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"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This installment: A noteworthy case study.

What caused a 71-year-old man with morbid obesity to develop a quickly worsening rash and swelling on his left chest wall? That's what Ankit Mangla, MD, of University Hospitals Seidman Cancer Center in Cleveland, and colleagues needed to determine.

As they described in a clinical challenge, the patient, who presented to the dermatology clinic, explained that he had noticed a minor rash a few days after receiving his then second dose of an mRNA COVID-19 vaccine. However, in the 6 weeks since then, he developed swelling on the left side of his chest, which along with his skin condition advanced rapidly.

He said his skin was not itchy, nor had there been any weeping, bleeding, or discharge. His medical history included metabolic syndrome, which was being managed with blood pressure medication and oral hypoglycemics.

Examination of the skin revealed a 19×10 cm-deep infiltrated pinkish purple papule in the left breast. There was also a smaller (15×7 cm) papule below his left shoulder blade. The breast examination was notable for abnormal tissue enlargement in both breasts, the left nipple was inverted, and there were no lumps or swelling of the lymph nodes evident on palpation.

Laboratory test results indicated stage 2 chronic kidney disease. Viral panel results were negative for hepatitis A, B, and C, and for HIV. Punch biopsy of the skin showed a diffuse island of atypical cells in the dermis.

On immunohistochemical staining, "the atypical cells stained positive for CK-7, GATA-3, and PAX-8 (weak focal staining) and negative for estrogen receptor (ER)/progesterone receptor (<1%), TTF [thyroid transcription factor]-1, SATB-2, CDX-2, and NKX-3.1," Mangla and co-authors wrote.

PET-CT scan revealed a "diffuse, infiltrating fluorodeoxyglucose (FDG)-avid cutaneous lesion on the left chest wall (standardized uptake value, 6.5) and multiple FDG-avid nodes in the axilla (bilaterally), left internal mammary, and left cervical chain," the authors wrote. Clinicians also took a core biopsy from the lymph node.

The team considered several conditions that may have caused the symptoms, including cutaneous angiosarcoma, inflammatory breast cancer (IBC), primary adnexal gland carcinoma, and vaccine-related leukocytoclastic vasculitis. As it turned out, the patient's history of receiving the COVID vaccine was a red herring in this case, Mangla and colleagues determined.

They ultimately diagnosed the patient with IBC after histopathologic examination of the lymph node biopsy showed invasive ductal carcinoma with micropapillary features and the immunohistochemistry report noted that staining was positive for GATA-3 and CK-7, as well as 40% ER expression.

"Next-generation sequencing showed a microsatellite stable status and variations in the CDKN2, ERBB2, and PIK3CA genes," with the findings pointing to a diagnosis of IBC with invasive ductal carcinoma, the authors said. The patient was started on systemic chemotherapy.

Discussion

Presentation with a skin lesion on the breast creates an added challenge in differentiating between adnexal tumors and breast cancer, Mangla and co-authors noted. Their patient's presentation of an extensive rash, retracted nipple, and a peau d'orange appearance of the skin reflected a common among patients with IBC, although peau d'orange skin may also be due to cellulitis and lymphatic blockage due to radiation.

Regarding the atypical cells from the skin punch biopsy staining positive for GATA-3 and CK-7, GATA-3 is often expressed in ER-positive breast cancers, and as a member of the GATA family of zinc-finger transcription, GATA-3 contributes to the development and morphogenesis of breast tissue.

Importantly, GATA-3 may also be expressed by tumors of the salivary gland, urothelial system, skin and adnexa, and pancreas, as well as mesothelioma. As modified and specialized apocrine glands, glands of the breast "share structural and functional homology with sweat glands," the case authors said.

Staining findings for adnexal tumors are positive for P63, CK5/6, and CK-7, as well as for GATA-3.

This case was a diagnostic challenge because the patient had no discrete breast mass and the PET scan revealed an FDG-avid infiltrating mass in the chest wall with involvement of several lymph nodes in the axillary and internal mammary chain.

And while the core-needle biopsy of the chest wall mass had a similar staining pattern, it was positive for ER, in contrast to the skin biopsy, which tested negative for ER and progesterone receptor. ER positivity on its own is not enough to distinguish a tumor of the adnexal gland from breast cancer, Mangla and co-authors explained.

Positive test results for CDKN2, ERBB2, and particularly the phosphatidylinositol-3-kinases-CA () variation, which is commonly associated with ER-positive/ERBB2-negative breast cancer, confirmed the breast cancer diagnosis.

Similarly, about 30% of breast cancers express ERBB2 (i.e., HER2 or HER2neu), but tumors of the adnexal gland are not known to express PIK3CA or ERBB2.

This is why the molecular profile of this patient's tumor tissue was most consistent with that of breast carcinoma, the case authors explained. About 1% of breast cancers occur in men; the mass tends to develop behind the areola, and is usually characterized by skin ulceration, retraction, bleeding from the nipple, and axillary lymphadenopathy.

IBC is an aggressive form of breast cancer, and while it causes 2-4% of all breast cancers and 7-10% of breast cancer-related deaths in the U.S., it occurs only extremely rarely in men, the authors noted.

As well, the absence of screening guidelines and the overall limited understanding of gynecomastia -- which often affects obese men -- frequently delays diagnosis until the cancer is advanced.

Mangla and co-authors added that although most IBC patients have redness, warmth, and tenderness typical of inflammation, the cancer does sometimes manifest as painless skin induration due to lymphatic invasion of the dermis. Involvement of tends to mean a poor prognosis; initial use of surgery is contraindicated, regardless of the extent.

"This report highlights the importance of using the complete clinicopathologic features, including tumor morphologic characteristics, immunohistochemical staining, and molecular profiling, to arrive at the correct diagnosis," the team concluded.

Read previous installments in this series:

Part 1: Breast Cancer -- The Basics of Diagnosis, Staging, and Treatment

Part 2: Breast Cancer: Making the Diagnosis With Breast Biopsy

Part 3: What to Know About Management of Early-Stage Breast Cancer

Part 4: New Treatment Options for Locally Advanced and Metastatic Breast Cancer

Part 5: Genetic Testing in Breast Cancer: Mutations, Multigene Panels, and More