Maxillofacial neuroendocrine carcinoma is relatively rare and can be primary or metastatic. Primary cutaneous neuroendocrine carcinoma, also known as Merkel cell carcinoma, has been reported only rarely in the domestic and international literature. Maxillofacial neuroendocrine carcinoma, both primary and metastatic, is rare and occurs mostly in middle-aged and elderly people [1, 2, 3, 4]. At present, the diagnosis of neuroendocrine carcinoma must still rely on histopathological confirmation, and it is difficult to first consider neuroendocrine carcinoma from clinical manifestations and signs alone. In this paper, we attempted to analyze the clinical manifestations of endocrine carcinoma of the tongue root trying to find the possibility of primary Merkel cell carcinoma or metastatic neuroendocrine carcinoma can be considered when it does not match with some common disease manifestations. In contrast, there is only one report of neuroendocrine carcinoma originating from the tongue in Oral Surg Oral Med Oral Pathol Oral Radiol Endod in July 2006 [5], which is claimed to be the first case in the world.
In this paper, we analyze the clinical presentation, biological behavior and pathological manifestations, and propose the principles of diagnosis and treatment, taking into account the literature.
I. Case presentation
The patient, a 60-year-old male, was admitted to the hospital on April 17, 2006, mainly because of a left tongue root mass found two years ago and growing rapidly for more than two months. The patient found a “soybean” sized swelling at the root of the left tongue two years ago and did not receive any special treatment at that time. Two months ago, the swelling was suddenly found to be rapidly increasing in size and was seen at a local hospital, where the specific treatment and diagnosis were unknown. For further treatment. On April 17, 2006, he came to our dental clinic and was admitted as “left tongue root swelling”. Since the onset of the disease, he had normal mental health, diet and sleep, and normal urination and defecation. He was physically fit and had a history of coronary heart disease and hypertension, and denied any history of gastric disease, diabetes, hepatitis, tuberculosis, hyperthyroidism, etc. He denied any history of trauma or blood transfusion. History of trauma and blood transfusion was denied. No history of food allergy. Personal history: born in the place of origin. No history of exposure to epidemic water, radioactive and chemical toxins. Keep up with vaccinations. No other undesirable hobbies. Family history: Mother and father deceased. No history of similar diseases in the family and no family history of hereditary diseases. Admission examination: general condition is good, no abnormalities in the heart, lungs and abdomen.
Specialized conditions: no facial abnormalities. There was no redness, swelling or pressure pain in the bilateral temporomandibular joint area, normal mouth opening and mouth opening pattern, and no cyanosis of the mouth and lips. There was no abnormality in the hard and soft palate. A 2×2.5×2.5 cm sized mass was seen at the root of the left tongue, with a congested surface mucosa, a purple center, a hard base, and no obvious tenderness. There was no redness or swelling at the mouth of each salivary gland duct, and there was clear salivary overflow. There was no obvious abnormality in the occlusal relationship. The pharynx was not red, the tonsils were not enlarged bilaterally, and the uvula was centered. No enlarged lymph nodes were palpated in the neck. Preliminary diagnosis: swelling at the left tongue root. The main preoperative differential diagnoses were: 1. squamous cell carcinoma; 2. lymphoma . After adequate preoperative preparation, an enlarged excision of the left tongue root mass was performed under general anesthesia on April 19, 2006. An incision was made along 1.0 cm around the swelling and the swelling was completely removed. The resected tissue was sent for freezing during the operation, and the freezing result was reported as: lymphoma. The wound was irrigated and sutured in place. The excised specimen was sent for pathological examination.
The patient was discharged from the hospital on April 24, 2006, after explaining to the patient and his family the precautions for discharge, and the hospital stay was 7 days. No hospital-acquired infections or complications occurred during the hospitalization. The patient was informed to come to the hospital two days later to take routine pathology, which recommended immunohistochemistry for further diagnosis, so the patient was informed of further diagnosis, and the pathology finally reported (left tongue root) small cell malignant tumor. carcinoma, partly with squamous carcinoma differentiation. No cancer was seen on the outer, posterior, inner, or basal margins of the mass.
