Exploring an Unfathomed Entiry: A Pooled Analysis of Solitory Skeletal Muscle Metastasis from Head and Neck Squamous Cell Carcinoma

Abstract

Background

Skeletal muscle is relatively uncommon site for metastasis in head and neck primary. This study was conducted to report our experience of three such cases and analyze the previously reported cases to assess the overall outcomes and formulate a treatment plan for these patients.

Methods

We pooled the data extracted on extensive literature review and analyzed.

Results

A total of 17 patients were analyzed for this study. All the patients had locally advanced primary and 14/17 developed metachronous metastasis. Median duration to development of metastasis was 8.5 months, and 13/17 patients had skeletal muscle as the only site of metastasis. Only 6/13 were treated with aggressive intent, 4 of which who underwent surgical resection had the best survival outcomes.

Conclusions

Isolated skeletal muscle metastasis in a head and neck primary is relatively rare, and in future, the research work needs to be taken up afresh, on prospective model, with adequate patient sample, to draw a scientifically valid conclusion.

Introduction

Head and neck cancers contribute significantly to global cancer burden, and their metastatic potential is different from many other malignancies as they are more likely to follow an orderly pattern of spread and fewer patients tend to develop disease beyond nodal basin [1–4].

Primary tumors of skeletal muscles are more common than metastasis and unlike liver, lung, bone and brain; skeletal muscles are uncommon sites for metastasis [1]. Metastasis into skeletal muscles has varied tumor histologies including adenocarcinoma, melanoma and squamous cell carcinoma. The most frequent primary tumor reported in case of squamous cell histology is from primary of lung and cervix [2, 3]. Skeletal muscle metastases (SMM) are rare, and their incidence has been reported to be around 0.03–0.16% [2]. The literature has sparse data pertaining to skeletal muscle metastasis, and only a few series have been reported which have described clinico-pathological details and imaging feature, which includes all primaries [2, 3, 5–21].

This is the first effort to analyze this particular subset of patients describing head neck cancer patients with skeletal metastasis. The purpose of this paper is to evaluate the existing literature in addition to our experience regarding skeletal muscles metastasis in head and neck cancers so as to find out appropriate management and report our experience to add to the existing limited data.

Method and Materials

We reviewed our database of head and neck cancer patients to identify the patients with skeletal muscle metastasis from January 2009 to December 2016. More than 9 thousand patients of head and neck cancer were identified, among which 15% had metastatic disease either upfront or developed later. Only three patients were found to have skeletal muscle metastasis, and we analyzed data pertaining to clinical, imaging and oncological outcomes of these patients. With an attempt to find a meaningful conclusion, we pooled the reported case reports in the literature on the same subject. Similar studies were searched from the literature using the key word of “skeletal muscle metastasis,” “muscle metastasis,” “metastasis from head and neck cancer,” and skeletal muscle metastasis with combination of various subsites of the head and neck cancers including tongue, alveolus, gingiva, buccal mucosa, lip, larynx, pharynx, hypopharynx, oropharynx on PubMed, Embase and Google scholar. All articles in the English language were analyzed for relevance to our study. We also looked into secondary references with intent not to miss any such report. The articles with details on clinico-pathological and/or management were included for analysis. We could able to identify a total of 14 cases having the skeletal muscles as metastatic site form a primary head and neck squamous cell carcinoma (Tables 1, 2). In order to have a uniform set of patients for analysis non-squamous primary from other head and neck subsites like thyroid, salivary glands were excluded. Pooled analysis of the reports and our database made a total of 17 cases, which were selected for final analysis, and their clinico-pathological details and oncological outcomes were recorded in excel spreadsheet and analyzed. Due to the retrospective nature of this study, it was granted an exemption in writing by the institutional review board.

Table 1.

Clinical, management and survival details of the patients with skeletal muscle metastasis from oral cavity cancer

