Rare Sites of Metastases to the Breast and Integumentary System in Advanced Cervical Cancer at Initial Presentation in Eastern Uganda: A Case Report

Abstract

Background

Cervical cancer (CC) is the leading Gynaecological cancer in Uganda with an estimated 6959 women diagnosed, and 4607 annual deaths. About 60–80% of CC patients present with advanced stage disease with either local spread or with distant metastases. For those with distant metastases, the most common sites of spread are the lungs and supraclavicular lymph nodes. Breast and integumentary system metastases are very rare. We present a case with such metastases managed in eastern Uganda.

Case Presentation

A 72 years old, Ugandan black African female, came in with a 13 months history of intermittent postmenopausal bleeding and associated abnormal vaginal discharge. She had repeatedly been managed from the nearest health facility for recurrent urinary tract infection and sexually transmitted diseases with no improvement. On examination at Mbale Regional Referral Hospital, she had poor performance status, cachexic, with bilateral pitting, tender poedal oedema, left breast masses and cutaneous nodules on the anterior aspect of the left thigh. Abdominal exam revealed a bulky uterus. On vagina examination, a large easily bleeding cervical tumour measuring about 8 cm × 7 cm and involving the upper 1/3 of the vagina was found. Bimanual pelvic exam revealed bilateral parametria involvement and bilateral pelvic side wall extension. Biopsies of the cervical, breast and the cutaneous masses were positive for high grade adenocarcinoma. Immunohistochemistry (IHC) for breast and cutaneous biopsies was positive for 16-kilodalton protein (P16), and negative for Oestrogen receptors (ER) and Progesterone receptors (PR). A diagnosis of cervical adenocarcinoma stage IVB (with breast and integument system metastases), with obstructive uropathy and probable deep venous thrombosis was made. She was offered total palliation and unfortunately succumbed on day 3 of admission.

Conclusion

Cervical adenocarcinoma stage IVB with breast and integumentary metastases portends poor prognosis. Gynaecologic Oncologists and other service providers need to do thorough exam and investigations to rule out metastases to rare sites. This will aid appropriate counselling during care.

Background

Cervical cancer (CC) is one of the major public health burdens of the World. It accounts for about 20% of the world’s 1,047,000 global orphans due to cancer and is only bettered by breast cancer at 25%.¹ Furthermore, annually, 22% of all female cancers and 12% of all newly diagnosed cancers in both men and women are attributable to cancer of the cervix in the African region.² Moreover, of the 20 countries in the world with the highest burden of cervical cancer, 18 are in the World Health Organisation (WHO) African region with Eswatini leading followed by Malawi. Despite the WHO launch of the 90-70-90 strategy of eliminating cervical cancer in 2020, the WHO African region launch of the, the region accounted for 23% of global cervical cancer mortality as of 2022.³

In Uganda, annual estimates indicate that 6959 women are diagnosed with cervical cancer (accounting for 33.8% of all cancers in women) and 4607 die from the disease making cervical cancer the most frequent cancer among women.⁴ Notably, Uganda has one of the highest CC incidence rates in the world, with an age-standardized rate of 41.4 per 100,000 people compared to the global average of 14.1 per 100,000 women.^4,5

In terms of histological subtypes, squamous cell carcinoma (SCC) is the leading type. Wang et al, reported that 82.7% and 12.2% of the global CC are squamous cell carcinomas and Adenocarcinomas, respectively. The highest incidence of SCC was observed in Sub-Saharan Africa (29.79/100,000 population) and that of adenocarcinoma (AC) in South-Eastern Asia (3.67/100,000 population). According to age-specific trends, SCC peaks at approximately age 55 years and AC plateaus after age 45 years.⁶ Moreover, a rise in incidence of adenocarcinoma histiotypes has been reported among patients in the United States of America.^7,8

Patients with AC portend higher odds of distant spread than those of SCC. AC have a higher incidence of spread to the paraaortic lymph nodes, uterine corpus, and adrenal gland, and may be more associated with ascites and pleural effusion.^9,10 Adenocarcinomas are also associated with an increased risk for distant recurrence resulting from haematogenous spread compared with SCC.⁹

In the presence of distant metastases to the rare sites such as breast and integumentary system, it is important to differentiate cervical cancer primaries and non-cervical primaries, because management and prognosis differ. Immunohistiochemistry (IHC) is standard in this case.^11–13

It is important to discern AC from SCC because of the associated poor prognosis in terms of progression free survival and overall survival^{8–10,14–16} largely because of much more likelihood of haematogenous spread and distant recurrence.^9,10 This is important in counselling and discussing prognosis with the patient and her family. Although, majority of the CC patients 60–80%, present in stage III–IV,^17,18 metastases to the breast and the integument system are rare. We report a case of such rare metastases that presented at MRRH.

