When to sweat: A history of chemotherapy in malignant sweat gland tumors. A unique case report and literature review

Abstract

Sarcomatoid sweat gland carcinomas are rare among cutaneous cancers, with less than 20 cases described. A 54-year-old woman with sarcomatoid sweat gland carcinoma of the right upper extremity suffered extensive recurrence at 15 months, unresponsive to chemotherapy. There is no standard treatment or chemotherapy regimens for metastatic sweat gland carcinoma.

BACKGROUND

Sarcomatoid sweat gland carcinomas are rare among cutaneous cancers, with less than 20 cases described. A 54-year-old woman with sarcomatoid sweat gland carcinoma of the right upper extremity suffered extensive recurrence at 15 months, unresponsive to chemotherapy. There is no standard treatment or chemotherapy regimens for metastatic sweat gland carcinoma.

Tumors arising from sweat glands, or cutaneous adnexal tumors, comprise a small number of cutaneous tumors. 0.005%–0.01% of all cutaneous tumors are eccrine porocarcinomas, the most common type of cutaneous adnexal tumor.¹ Sarcomatoid carcinoma is an exceedingly rare biphasic malignancy consisting of an epithelial, carcinomatous component and a mesenchymal, sarcomatous component.² It has been known through publication history by other names, including carcinosarcoma, metaplastic carcinoma, and malignant mixed tumor.³ It arises more commonly from primary visceral sites such as the uterus, ovaries, breast, bladder, and lungs, and much less commonly as a primary skin lesion.⁴ When it does occur as a primary skin lesion, its epithelial component most often occurs as an epidermal-derived carcinoma or skin adnexal carcinoma.^2,5,6 Epidermal-derived carcinomas are more common and include basal or squamous cell carcinomas which tend to occur on sun-exposed skin of the head and neck, involve older patients, and yield more favorable prognoses with 5-year survival of 70%.^2,5,6 Skin adnexal carcinomas are much rarer and include spiradenocarcinoma, malignant proliferating trichilemmal tumors/cysts, porocarcinomas, and pilomatrical carcinomas.^2,5,6 These lesions tend to involve younger patients, grow from long-standing tumor nodules over many years, and are associated with aggressive behavior and poorer prognosis with 5-year survival of 25%.^2,5,6

Treatment for sarcomatoid carcinoma can vary depending on whether it is local or metastatic. Local disease is treated with wide local excision and Mohs micrographic surgery in several cases.⁷ There is limited evidence on the efficacy of radiation in local disease.⁷ Chemotherapy for metastatic sweat gland carcinoma are guided based on limited case reports. Even then, only modest responses have been shown.⁷

CASE REPORT

A 54-year-old female presented with an ulcerating mass of the right medial upper arm and underwent biopsy at an outside hospital. Pathology revealed poorly differentiated carcinoma with foci of squamoid and glandular differentiation as well as sarcomatoid features. The mass had previously been slow growing and subcutaneous without overlying skin changes for 8 years. The patient was referred to our institution shortly after for a more comprehensive evaluation of her biopsy, and for re-excision of the lesion with more surgically appropriate margins. Upon presentation, a PET-CT showed a 1.9 cm soft tissue density of the right medial upper arm, but no distal metastatic disease or lymphadenopathy. She then underwent wide local excision of the mass which measured 2 × 1 cm with a 1.5 cm margin.

Formalin-fixed, paraffin-embedded tissue blocks from all cases were examined by H&E-stained sections and immunohistochemistry. Immunohistochemical stains were performed using the following commercially available antibodies: CK 5/6, CK7, CK20, CAM5.2, vimentin, S-100, S-100 red, p63, TTF-1, ER, PR, chromogranin, synaptophysin, glypican-3, Ki67 from Roche/Ventana; and Sox10, GATA-3, CEA, Napsin-A, Pax8, and IMP3 from Cell Marque. Appropriate positive and negative controls were used throughout the study.

Pathology revealed a biphasic malignant neoplasm consistent with sarcomatoid sweat gland carcinoma. The epithelial component contained glandular and squamoid epithelial cells with pleomorphic spindled myoepithelial cells. The margins were negative and there was no sentinel lymph node biopsy performed. H&E slides can be seen in Figure 1, taken from a portion of the same slides found in Figure S2, images A and B. Original excisional biopsy images can also be reviewed in Figure S1.