Case	Primary site	Stage	S/M	Complaints	Muscle group	S/D	Rx	Status	Outcome
Elkowitz et al. [13] O1	Tongue	NR	M	Pain Walking Difficulty	Psoas Muscle (Single)	S	BSC	< 1 month	Dead
Touheti et al. [9] O2	Gingiva	NR	M	Pain Swelling	Forearm Muscle (Single)	D	RT	2 months	AWD
Vuslat Yurut-Caloglu et al. [14] O3	Tongue	pT2 N2b M0	M	Pain Shoulder Deformity	Pectoral Shoulder (Multiple)	S	pRT	< 1 months	Dead
Singh et al. [15] O4	GBS	pT4 N1 M0	M	Lump No pain	Abdominal Wall (Single)	D	BSC	3 months	Dead
Smeets et al. [12] O5	Tongue	cT4 N3 M1	S	Incidental Lump On exam	Abdominal Wall Thigh (Multiple)	D	BSC	1 Month	Dead
Wurm et al. [16] O6	FOM	pT3 N1 M0	M	Pain Swelling Like Abscess	Arm (Single)	S	RT	NR	NR
Our study 2017 O7	Gingiva	cT4a N2b M1	S	Incidental Mass On PET	Quadratus lumborum muscle (Single)	S	CT	8 months	AWD
Our study 2017 O8	Gingiva	pT4a N2b M0	M	Pain Swelling	Vastus Medialis (Single)	D	CT	2 months	AWD

AWD alive with disease, BSC best supportive care, CT chemotherapy, D dead, pRT palliative radiotherapy, RT radiotherapy, S/D solitary site/disseminated, S/M synchronous/metachronous

Table 2.

Clinical, management and survival details of the patients with skeletal muscle metastasis from laryngopharyngeal cancer

Case	Primary site	Stage	S/M	Complains	C/O	S/D	Rx	Status	Outcome
Sudo et al. [10] L1	Hypopharynx	NR	M	Painful swelling	Soleues	S	NR	9 months	Dead
Yucel et al. [17] L2	Larynx	pT4a N3 M0	M	Pain	Scapular muscles	S	CTRT	NR	NR
Marioni et al. [1] L3	Larynx	pT4 N0 M0	M	Pain	Gluteus maximus	S	Sx	13 months	NED
Korkmaz et al. [19] L4	Larynx Oropharynx	pT4a N2b M0	M	Incidental mass	Forearm	S	RT	2 months	Dead
Gupta et al. [20] L5	Larynx	cT3 N3 M1	S	Pain Reduced ROM	Scapular	S	RT	10 months	AWD
Kalahci et al. [11] L6	Larynx	pT3 N2b M0	M	Painful swelling	Rectus Femoris	S	Sx	24 months	Dead
Klune et al. [8] L7	Larynx	pT3 N2b M0	M	Incidental mass	Rectus abdominalis	S	Sx	NR	NED
Lucas et al. [21] L8	Larynx	pT4a N2c M0	M	Painful swelling	Bilateral thigh	D	pRT Spine	4 months	Dead
Our study L9	Larynx	pT4a N2b M0	M	Incidental mass on CXR	Pectoral	S	Sx	3 months	NED

AWD alive with disease, BSC best supportive care, CT chemotherapy, D dead, pRT palliative radiotherapy, RT radiotherapy, S/D solitary site/disseminated, S/M synchronous/metachronous

Results

Our Experience

We treated 3 such cases during the study duration. The first one was a case of carcinoma left lower alveolus with clinical staging of cT4aN2b. In view of locally advanced disease, PET CT whole body was done for staging which revealed unexpected metabolically active lesion at right quadratus lumborum muscle apart from local and regional nodal disease and final cT4aN2bM1 stage was assigned (Fig. 1). As the only site of distant disease core biopsy from mass was done, which confirmed its origin from same tumor (P40 and 34 beta E-12 positive and CK and CK20 negative on immunohistochemistry panel). He received 3 cycles of paclitaxel- and cisplatin-based chemotherapy, and follow-up PET scan showed serial reduction in size and activity of both the lesions. After 6 cycles of chemotherapy, complete anatomical and metabolic response was reported in muscle lesion while the primary lesion remained stable. The case was discussed in multispecialty clinic and was advised radiotherapy to the primary site, as the lesion was surgically unresectable. He received 30 Gy/15# of RT, and at last follow-up (8 months from last treatment) he was alive with disease.

Fig. 1.

PET CT fused axial images—hypermetabolic metastatic deposit involving the right quadratus lumborum muscle (Panel A & B) with axial CT and PET CT fused images show centrally necrotic mass lesion showing peripheral hypermetabolic uptake in the right adductor longus muscle (Panel C& D)

Another case was a 50-year-old man with squamous cell carcinoma of right pyriform fossa (cT4N1M0). He underwent total laryngectomy with bilateral neck dissection and neopharyngeal reconstruction using radial artery-based free forearm flap. The final histological stage was pT4N2b high-grade SCC, with perineural invasion (PNI) and nodal extra capsular extension (ECE). He received adjuvant chemoradiotherapy (65.2 Gy/35#, with concurrent 5 weekly cycles of cisplatin 50 mg/m²). He was on regular follow-up. At 12 months, his follow-up X-ray chest showed a rounded opacity in left lung field area. Further PET CT done revealed a mass lesion measuring 5 × 5 cm in relation to pectoralis muscles. Fine needle aspiration cytology was taken from lesion, which was suggestive of squamous carcinoma. The case was discussed in tumor board and is being planned for chest wall resection.