Case Presentation

We present a 72 years old, Para 11+3 over 20 years postmenopausal, Ugandan black African female who presented to Mbale Regional referral hospital (MRRH) Gynaecological emergency ward as a referral from a private facility in September 2024. She reported a 13 months history of intermittent par vagina bleeding with associated intermittent episodes of purulent vaginal discharge. She had been to the nearest district health facility since the initial episode, from where she had repeated episodes of treatment for urinary tract infection and sexually transmitted diseases.

She continued to waste away with worsening symptoms of general body weakness to an extent of needing support to sit upright and inability for self-care. She reported a 3 weeks history of lower limbs swelling. She was later sent to a private hospital in Mbale to do investigations. Owing to her ailing condition, an abdominal pelvic ultrasound scan was done and showed a cervical mass of 5 × 5 cm, with no ascites, no abdominal or pelvic lymph node involvement and no abdominal visceral involvement. She was subsequently advised to come to MRRH.

Significant gynaecologic history included no history of use of modern contraceptives and had never screened for cervical cancer.

On arrival at our hospital, she was severely wasted with poor performance status of Eastern Cooperative Oncology Group (ECOG) 4, mildly pale, afebrile with axillary temperature of 36.2°C, bilateral tender grade 3 pedal oedema, No lymphadenopathy.

Thyroid exam was normal.

Breast exam: Revealed 3 solid nontender masses with two in the upper outer quadrant and one in the outer lower quadrant of the left breast. The masses were free from the overlying skin and mobile with the largest mass measuring about 3 × 3 cm. The right breast was normal. There was no any notable discharge from either breast.

Thyroid exam was largely normal.

Abdominal exam revealed moderate tenderness in the suprapubic area.

Vagina examination: Vulva was largely normal. There was evidence of offensive purulent discharge per vaginum.

On speculum vaginal examination, we noted an easily bleeding fungating cervical mass that measured about 8 × 7 cm and involved the upper 1/3 of the vagina (Figure 1A).

Figure 1.

(A–D) A-On speculum exam a cervical mass is seen as indicated by the arrow. In B-Skin nodules over the left thigh below the inguinal ligament are seen as indicated by the arrows. In C-excision biopsy of the left breast mass is being taken (arrow) and D-chest x-ray, shows no evidence of metastases.

Bimanual exam revealed induration in both parametria with bilateral pelvic side wall extension. Note was made of moderate tenderness during examination.

Digital rectal exam revealed a largely empty rectum with no blood on examining finger.

Integument system: There were two nodular masses on the Left upper thigh just about 2 cm inferior to the inguinal ligament and overlying the iliacus, psoas Major and pectinus muscles and medial to the anatomical location of the left sartorious. The nodules were solid, firm, nontender and free from underlying muscles (Figure 1B).

The patient was admitted on ward and Renal and liver function tests revealed a hyperkalaemmia of 7.6 mmol/L, creatinine = 350µmol/l (range 60–115), urea = 16.67 µmol/L (2.76–8.07) and hypoalbuminaemia = 20g/L (laboratory ranges 28–54).

Diagnosis

72-yr old Para 11+3 with probable Cervical carcinoma (tentatively stage IVB), with obstructive uropathy and Ureamia with severe hyperkalaemia, poor performance status and probable bilateral Deep venous Thrombosis.

Plan of Management and Prognosis

A family conference was held with the family and agreed to provide her with total palliation (pain relief using 2.5 mg of oral morphine 6 hrly and rehydration with 100 mls of isotonic saline fluid per hour).

On day 3 of her admission, she succumbed to the disease.