The patient returned for frequent MRI surveillance of the arm over the next 10 months which showed consistent enhancement of the surgical site, thought to be secondary to skin changes and less likely residual tumor.

Fifteen months after the initial resection, the patient presented to the emergency department twice. The first time was for abdominal pain thought to be dyspepsia, then several weeks later for chest pain and 12-pound weight loss over the previous month. Radiography with CT scan of chest, abdomen, and pelvis showed multiple new masses measuring up to 9 cm in size in the right and left lungs, as well as the right hilar and subcarinal areas. New masses measuring 1.2 and 2.2 cm in size were also, respectively, detected in the liver and pancreas. These masses are shown in Figure 2. Bronchoscopy with biopsy of the pulmonary masses revealed metastatic sarcomatoid sweat gland carcinoma. Pathologic images and descriptions can be found in Figures S3 and S4. The patient was to be referred for outpatient palliative radiation of the lung metastases.

However, several days later the patient presented again to the emergency department for dizziness, left sided weakness, right facial droop, bifrontal throbbing headache, and altered mental status. CT scan of the head showed a large right frontal lobe mass measuring 4.2 cm, associated vasogenic edema, petechial hemorrhage, leftward midline shift, and mild subfalcine herniation. The mass is shown in Figure 3. Patient underwent right frontal craniotomy for tumor resection with symptomatic relief and resolution of the above symptoms. Pathology was consistent with previous results. Pathology slides and descriptions can be seen in Figure S5.

Her condition continued to deteriorate over the next few weeks with the development of hypoxemic respiratory failure secondary to worsening pulmonary metastases. Next-generation sequencing did not reveal targetable mutations, and ER and HER2 staining was negative. Without actionable mutations for targeted therapy, she received carboplatin and paclitaxel and was referred to radiation oncology for external beam radiation therapy of the pulmonary mass; however, the patient elected for best supportive care and expired.

DISCUSSION

Here we present a case that was both diagnostically challenging from a pathological perspective as well as clinically challenging with no standard treatment. Cutaneous sarcomatoid carcinomas are diagnostically challenging in that they are a very rare entity that can be easily confused with other diseases. A poorly differentiated carcinomatous element may be missed if ductal or glandular structures that hint at an epithelial origin are poorly formed.^5,8 The sarcomatoid carcinoma can potentially be confused with a wide variety of tumors including squamous cell carcinoma, breast ductal carcinoma, other skin adnexal carcinomas, and a variety of other mixed tumors of the skin which is why staining is vital to a correct diagnosis.^5,8,9–13

Metastases of cutaneous sarcomatoid carcinomas may consist predominantly or exclusively of the sarcomatous element, carcinomatous element, or both.^5,8 In our patient's case, the metastases to the lung and brain consisted predominantly of the sarcomatous population. This is in contrast to the primary cutaneous lesion in which the carcinomatous and sarcomatous populations were of comparable proportions. This finding may signify that sweat gland carcinomas with sarcomatous components may become more aggressive or metastasize more easily.^5,8 In our patient's case, the metastasis occurred and spread very rapidly.

Our decision to treat the patient with palliative carboplatin and paclitaxel was based on several previous cases receiving a combination of platinum-based and taxol chemotherapy.^14–20 Given the rarity of this case, we wanted to perform an extensive literature search to compare treatments of previous cases.

At first our literature search included only sweat gland tumors with sarcomatoid differentiation. However, this yielded minimal results as cases number less than 20 and many had local disease only. We widened our search to all malignant sweat gland tumors to grasp a better understanding of treatment outcomes. Key words included “malignant sweat gland carcinoma” which yielded 25 relevant articles out of 214 in total. We excluded articles pertaining to the breast or vaginal ductal carcinoma. Another literature search with keywords “metastatic sweat gland carcinoma” yielded 16 results, 7 of which were relevant. Six articles were excluded due to foreign language text. Given the variety in nomenclature of sweat gland carcinomas, references of included articles were used to identify many additional case reports dating back to the 1960s.