And the third case was a 47-year-old gentle man who was initially treated for carcinoma left lower alveolus with primary surgery (pT4aN2bM0) followed by adjuvant chemoradiation at our institute and was on regular follow-up. Follow-up clinical examination and MRI scan at 6 months were normal. One-year post-treatment, he presented to us with complaints of pain and swelling over right thigh. On examination, there was a well-defined swelling of 4 × 4 cm size over right upper thigh in the medial aspect. Rest of the clinical examination was essentially normal. Ultrasound was done to characterize the lesion, which revealed a hypoechoic lesion in the muscular plane of medial compartment of thigh. Fine needle aspiration cytology from lesion was reported as squamous cell carcinoma. Whole body PET CT was done to stage the disease which revealed few metabolically active lung nodules, single liver lesion and muscle lesion without metabolically active lesion at loco-regional site (Fig. 1). In view of disseminated metastatic disease, he was referred for palliative chemotherapy. He is alive with disease at last follow-up, which was 3 months ago.

Pooled Analysis

A total of 17 patients were analyzed which included 8 from oral cavity primary (3 gingiva, 3 tongue, one each gingivobuccal sulcus and floor of mouth) (Table 1), while nine other had laryngopharyngeal primaries (8 larynx and 1 hypopharynx Table 2). The majority of the patients were in 5th to 6th decade of life with a median age of 58.05 years. Three patients were female, while rest others were male. The stage of the primary disease was not reported in 3 patients, 9/14 (64%) patients were T4, and 11/14 (78.5%) patients were having N2–N3 disease. High-risk features were not mentioned in most of the series, but poor differentiation, PNI positivity and extra nodal extension were common features in the reports that have mentioned comprehensive pathological findings.

Only 3 patients presented as synchronous skeletal muscle metastasis, while rest 14 patients had metachronous metastasis. The median duration to development of metastasis was 8.5 months (range 3 weeks–36 months). Four patients developed muscles metastasis as a part of disseminated disease, and rest 13 had skeletal muscle as the only site of the metastasis. Among the patients with isolated muscle involvement, extremities were the most common site involved (6 in upper limb and 3 in lower limb) while four patients had trunk muscles involved (2 abdominal wall and 2 paravertebral muscles). Among the patients who had synchronous metastasis (3/17), one patient was symptomatic while other two were detected on staging investigations.

Among the patients who developed metachronous skeletal muscle metastasis, 3/14 patients were incidental finding, while 11/14 (78.5%) were symptomatic. Pain was the most frequent symptom and found in 10/11 patients, while only one presented with painless lump at abdominal wall.

MRI was the most commonly used modality to assess the metastatic lesions. Imaging findings were variably described as heterogenous mass and peritumoral enhancement associated with central necrosis, but no characteristic finding has been described.

Seven of the 17 patients had PET CT scan and in three patients it detected unsuspected metastasis, two of these patients already had disseminated disease and management remained essentially palliative. In one patient (Table 2, case L9), the treatment intent was changed from curative to palliative. So overall PET CT changed management in one of the seven cases (14.3%). Tissue diagnosis was done using either FNAC (6 cases), core biopsy (2 cases) or incisional biopsy (2 cases), while seven studies in literature has not report their method of tissue diagnosis.

Among the patients with metachronous metastasis, six patients were treated with curative intent (oligometastatic) 4 of whom underwent surgical resection have shown best of survival outcome; three were disease free at last follow-up (3 months, 13 months and Not Reported) and one succumbed to the disease after 24 months. Two patients received definitive radiotherapy among them one died after 5 months and other is alive with disease at 2 months. As mentioned above three patients had synchronous metastatic disease; hence, the intent of treatment was palliative. Only one patient with solitary SMM involvement of shoulder was initially treated with palliative intent to control pain at metastatic site, and as there was a complete response at metastatic site, radical dose concurrent chemoradiotherapy was given to primary site and patient is alive with disease at 10 months of follow-up; other two cases were offered supportive care (died, 1 month) and palliative chemotherapy (alive with disease at 8 months).