Histology Results

Histology results from all the biopsies showed similar tumour composed of highly pleomorphic round epithelial cells forming clusters, micropapillary and glandular structures and sheets in dimorphic stroma. There was evidence of tumour necrosis and increased mitotic figures with lymphovascular space invasion (Figures 2–4). This was evidence of high‑grade metastatic adenocarcinoma.

Figure 2.

Micrograph of the skin nodules showing highly pleomorphic round epithelial cells forming clusters, micropapillary and glandular structures and sheets in dimorphic stroma.

Figure 3.

Micrograph of the breast lesion showing highly pleomorphic round epithelial cells forming clusters, micropapillary and glandular structures and sheets in dimorphic stroma.

Figure 4.

Photomicrograph of the cervical mass punch biopsy histology showing highly pleomorphic round epithelial cells forming clusters, micropapillary and glandular structures and sheets in dimorphic stroma. There is evidence of tumour necrosis and increased mitotic figures with lymphovascular space invasion.

Immunohistochemistry was positive for P16 and negative for ER, PR on breast and cutaneous biopsies as shown below in Figure 5.

Figure 5.

Photomicrographs (A–D): in (A) – breast and integumentary tissue (cutaneous lesions) were P16 positive and negative for ER and PR in (C and D), respectively.

Diagnosis confirmed: 72‑yr‑old Para 11+3 with cervical adenocarcinoma stage IVB, with obstructive uropathy, Ureamia with severe hyperkalaemia, poor performance status and probable bilateral deep venous thrombosis.

Discussion

Despite the launch of the 90-70-90 strategy of cervical cancer elimination, coverage remains elusive. In 2026, global estimates indicate that only about 33% of girls had received at least one dose of HPV vaccine³ and as of 2019, only 33% of women aged 30–49 years had ever been screened.¹⁹ A recent study in northern Uganda amongst HIV positive patients, Atepo et al reported that only 49.6% had ever undergone cervical cancer screening²⁰ reaffirming the fact that the 70% target had not been achieved. This failure to achieve the first two targets of 90 and 70 directly affect the stage at presentation in Uganda and other parts of the world.

In Uganda, about 60–80% of patients present with advanced stage disease CC (Stages III–IV) and present challenges in management since quite often, a number of complications are present^17,18,21 and offer little or no chance of complete remission.²¹ Similar challenges have been reported in other parts of the World especially in low and middle income countries (LMIC).^22–25 Late stage (stage IVA-IVB) at presentation has also been reported in the developed world amongst the blacks and other underserved populations.⁸ Our patient presented at stage IVB with distant metastases to the breast and the integumentary system.

In terms of histological subtype, squamous cell carcinoma is the leading type and adenocarcinoma is rare. Wang et al, reported that globally squamous cell carcinoma (SCC) accounted for 82.7% of global cervical cancer cases, while Adenocarcinoma (AC) contributing to 12.2%. The highest incidence of SCC was observed in Sub-Saharan Africa (29.79/100,000 population) and that of adenocarcinoma (AC) in South-Eastern Asia (3.67/100,000 population). SCC was reported to peak at about 55 years age and that of AC to plateau after age 45 years.⁶ Moreover, a rise in incidence of adenocarcinoma histiotypes has been reported among patients in the United states^7,8 among reproductive age women and decreasing among those aged at least 70 yrs.⁸ Our patient was a 72 yr old who presented with advanced metastatic stage IVB adenocarcinoma disease as per the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging,²⁶ with breast and integumentary system metastases and European Cooperative Oncology Group (ECOG) 4.

Overall survival (OS) with CC largely depends on the stage of the disease.²⁷ Patients with AC have higher odds of distant spread involving the paraaortic lymph nodes, uterine corpus, and adrenal gland, and may be more associated with ascites, pleural effusion¹⁰ and increased risk for distant recurrence resulting from haematogenous spread when compared with SCC.^9,10 Subsequently, the five-year OS of stage IVB CC is about 14.7%, which is almost 50% lower compared to stage IVA, at approximately 24%.²⁸ Furthermore, Kassa et al reported a pooled 5 yr OS rate for cervical cancer patients in East Africa was 36% with a range of 26–43%.²⁵ Notably, AC has worse prognosis compared to SCC even in early stage disease cervical cancer (IA2–IIA2).¹⁶ A meta-analysis by Yao et al also reported worse disease-free survival (DFS) and overall survival (OS) in patients with AC compared to patients with SCC undergoing definitive radiotherapy or concurrent chemoradiotherapy.²⁹ Others studies have reported the same findings.^30–32