In our literature review, we found 15 distinct cases of specifically spindle cell sarcomatoid differentiation in various sweat gland tumors. However, this number is given with a degree of uncertainty due to the lack of consistent nomenclature in the literature. These are outlined in Table 1. Three additional cases were noted in Robson et al.; however, it is unclear if these overlap with previous cases as no source was tied to these in their review.¹ Patel et al. and McKee et al. described sweat gland tumors with mesenchymal elements that were non spindle cell and were therefore not included in Table 1.^21,22

TABLE 1 Sarcomatoid Cases. Key: EPC eccrine porocarcinoma. NR: not reported. FU-fluorouracil.

Case reference	Age, Gender	Site	Duration	Dx	Systemic Dx	Radiation	Chemo Regimen	Follow-up (months)	Outcome
Debska 197233	NR	NR	NR	Sarcomatous Spiradenoma	Unknown	No	No	NR	NR
Debska 197233	NR	NR	NR	Sarcomatous Spiradenoma	Brain, lung bone	No	NR	11	Death
Merrigi 198934	NR	NR	NR	Sarcomatous Spiradenoma	Lung	No	NR	2	Death
McCluggage 199735	60 M	Perineum	10 years	Sarcomatous Spiradenoma	Nodal, Lung	No	None	3	NR
Ishikawa 200136	37 F	Axilla	20 years	Sarcomatous Spiradenoma	Nodes, lung, abdominal, brain	Yes	5-FU, epirubicin, vincristine, carboplatin. Then cyclophosphamide, methotrexate and 5-FU	7	Death
Goh 200737	82 F	Chest	Many years	Sarcomatoid EPC	None	No	None	2	Alive
Goh 200737	74 F	Lower L Leg	Long-standing	Sarcomatoid EPC	None	No	None	48	Alive
Kazakov 20083	89 F	Buttock	NR	Sarcomatoid Apocrine Porocarcinoma	NR	NR	NR	NR	NR
Le 201613	84 F	Scalp	Several months	Biphasic Sarcomtaoid Porocarcinoma	None	No	None	60	Alive
Parra-Medina 201612	75 M	Right hallux	29 months	Sarcomatoid EPC	None	No	None	NR	NR
Panse 20172	80 F	Right leg	NR	Sarcomatoid Porocarcinoma	None	No	None	NR	NR
Ponzetti 20176	58 M	Left parietal	35 years	Sarcomatoid EPC	Diffuse	Yes	Cetuximab	52	Death
Val-Bernal 20195	42 M	Left laterocervical	5 months	Sarcomatoid EPC	Nodes	No	None	2	Alive
Present	54 F	R medial arm	5 years	Sarcomatoid sweat gland carcinoma	Diffuse, brain	No	Paclitaxel +carboplatin	1	Death

Cases with local spread and lymph nodal disease are outlined in Table 2. Cases with diffuse metastatic disease are outlined in Table 3. As many cases as possible were included, but given the variety in nomenclature of sweat gland carcinomas, the tables are not exhaustive, but represent a majority.

TABLE 2 Regional and Lymph Nodal Disease. Key: ?: unspecified value. EPC eccrine porocarcinoma. NR: not reported. FUfluorouracil. IFN: interferon. IL: interleukin.

