A Rare Case of Metastatic Spiradenocarcinoma With CDKN2A Mutation

Johnathan Q. Trinh, MD, et al discuss a novel case of a patient with an
aggressive CDKN2A-mutated spiradenocarcinoma who responded to a CDK4/6 inhibitor.

A 70-year-old woman with no prior oncologic history presented with a rapidly enlarging growth on the first dorsal web of her right hand. She initially noticed it 2 years prior and received a diagnosis of ganglion cyst. A few months prior to presentation, she noticed the growth had reddened with increased vascularity and grown to approximately 1.3×2.5 cm. At this time, an excisional biopsy was pursued. Pathology results demonstrated a spiradenoma with adjacent cords and nests of atypical cells with a high nuclear-to-cytoplasmic ratio and areas of tumor necrosis.

Immunophenotyping was positive for SOX10 and GATA3 and negative for chromogranin, synaptophysin, and CK20. Based on the histologic features and immunohistochemical staining, the diagnosis of spiradenocarcinoma was made. This was followed by a wide local excision with 1.5- to 2-cm margins around a 5-cm transverse incision tumor bed along with sentinel lymph node biopsy after lymphoscintigraphy mapped to a deep right axillary level 2 node. Pathology of the primary site confirmed residual spiradenocarcinoma present in the center of the specimen, extending to the deep margin. Staining of the right axillary lymph node demonstrated a 5.5-mm focus of metastatic carcinoma with extracapsular extension.

A staging PET-CT scan only showed postoperative changes with no distant disease. Comprehensive level 1 to 3 radical axillary lymph node dissection was performed and showed no evidence of carcinoma. One month later, the patient developed a 1- to 2-cm mobile, palpable nodule in the thenar area on the dorsal aspect of her right hand. Punch biopsies of this mass showed spiradenocarcinoma at deep and lateral margins. The PET-CT scan did not demonstrate any other sites of disease. This was followed by a resection of the recurrent tumor, 4 to 5 cm deep into the hand with 2-cm margins, along with excisional biopsies of 2 epitrochlear lymph nodes. Pathology did not show any evidence of malignancy. A repeat ultrasound of the epitrochlear area 3 weeks later showed an abnormal right epitrochlear lymph node, suspicious for metastasis. A biopsy demonstrated malignant cells morphologically similar to the previously resected spiradenocarcinoma. Resection of epitrochlear lymph node with deep forearm dissection showed a 1.3-cm focus of metastatic spiradenocarcinoma with the presence of focal extranodal soft tissue, positive for SOX10 and GATA3.

The patient was treated with 5000 cGy of adjuvant radiation therapy to the epitrochlear region. The patient opted to forgo radiation treatment to the primary tumor site due to concerns of impairment with her surgical skin graft. The PET-CT scan did not show recurrence or metastases at that time. Six months later, a repeat scan showed a new hypermetabolic mediastinal lymph node concerning for metastatic disease. Flexible bronchoscopy and video-assisted thoracoscopy intraoperatively showed several pleural and parenchymal nodules, leading to a right lower lobe wedge resection and 2 pleural biopsies. The pathology of all samples returned as metastatic spiradenocarcinoma.

FoundationOne testing was performed and demonstrated the presence of a nonsense-substitution CDKN2A mutation. PD-L1 testing was negative (< 1%), tumor mutational burden was low, and microsatellite status was stable. The patient was then started on paclitaxel 200 mg/m2 and carboplatin of area under the curve (AUC) 6 every 3 weeks. Interval CT scans showed stable disease, and the regimen was stopped after 4 cycles due to grade 3 peripheral neuropathy. A follow-up PET-CT scan approximately 3.5 months after the patient stopped chemotherapy showed integral progression of multifocal lesions with new mediastinal, right hilar, right lung parenchyma, right pleural, and right lateral chest wall lesions with a maximum standard uptake value of 14.5. The patient was then treated with carboplatin AUC 6 and pemetrexed 500 mg/m². After 4 cycles, a PET-CT scan showed interval progression of extensive right lung parenchymal, right pleural, and right chest wall metastatic disease.