Since the diagnosis was “small cell neuroendocrine carcinoma with partial squamous cell differentiation”, he was again admitted to the hospital on April 28, 2006, 9 days after surgery for small cell neuroendocrine carcinoma of the left tongue root. Specialized conditions: no facial abnormalities. There was no redness, swelling or pressure pain in the bilateral temporomandibular joint area, normal mouth opening and open mouth pattern, and no cyanosis of the lips. There was no abnormality in the hard and soft palate, and a postoperative scar was seen at the root of the left tongue. There was no redness or swelling at the mouth of each salivary gland duct, and there was clear salivary overflow. There was no significant abnormality in the occlusal relationship. The pharynx was not red, the tonsils were not enlarged bilaterally, and the uvula was centered. No enlarged lymph nodes were palpated in the neck. Preliminary diagnosis: small cell neuroendocrine carcinoma of the left tongue root. The patient’s diagnosis was clear and surgical treatment was necessary, and other adjuvant treatments such as adjuvant radiotherapy and immunotherapy should be considered. On April 30, 2006, a lymph node dissection of the left suprascapular hyoid bone was performed under general anesthesia. A downward T-shaped incision was made at the midpoint of the mandibular body up to 2 cm below the plane of the clavicle. the depth of the incision reached the broad cervical muscle, and the cervical flap and rhomboid flap were prepared. The skin along the incision is separated from the deeper tissues along with the cervical muscle. The submandibular flap was separated upward to the lower edge of the mandible, and the flap was turned forward to the midline of the neck. The flap is turned backward to the anterior border of the trapezius muscle and the lower part of the flap is separated to the inferior border of the scapulolingualis muscle. The anterior and posterior edges of the sternocleidomastoid muscle and the ventral side of the muscle are separated to free it from the internal jugular vein and common carotid artery on its deep side, and then pulled laterally with gauze. The scapulohyoid muscle was identified on its deep surface to reveal the carotid sheath. The carotid sheath is dissected in layers to fully expose the internal jugular vein, common carotid artery and vagus nerve, and the internal jugular vein is bluntly separated.
The deep cervical fascia and fat were incised along the inferior border of the scapulolingual muscle toward the anterior border of the oblique muscle. In the posterior inferior corner of this area, the fat and fovea are dissected along the anterior edge of the trapezius muscle. The paraspinal nerve is seen at approximately the junction of the middle and lower 1/3 of the anterior border of the trapezius muscle, which is freed and protected. The dissection is continued upward to the posterior border of the sternocleidomastoid muscle. The branches of the cervical plexus are severed, except for the phrenic nerve, which is preserved.
The separated internal jugular vein was lifted upward and dissociated along the surface of the common carotid artery and vagus nerve up to the bifurcation of the common carotid artery. After incising the superficial layer of deep cervical fascia medial to the sternocleidomastoid muscle, the surface of the sternocleidomastoid muscle is dissected from anterior to posterior to the hyoid appendage of the scaphoid hyoid muscle. The sternocleidomastoid muscle was continued to be dissected upward, and the dissected tissue was drawn upward to reveal the carotid bifurcation, and the lymph nodes and cellular tissue in this area were peeled off and excised.
The cellular adipose tissue and lymph nodes in the subchin region were dissected along the superficial surface of the mandibular hyoid muscle between the anterior belly of the biceps muscle from the opposite side to the submandibular direction of the affected side. The superficial layer of deep cervical fascia was incised along the inferior border of the mandible, anteriorly to the anterior border of the bicipital muscle, posteriorly to the angle of the mandible, and the caudal lobe of the parotid gland was cut at the angle of the mandible, posteriorly to the mastoid process. The external maxillary artery and anterior anterior vein were cut and ligated, the submandibular gland was separated and removed, the submandibular gland duct was ligated, and the submandibular gland and its surrounding foveal adipose tissue and lymph nodes were dissociated in the posterior ventral direction of the diastasis. The proximal end of the facial artery was cut and double ligated at the lateral aspect of the submandibular gland and at the superior margin of the posterior ventral part of the diastasis. Then the above dissociated soft tissues were freed upward to the plane of the caudate, the superior end of the internal jugular vein was separated and protected, and the free tissue was removed. At this point, the cervical lymphatic dissection was completed. The wound was flushed with saline, and after thorough hemostasis, the broad neck muscle, subcutaneous tissue, and skin were sutured in counterpoint layer by layer, a negative pressure drain was placed, and sterile gauze covered the wound. The operation went smoothly, with intraoperative bleeding of about 350 ml and no blood transfusion. The anesthesia was satisfactory, and the operation lasted 6 hours, and the tube was removed and returned to the ward. The excised specimen was sent for pathological examination. Postoperative anti-inflammatory, supportive and symptomatic treatment was given. The recovery was smooth and the incision healed at grade A. Pathology return: (scaphoid hyoid muscle debridement, fat and lymphatic tissue) No metastatic cancer was seen in the lymph nodes (0/10). Immunohistochemical staining showed lymph nodes: AE1(-). No intra-hospital infection or complications occurred during hospitalization. Condition at discharge: general condition was good and vital signs were stable. The wound was healing well. Diagnosis at discharge: postoperative small cell neuroendocrine carcinoma of the left tongue root. Post-discharge precautions: 1. pay attention to rest and strengthen nutrition. 2. review regularly.
