol. 30 (8) (2017), pp. 1086-1099, 10.1038/modpathol. 2017. 32
17. Tognon C, Knezevich SR, Huntsman D et al, Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell2002;2:367–376.
18. Comprehensive genomic characterization of head and neck squamous cell carcinomas The Cancer Genome Atlas Network Naturevolume 517, pages576–582 (2015)
19. Kaplan I, Raiser V, Shuster A, Shlomi B, Rosenfeld E, Greenberg A, Hirshberg A, Yahalom R, Shnaiderman-Shapiro A, Vered M. Metastatic tumors in oral mucosa and jawbones: unusual primary origins and unusual oral locations. Acta Histochem. 2019;121:151448. doi: 10.1016/j.acthis.2019. 151448.
20. Eugene Panosetti MD, Bernard Luboinski MD, Gerard Mamelle MD, Jean-Marie Richard MD Multiple synchronous and metachronous cancers of the upper aerodigestive tract: A nine-year study doi:10.1288/00005537-198912000-00011
21. Testori, A., Cioffi, U., De Simone, M. et al.Multiple primary synchronous malignant tumors. BMC Res Notes 8, 730 (2015). https://doi.org/10.1186/s13104-015-1724-5
22. Yasumatsu R, Abe D, Kimura T, Iwata S, Ochiai M, Konya S, Kawamoto M, Umemoto M, Koike S, Sato M, Kitano M, Wakasaki T. Impact of Multiple Primary Cancers on the Prognosis of Early-stage Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma: A Single-center Retrospective Study. In Vivo. 2025 Nov-Dec;39(6):3581-3588. doi: 10.21873/invivo.14156. PMID: 41167659; PMCID: PMC12588252.
23. Nassira K, Haloui A, Bekhakh C, Seghrouchni N, Bennani A. Secretory Breast Carcinoma: A Rare Breast Cancer With an Excellent Behavior. Cureus. 2024 Nov 9;16(11):e73312. doi: 10.7759/cureus.73312. PMID: 39655117; PMCID: PMC11626254.