Case reference	Age, Gender	Site	Duration	Diagnosis	Systemic Dx	Regional lymph node bx	Radiation	Chemo Regimen	Stains	Follow-up	Outcome
Dummer 199238	74 M	Digit	18 months	Eccrine Porocarcinoma	Cutaneous and lymph nodes	No	No	Recombinant IL2 and alfa-2b		20 weeks	Remission
Huet 199639	55 M	Scrotum	4 years	EPC	lymph, cutaneous	No	Yes	IFN-alpha, isotretoin		9 months	Remission
Duke 200040	48 ?	Digit	NR	Digital Papillary	Lymph nodes	No	No	Adryamycin, dTIC		8 years	Remission
Chu 200141	64 M	Parotid	NR	Adenoid cystic	Nodes	Yes	Yes	None		2 years	Remission
Mirza 200229	70 M	Arm	1 year	Spiroadenocarinoma	Nodes	No	No	Tamoxifen x 5 years	ER+	41 months	Remission
Ban 200342	63 M	Axilla		MAC	Nodes	Yes	No	None		31 months	Remission
Gonzalez-Lopez 200343	71 M	Thigh	2 years	EPC	Nodes and cutaneous	No	Yes	Isotretoin then tegafur		5.6 years	Remission
Brickhov 200444	72 M	R calf	1 year	Sweat gland carcinoma	Nodes	No	No	None		NR	NR
Gutermerth 200445	67 M	Neck	NR	EPC	Local nodes and cutaneous	No	No	Paclitaxel + interferon-alpha		15 months	Remission
Shroeder 200430	64 F	Scalp	8 years	Ductal adenocarcinoma	Nodes, cutaneous, partotid	No	No	Tamoxifen	ER and PR+	3 years	Remission
Nash 200746	44 M	Chest	8 years	Hiradenocarcinoma	nodes	No	Yes	Traztusumab		NR	Remission
Shiohara 200747	64 M	Leg	5 years	EPC	Nodes	No	Yes	Mitomycin, vincristine, epirubicin, cisplatin, 5-FU, pepleomycin		5 years	Death
Shiohara 200747	75 M	Leg	20 years	EPC	None	No	No	Tegafur-uracil		2 years	Remission
Yamatashita 200848	61 M	Crus	25 years	EPC	nodes	No	Yes	Cisplatin +5-FU		1 year	Remission
Perez-Garcia 201049	69 M	Lower Leg	unknown	EPC	Nodes	No	No	Cisplatin + docletaxel induction		12 months	Remission
Marone 201150	42 M	Arm	NR	EPC	Cutaneous and lymph nodes	No	No	Bleomycin via electrochemotherapy		5 months	Remission
Guerro-Ramos 201351	73 M	Nose	8 months	EPC	Nodes	No	No	None		12 months	Remission
Rocas 201452	47 F	Breast	25 years	Adenoid cystic carcinoma	Nodes	No	Yes	None		9 months	Remission
Joseph 201553	56 M	Abdomen and Chest	NR	EPC	Nodes, cutaneous	No	No	Doxorubicin, mitomycin, vincristine, and 5-fluorouracil (5-FU) alternating with cisplatin and bleomycin then paclitaxel +carboplatin		14 months	Death
Otuska 201628	50 M	Axilla	NR	Apocrine adenocarcinoma	Local nodes and cutaneous	Yes	Yes	Traztusumab + pertuzemab + docetaxel	HER2+	11 months	Remission
Hibler 201731	60 M	Scalp	Many years	Apocrine adenocarcinoma	Nodes	No	Yes	Cisplatin + paclitaxel	ER and PR+	16 months	Remission
Velugals 201227	59 F	Arm	3 years	EPC	Noes	Yes	Yes	None		6 months	Remission
Zeidan 201054	76 M	Scalp	Years	EPC	Parotid	No	Yes	None		10 months	Remission

TABLE 3 Widespread Metastatic Disease. Key: ?: unspecified value. EPC eccrine porocarcinoma. NR: not reported. FUfluorouracil. IFN: interferon. IL: interleukin. ER: estrogen receptor. PR: progesterone receptor. HER2: human epidermal growth factor receptor 2.