Discussion

Cancer has inherent tendency to spread and practically no organ or site is immune to the metastasis. Different cancers have predilection for different organs for metastasis and most common sites of metastasis being lung, liver, bone and brain [22]. The incidence of distant metastasis with head and neck primaries is relatively less common than other cancers with reported rates of 5–26% in the literature [4]. Among head and neck cancers, the metastatic potential is variable for different subsites, their stage of presentation and histological type. Laryngeal, hypopharyngeal and oropharyngeal cancers are more likely to have distant metastasis while oral cavity, maxilla and glottis cancer are the rare ones. Tumor characteristics associated with distant metastasis are locally advanced disease, adenoid cystic and basaloid histology [8]. Commonest sites of metastasis from head and neck cancer are lung, bone, liver, skin, mediastinum, and bone marrow in decreasing order of frequency [8, 9]. As the entity itself is rare, its literature description is sparse. The largest review of 264 patients with skeletal muscle metastasis of different primary over a period of more than 50 years by Haygood et al. showed that most frequent cancers metastasizing to skeletal muscle are lung, renal cell carcinoma, breast and gastric cancers. Among these only 17% was isolated skeletal muscle metastasis while 46% had additional sites of metastasis. Among them, only 16 cases (3%) were of head and neck primary, but analysis was not done separately [3]. Many other series acknowledge their presence as a part of disseminated disease rather than a solitary site. [5–21]. Lack of proper screening of asymptomatic areas as well as poor sensitivity of tests to detect these lesions may be the other contributory factor. The inclusion of PET scan in staging method would increase its detection rate [3, 10].

Skeletal muscles are infrequent sites of metastasis despite making more than 50% of total body mass and having relatively rich vascular supply. The exact reason remains unknown and largely speculative [23–25]. Sridhar et al. has mentioned various likely mechanisms, which include rich, but variable blood flow to muscles under b-adrenergic control, in contrast to organ with high chances of metastatic having rich and constant flow [23]. The theory of physical barrier states that skeletal muscles prevent metastasis by their contractibility and mobility [24]. Seely et al. mentioned the importance of chemical barrier where lactic acid production in the skeletal muscles inhibits the growth of intramuscular metastases [25]. The possible mechanism of spread may either be hematogenous or lymphatic. Post-surgical cases may have aberrant vascular opening or drainage pattern and hence may surprise with unusual site of metastasis [5, 26, 27]. Often these are part of disseminated disease, and the obvious mechanism is hematogenous spread. It can be either arterial route or paravertebral venous plexus. Kulahchi et al. speculated that tumor cell might flow through azygous vein-vertebral venous connection and bypassing the pulmonary circulation, particularly post-surgery where internal jugular vein flow altered [11]. Another mechanism for skeletal muscle metastasis is tumor implantation. The concept of tumor seeding is known since 1885 when Gerster emphasized the importance of preventing tumor contamination to the tissue [28]. Pertaining to head and neck cancers tumor seeding at donor flap site, PEG site and neck soft tissue have been described [29–32].

Touheti et al. reported that majority of the patients with SMM have disseminated disease with lymph node, visceral and brain involvement, but these are patients who had primaries from various sites and includes only a single case of head and neck primary. Our analysis shows most patients have skeletal muscle as the solitary site of metastasis and hence are probable candidates for potential cure [9]. The clinical differentiation is difficult without biopsy from other differentials like soft tissue tumors and abscess, apart from their association with pain [9]. In our series, majority of the patients were symptomatic (82.4%; 11/14) and the most frequent presentation was pain at the site (78.5%; 10/14). Hence we suggest any patients with head and neck cancer with otherwise explained pain or swelling whether painful or not, should be suspected as metastasis and need further evaluation. There is no pathognomonic appearance or enhancement pattern on imaging, but it helps to assess extent of the disease and plan the biopsy. Even with best of the efforts differentiation of these cases from soft tissue sarcoma, myositis and tubercular abscesses are not always possible on imaging [5, 6, 9]. They are often seen as intramuscular lesion with heterogenous enhancement, but about 27% of the cases may show low central attenuation with rim enhancement and thus may be mistaken for abscess [5]. Recent papers have shown the importance of PET CT for staging of such cases with a good sensitivity, which may be the reason for increased detection rate of skeletal muscles metastasis [5, 8]. The most consistent finding on MRI is extensive peritumoral enhancement and central necrosis [9]. No specific finding on imaging was noted in our series, and among 7 patients in whom curative treatment was planned, PET had shown unsuspected disseminated disease in one patient, hence changed the management. Relatively less number of patients in the current series limits its generalizability, but it should be considered for at least the patients in whom curative treatment is planned. PET CT has been accepted as staging method for advanced disease and for follow-up [5, 8].