In a retrospective population based study by Suyu Li et al, cervical adenocarcinoma presented with single organ metastases in 73.3% of cases and the lungs were the most affected organ, followed by the liver and bones. Furthermore, they reported that distant organ metastasis, advanced age, positive lymph nodes, advanced stage, larger tumour diameter, and higher tumour grades are related to poor prognosis.¹⁵ This case is one of the rare cases with multiple organ site involvement and poor prognostic features such as advanced age at 72 yrs, large tumour size 8 × 7 cm and higher tumour grade. This was further complicated by probable bilateral thromboembolic events (suspected due to bilateral tender pitting oedema), poor renal function with obstructive uropathy, and uraemia with severe hyperkalaemia of 7.6 mmol/L.

Furthermore, the most common symptomatology of cervical cancer is vaginal bleeding,^17,24,33 offensive vaginal discharge, lower abdominal pain, haematuria, constipation^17,24,33 and comorbidities.²² However, unusual presentations have been reported. The unusual presentations could range from gynaecologic asymptomatology yet with advanced stage disease, needing the aid of advanced diagnostics such as 18F-flourodeoxyglucose positron emission tomography/computed tomography (PET/CT),³⁴ to rare metastatic sites such as small bowel and cyst in the hand.³⁵ Other rare presentation such as breast lesions^34,36–40 and dysphagia³⁴ have been reported especially in recurrent cancer of the cervix. Our patient had reported with postmenopausal bleeding at the nearest health centre IV about 13 months prior to presentation at MRRH, and had been repeatedly managed as a case of urinary tract infection and or sexually transmitted diseases. In Uganda, a health centre four is the first facility at which a patient is expected to interact with a medical officer. The hierarchy of health facilities and their level of functionality has been highlighted in one of our publications.⁴¹ Despite the treatments, she went on to deteriorate, and presented at our clinic with rare site of metastases involving the breast and cutaneous metastases.

Although mammary malignancies as metastatic lesions are extremely rare, evidence shows that a number are missed and only discovered at autopsy. The incidence rates reported are as low as 0.4–3% but rise to between 1.7–6.6% at postmortem autopsy.⁴² Similar to our case, adenocarcinoma and squamous carcinoma of the cervix metastases to the breast although rare, have been reported before.^36,43 However, most of the literature presents breast metastases in recurrent cervical cancer rather than at initial presentation^39,44,45 and could present as inflammatory breast disease.^46,47 In our case it a was at initial presentation not a recurrence.

Cervical cancer metastases to the integumentary system are more likely to involve the lower abdomen and lower extremities more than the face, upper extremities, and chest. These patients have been reported to have poor prognosis^48,49 and Brady et al reported a 3 months timeline from diagnosis to death.⁴⁹ In our case, the left thigh was involved and the patient died on the third day of admission. The presentation of cutaneous lesions is most often in form of non-tender nodules although cases of cutaneous lymphangitis carcinomatosa^50,51 have been reported. Our patient had non-tender cutaneous nodules on the left thigh.

Moreover, cervical cancer metastases to the integumentary system are rarer than metastases to the breast with an incidence rate of 0.1–2%.^49,52 Imachi et el reported cutaneous metastases ranging from 0.8% in stage I, 1.2% in stage II/III, and 4.8% in stage IV and the odds of cutaneous metastases were higher with adenocarcinoma histology than squamous cell carcinoma.⁴⁸ However, the initial presentation of cervical cancer with cutaneous metastases has been reported^53,54 just like in our case.