Case Reference	Age, Gender	Site	Duration	Diagnosis	Follow-up	Systemic Dx	Radiation	Chemo Regimen	Stains	Outcome
Briscoe 197823	60 M	R toe	2 years	Eccrine porocarcinoma	15 months	Diffuse cutaneous, lymph	None	Fluorouracil and melphalan w/ limb hyperthermia, maintenance chemo with flurouracil and cyclophosphamide		Remision
Coonley 198524	20 cases			Sweat gland carcinoma			8%	17 patients, various agents, avg 10 month survival
Piedbois 198725	45 F	L labia majora	NR	Sweat gland carcinoma	50 months	Diffuse	none	Doxorubicin, mitomycin, vincristine, 5-fluorouracil q4 weeks in rotation with cisplatin and bleomycin- 9 cycles		Initial remission, then death
Swanson 198926	78 M	L forearm	NR	EPC	3 months	Nodes, mediastinum	Yes	5- FU		Death
Bellman 199555	68 M	Eyelid	10 years	Poorly differentiated sweat gland carcinoma	2 years	Skin, bone marrow	No	5-FU × 15 cycles		Death
Tay 199756	72 F	Shin	50 years	Spiroadenocarinoma	20 months	Nodes, bone, lung	Yes	Hyperthermic melphalan, 5-FU		Death
Muraki 199757	83 M	Penile Shaft	NR	EPC	4 months	Diffuse	No	Methotrexate, cisplatin, adriamycin, and bleomycin		Death
Sigal 199658	54 F	Scalp	9 years	EPC	2.5 years	Diffuse	Yes	VP-16 + cisplatin then interferon and roaccutane		Death
Grimme 199959	47 M	Scalp	6 weeks	EPC	4 weeks	Diffuse	Yes	Bleomycin, 5-FU then IL2, carboplatin		Death
Biondi 200060	52 M	Mandibular region	NR	EPC	5 months	Diffuse	No	Cisplatin, doxirubicin and cyclophosphamide		Death
Duke 200040	38?	Digit	NR	Digital Papillary	9 years	Lung	No	Etoposide + Cisplatin, then adriamycin		Remission
Duke 200040	58?	Digit	NR	Digital Papillary	4 years	Axillary and Lung	No	Etoposide cisplatin		Death
Plunkett 200161	45 F	Shoulder	3 years	EPC	5 months	Nodes, bone, lung	Yes	Epirubicin- no improvement, then docetaxel x12 cycles		Remission
Goel 200362	40 M	Foot	NR	EPC	10 months	Diffuse	Yes	Interferon alfa, isotretoin, carboplatin, taxol, vincristine, and irinotecan		Death
Chou 200463	50 M	Thigh	30 years	Eccrine spiradenoma	4 months	Nodes, pulm	No	Epirubicin and ifosimide		Death
deBree 200464	69 M	L leg	15 years	EPC	25 months	Local, lung, lymph	No	Topical 5-FU + docetaxel		Remission
Nishizawa 200665	65 M	Abdomen	20 years	Syringoid eccrine carcinoma	6 months	Nodes, lung, ileum	No	5-fluorouracil, epirubicin, mitomycin C, vincristine, carboplatin		Stable Disease
Kim 200766	42 M	Palm	NR	EPC	8 years	diffuse	Yes- palliative	Cyclophosphamide, cisplatin, and doxorubicin		Death
Shiohara 200747	62 F	Scalp	3.5 years	EPC	2 years	lung, brain, bone	Yes	Cisplatin, adriamycin, VDS		Death
Shiohara 200747	81 F	Buttock	1 year	EPC	3.8 years	Nodes, bone	No	Cisplatin, 5-FU		Death
Ishida 200967	72 M	Thigh	3 years	EPC	8 months	nodes, liver, bone	No	Carboplatin + farmarubicin		Death
Yi 201068	63 F	Thigh	NR	Trichilemmal carcinoma	7 months	Nodes, lung, bone	No	Cisplatin +cyclophosphamide		Death
Hidaka 201269	62 M	Scalp	3 years	Cutaneous apocine carcinoma	6 months	Lymph and liver	Yes	Cisplatin +5-FU, then traztusumab- initial remission, then lapatinib and capecitabine		Remission
Kurashige 201370	50 M	Arm	6 months	Eccrine porocarcinoma	8 months	Diffuse	Yes	Docetaxel + cisplatin		Death
Arslan 201471	76 M	Scalp	NR	Pilomatrix Carcinoma	6 months	Nodes, Lung	No	Cyclophosphamide +etoposide x6		Remission
Miller 201532	32 M	Axilla	2 years	Apocrine Hiradenocarcinoma	18 months	Diffuse	Yes x 2	Carboplatin+ paclitaxel + Tamoxifen, then vismodegib and anti-LAG3 monoclonal ab	ER and PR+	Remission
Brown 201614	54 M	Scalp	Many years	Cutaneous adnexal carcinoma	43 months	Skin, nodes, parotid	Yes	Carboplatin, paclitaxel, traztusumab	HER2+	Remission
Mandilaya 201615	66 F	Forearm	NR	EPC	unknown	Nodes, cutaneous and lung	Yes x 2	Cisplatin and docetaxel		Disease Free
Godillot 201716	64 F	Pubic Region	NR	EPC	6 months	Lymph nodes, lung, bone, uterus	Yes	Cetuximab + paclitaxel		Death
Larson 201817	66 F	Calf	NR	EPC	12 months	diffuse	Yes	Melphalan and actinomycin D and hyperthermia, then paclitaxel and carboplatin, then Capecitabine	HER2+	Death
Khaja 201918	67 M	Scalp	4 months	EPC	4.5 years	Nodes, cutaneous, ear	No	Docletaxel + carboplatin		Death
Fernandez-Ferrara 202019	67 M	Intergluteal	NR	EPC	NR	Nodes and lung	No	Etoposide, vincristine, carboplatin.		NR
Gupta 202020	75 F	Scalp	NR	Eccrine porocarcinoma + chondroid syringoma	39 months	Brain, bone	1 × treatment, 1 × palliative	Paclitaxel + carboplatin, then pembrolizumab palliative		Death
Gupta 202020	79 M	Cheek	NR	Poorly differentiated eccrine carcinoma	19 months	Bone, diffuse abdomen and chest	2 treatments	Doclitaxel		Death