Given the finding of CDKN2A mutation, the patient was enrolled into the palbociclib arm of the nonrandomized phase 2 TAPUR trial (NCT02693535), which is exploring targeted anticancer drugs for patients with potentially actionable genomic alterations.¹ The patient received 125 mg daily of palbociclib for 21 days on a 28-day cycle.¹ CT scans of the chest, abdomen, and pelvis after 2 cycles showed decreased size of pulmonary nodules, decreased pleural thickening, decreased size of right hilar mass, decreased mediastinal lymphadenopathy, and overall response to treatment. During the third cycle, she developed chest pain and dyspnea. CT angiogram showed severe narrowing of the right upper lobe pulmonary artery branch and near complete occlusion of the right anterior lower lobe bronchus due to tumor compression, along with increased size and number of bilateral pulmonary nodules. Meeting RECIST criteria for disease progression, palbociclib was discontinued and she was started on palliative radiation to the right hilum and mediastinum. PET-CT scan showed extensive worsening of metastatic disease with extensive new metastases throughout the spine, liver, spleen, and skeleton, along with worsening of thoracic metastatic disease. The patient elected to enroll in hospice and was aged 73 years when she died, 5 years after initial diagnosis.

Discussion and Literature Review

Spiradenocarcinomas are rare malignant adnexal neoplasms arising from eccrine sweat glands, often from prior benign spiradenomas.² Histologically, they often exhibit areas of spiradenoma architecture with abrupt transition to malignant morphology, including evidence of nuclear atypia, increased mitotic activity, and necrosis.³ They typically stain positive for most cytokeratins, with CK5-7 being the most frequently reported marker.²

Since spiradenocarcinoma’s first description in 1972, fewer than 200 cases have been reported, including fewer than 30 metastatic cases.^2,4 Due to its rarity, no consensus on treatment guidelines currently exists. Although surgical resection for nonmetastatic disease with lymph node dissection of tumor-involved regional lymph nodes has demonstrated success, treatment for metastatic disease has been proven to be far more difficult.⁵ Tamoxifen has shown significant success in a patient with estrogen receptor–positive spiradenocarcinoma.⁶ Pembrolizumab has demonstrated a partial benefit in patients with positive PD-L1 expression.^6,7

The CDKN2A tumor suppressor gene, first identified in 1994, was previously reported with different names (p16ink4, p16ink4a, CDK41, MTS1, and p16).8 Loss of this gene contributes to the bypass of critical senescent signals and subsequent progression to malignant disease.9 Its mutation or inactivation has been implicated in many types of cancers, such as melanoma and pancreatic cancer.⁸

Xenograft models of palbociclib, an oral low-nanomolar reversible inhibitor of CDK4/6, showed that tumor xenografts lacking CDKN2A were sensitive to the drug.¹⁰ The role of CDKN2A levels in gauging response to targeted therapies has only been marginally explored, but now with highly targeted compounds antagonizing this pathway in clinical use, examining the impact of these levels in future studies may be beneficial for patient stratification. For instance, elevated CDKN2A levels may suggest a poor response to these compounds, aiding with patient exclusion from these treatments.⁹

To our knowledge, we present the first case of CDKN2A-mutated metastatic spiradenocarcinoma. After 2 regimens of combined chemotherapy failed, our patient was started on palbociclib, which led to improvement in multiple metastatic lesions. Her disease ultimately progressed, and our patient died. However, spiradenocarcinoma is incredibly rare and lacks clear answers on treatment in advanced disease. This case highlights the benefit of targeted therapy, if applicable, as systemic therapy.

Corresponding author

Jonathan Q. Trinh, MD

Department of Internal Medicine

982055 Nebraska Medical Center

University of Nebraska Medical Center

Omaha, NE

Email: jtrinh@unmc.edu

References

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