Although the mechanism of cervical cancer metastases to the breast and integument system is still unclear, chemokines role in epithelial mesenchymal transition and angiongenesis is implicated especially CXCR4/CXCL12.⁵⁵ Additionally, the extracellular matrix (ECM), a supramolecular aggregate composed of extracellular proteins, proteoglycans, and glycoproteins plays a role in tumourigenesis through ability of the tumour to remodel its own ECM and that of the distant organs.⁵⁶ It is likely that these metastases occurred by a haematogenous or a lymphatic route. Lymphatic metastasis to the breast is thought to occur by either retrograde flow via the para-aortic lymph nodes to the subclavian lymph node chain with subsequent back flow to the axillary lymph node groups and then to the subareolar and circumareoloar plexuses with final termination within the perilobular and interlobular plexuses within the breast or by retrograde flow from the anterior parasternal lymph nodes to the medial aspect of the breast.⁴³ It is important to differentiate cervical cancer primary from non-cervical primaries, because treatment is different. IHC is key in this initiative, and choosing the right panel is fundamental. Such may include, but is not limited to Trichorhinophalangeal syndrome 1 (TRPS1) which is highly sensitive for both luminal and triple-negative breast cancers and negative cervical adenocarcinoma, PAX 8 (Paired Box Gene 8) that would be positive in about 70% of cervical cancer primaries and negative for breast cancer primaries. Additionally Mammaglobin and GCDFP-15 (Gross cystic diseases fluid protein −15) would be negative for CC primary and positive for breast cancer primary, GATA3 (Guanine, Adenine, Thymine and Adenine-3) would be negative for primary CC and diffusely positive for primary Breast.^11–13

We were able to do immunohistochemistry (IHC) for the breast and cutaneous lesions and all were positive for P16, and negative for ER and PR. IHC P16 reactivity has been reported before.^40,57 P16 is a putative molecular biomarker of adenocarcinoma and implicates HPV-induced cell cycle dysregulation.⁵⁸ Although HPV negative Adenocarcinoma in 15–20% cases have been reported,⁵⁹ HPV-16 and HPV-18 serotypes are implicated in most adenocarcinomas.⁶⁰ HPV negative/independent adenocarcinoma is associated with poor clinicopathological characteristics and survival outcomes compared to HPV positive/associated adenocarcinoma.^58,61 Our patient had HPV positive disease.

From the literature, treatment of such patient would have been for palliative purposes and combination chemotherapy with platinum and taxane with addition of Bevacizumab, lead to better outcomes.^50,62 However, given the poor performance status of 4 with obstructive uropathy and uraemia, with severe hyperkalemia, and probably bilateral deep venous thrombosis, following the family conference, a decision to undertake total palliation was made. Unfortunately, the patient succumbed on day 3 of admission.

What are the Challenges?

Uganda grapples with a high burden of cervical cancer as explained above^4,63 but with only two functional comprehensive cancer treatment centres; Uganda cancer institute about 240 km from Mbale Regional Referral Hospital and the newly opened Gulu Regional cancer centre (UCI).^18,64 There are no pathology labs at the regional referral hospitals. We relied on results from a private laboratory and had to take blocks for IHC at UCI. These challenges present significant delay in access to care. Fortunately Uganda government is committed to funding and operationalisation of regional cancer centres in different regions of Uganda.

Limitations

We were unable to have a more extensive IHC panel since these are paid for services at UCI and others like Trichorhinophalangeal syndrome 1 (TRPS1), Mammaglobin and GCDFP-15 (Gross cystic diseases fluid protein −15), GATA3 (Guanine, Adenine, Thymine and Adenine-3) are unavailable. Some pictures may not be the best.

Conclusion

In this case of advanced cervical cancer stage IVB adenocarcinoma histology subtype with rare multiple sites of metastases involving the integumentary system and the breast, IHC remains the gold standard for differentiating the primary from metastatic lesions. This is important since it influences choice of treatment.

Additionally Gynaecological Oncologists and other service providers need to take extra care and search for rare sites of metastases in cervical adenocarcinoma as it will influence family conferencing and counseling during management.

Family Perspective

The family thanked the team for timely information and desisting from burdening them with unnecessary work up and treatments.

Funding Statement

There was no any funding for work in this case report.

Abbreviations

CC, Cervical cancer; ECM, Extracellular matrix; ER, Oestrogen receptor; PR, Progestreone Receptor; MRRH, Mbale regional referral hospital; IHC, Immunohistochemistry; UCI, Uganda Cancer Institute.

Data Sharing Statement

There is no data base generated for this case report.

Ethics Approval

There was no need for institutional ethical approval from Mbale Regional Referral Hospital Ethics Committee (Mbale REC) to publish the case.

Consent to Participate

Written informed consent was obtained from the patient’s legal representative for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

We declare no financial interests for authorship of this case report.