Much of the early literature describes metastatic sweat gland carcinoma as both radio and chemo-resistant, with poor prognosis.^23–26 Most data on prognosticating factors and mortality comes from eccrine porocarcinomas (EPC) as the most common sweat gland tumor. The most recent meta-analysis of 116 cases of EPC by Le et al. found negative prognosticating factors to include: ulceration, high mitotic activity, absence of surgery, use of chemotherapy, and distant metastasis.⁷ The 1-year overall survival rate was 93.0% versus 3 year of 70.3%.⁷ Patients with a positive lymph node status had a mortality rate of 39.1% versus 11.4% in those without.⁷ Those with distant metastases had a 1-year survival rate of 42.9% and 3-year overall survival of 0% versus >90% for both without metastasis.⁷

For nonmetastatic disease, most reports described wide local excision as the surgical choice. There is one report describing Mohs surgery, but there is no formal comparison of the two different surgical techniques and outcomes.²⁷ Neoadjuvant chemotherapy prior to excision has been reported once.²⁸ Very few cases performed initial sentinel lymph node biopsies as there has been no clear evidence of a mortality benefit; however, it is worth noting that this has also not been specifically studied.²⁷

There were seven cases that had some combination of ER, PR, or HER2 positivity, five of which used more targeted therapy with either traztusumab or tamoxifen. All of these five cases achieved remission at the end of designated time points.^{14,17,28–32}

In conclusion, we have described the clinical and pathologic features of sweat gland carcinoma, particularly those with a spindle cell sarcomatous element. Sarcomatous sweat gland carcinomas are rare entities with less than 20 cases on literature review. The sarcomatous elements seem to increase with metastasis. Metastatic survival rates are poor, cited as low as 39.5% three-year overall survival.⁷ These statistics are also limited to eccrine porocarcinoma, as other subytpes are more rare. There are no standard guidelines for type of surgical excision, the use of sentinel lymph node biopsy, radiotherapy, or chemotherapy regimen.⁷ Given the success of endocrine or HER2-targeted therapy in four cases, checking all tumors for ER, PR, and HER2 positivity could provide treatment options withlower risks of toxicity.²⁹ Overall, there are many opportunities for further research into the treatment of metastatic sweat gland tumors of all subtypes, particularly those with sarcomatous elements.

AUTHOR CONTRIBUTIONS

Jessica Matthiesen: Conceptualization; data curation; formal analysis; writing – original draft; writing – review and editing. Richard Chiu: Conceptualization; data curation; writing – original draft. Tiffanie Do: Conceptualization; writing – review and editing. Sepideh Bamdad: Writing – review and editing. Jennifer Lee: Resources; supervision; writing – review and editing. Shi-Kaung Peng: Resources; supervision; writing – review and editing.

FUNDING INFORMATION

None.

CONFLICTS OF INTEREST STATEMENT

The authors of this manuscript have no conflicts to disclose.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are openly available in Clinical Case Reports at http://doi.org/10/1002/ccr3.7182. (Data openly available in a public repository that issues datasets with DOIs).

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.