Metastatic head and neck cancer has poor prognosis with the best of available chemotherapy which provides 10–15% overall survival. According to Hellmann and Weichselbaum, oligometastasis is an intermediate stage of disease with a prognosis in between local and metastatic disease and aggressive management does help to improve overall survival [33]. With acceptance of this spectrum theory, many patients with metastasis were treated with curative intent and have shown handsome outcomes.. Many series and reports have shown better outcomes with multimodality approaches using surgery and radiotherapy for metastatic head and neck cancers, but there is no randomized control trials data available [34–36]. Recent systemic analysis by Young et al. pointed out that offering pulmonary metastasectomy in selected group of patients but whether these results can be extrapolated to other sites of oligometastasis, is yet to be seen [37]. French group evaluated existing literature regarding management of oligometastatic head and neck cancer and concluded that local ablative treatment has potential to maintain quality of life and potentially improve overall survival with existing literature favoring surgery over radiotherapy. The existing data cannot conclude the optimal combination or sequencing of these methods, and there is a need for effective analysis of quality of life in addition to oncological benefits [38]. Owing to a limited number of patients, one cannot draw any firm conclusion, but it is evident that patients with oligometastasis in whom surgery has been performed did better when compared to those who received palliative chemotherapy. We believe that patients with resectable oligometastatic disease can be offered curative treatment, but this needs to be tested in larger studies with longer follow-up.

Synchronous oligometastasis is even less common, and hence their management option is less well defined. Ampil et al. reported one such series where radical dose radiotherapy was given to local site and to metastatic site [39]. Management of these cases needs multidisciplinary action plan and largely depends on extent of the disease, primary histology, performance status of the patient. In our analysis only 3 patients presented with synchronous metastasis and one of them had been treated with radical radiotherapy to both primary and metastatic site, he failed after 9 months, and another patient who was put on palliative chemotherapy was alive with disease at 8 months of follow-up. Prognosis of patients with shorter disease-free interval, extensive disseminated disease, poor performance status remains grave and such patients are usually left with option of best supportive care, palliative chemotherapy or radiotherapy. Patients with disseminated metastasis and poor performance status are better treated with supportive care with primary goal of maintaining quality of life [12].

The main drawback of the study is the availability of relatively very few series or case reports. The present study is analyzing cases from different case reports, which are described over a long time frame in the era of ever changing medicine. The documentation in case reports is also not uniform and only a few of them has a comprehensive analysis of the patient data. Small individual studies reported cannot form the basis of management recommendation, and present study is the most comprehensive analysis of this rare subset of head and neck cancer patients.

Conclusions

Currently, there are no guidelines for management of SMM from head and neck primaries; with our analysis, we may draw following conclusions.

1. SMM is exceedingly rare, but the clinician should be aware that no site is immune to metastasis.

2. There are no definitive clinical findings, but pain points more toward metastasis rather than primary sarcoma; other differentials include abscess and tubercular lesions.

3. Locally advanced primary, adverse pathological factors like high grade, perineural invasion and extra nodal extension are more likely to be associated with metastatic disease and SMM is not an exception.

4. Metachronous SMM involvement is more common than synchronous involvement in case of Head and neck cancer primaries.

5. Imaging findings are not specific and not characteristic of pathology, but suggestive only and tissue diagnosis is always required.

6. Whole body PET CT has the potential to identify unsuspected metastasis and change the management, to be considered for the patients in staging of a locally advanced head and neck primary and in patients with oligometastatic disease in whom curative treatment is planned.

7. Management should be individualized and multispecialty discussions are of paramount importance. In case of SMM, surgery is a reasonable option if it is oligometastatic disease, which provides reasonable quality of life and better overall survival.

8. Follow-up needs to be aggressive and not well defined.

Compliance with Ethical Standards

Conflict of interest

Authors do not have any conflict of interest.

Human and Animals Rights

The study was a retrospective analysis and pooled analysis of published reports. No human or animal was involved or no intervention has been done.

Informed Consent

The study was a retrospective analysis and pooled analysis of published reports. Informed consent from discussed individuals was taken.