II. Diagnosis and treatment thinking process
Primary cutaneous neuroendocrine carcinoma, also known as Merkel cell carcinoma, used to be called trabecular carcinoma, small cell carcinoma, endocrine carcinoma or cutaneous neuroendocrine carcinoma, is a rare and highly malignant tumor. Epidermis and dermis, later called Merkel cells, are generally believed to be neuroendocrine related in origin, and these cells have specific, progressively adapting tactile receptor functions. In the 1970s Toker first described Merkel cell tumors as Merkel cells from the skin. Neuroendocrine tumors occurring in the oral cavity and jaws are rare, including paragangliomas, infantile malignant neuroectodermal tumors, small cell carcinomas, and Merkel cell carcinomas, and perioral and intraoral Merkel cell carcinomas are also rare [6]. There are only a few cases reported in the literature that occurred in the mucosal tissue of the head and neck, and Yom SS [5] et al. reported a case of Merkel cell carcinoma that occurred in the tongue mucosa in a 57-year-old Caucasian man, and the authors concluded that neuroendocrine carcinoma should be included in the diagnosis considered when lesions are present in the mucosal tissue of the head and neck, especially when the lesions occur in the submucosa. Based on the time of onset, this patient can be considered as the second case.
Neuroendocrine carcinoma relies on histopathology to confirm the diagnosis, and it is difficult to first consider neuroendocrine carcinoma only from clinical manifestations and signs. In this case, it needs to be differentiated from squamous cell carcinoma, malignant lymphoma, and malignant melanoma as follows.
1.Squamous cell carcinoma: It occurs in patients over 50 years old, and tongue cancer has a short course and develops quickly. At the beginning, a small hard node on the tongue can be seen, which gradually forms obvious swelling or grows into cauliflower shape and can be painful and erosive; or a small ulcer with slightly elevated edge can appear in the central area of the lump, and the ulcer will not heal, and the base will gradually infiltrate and become enlarged and hard.
2, malignant lymphoma [7]: oral primary malignant lymphoma is less common, and the sites of this tumor in the oral cavity are palate, gums, tongue, cheek, and floor of the mouth in order of occurrence, mostly manifesting as ulcerated masses, and the most common clinical symptoms and signs are local pain, ulcerated masses, and in some cases, dysphagia and loosening of teeth. Few of them are nodules with smooth surface and no obvious clinical symptoms.
3.Malignant melanoma: malignant melanoma originates from melanocytes and mostly occurs on the basis of junctional nevus or melanotic spots. About 30% of the mucosal melanoma in the oral cavity can become malignant. Moles and pigmented spots are often the precursor lesions. Any rapid growth, pigmentation, satellite nodules, basal infiltration, ulceration and pain should be suspected of malignant transformation, especially the sudden increase of focal lymph nodes. The most common sites in the oral cavity are the palate, gums and buccal mucosa; the tumor is a blue-black, flat or slightly raised mass that spreads rapidly to the surrounding area and infiltrates into the submucosa and bone tissue. About 70% of the tumors metastasize to local lymph nodes at an early stage. 40% of the tumors may have distant metastasis.
Maxillofacial neuroendocrine carcinoma, whether primary or metastatic, is uncommon, mostly occurring in middle-aged and elderly people. The tumor appears as a fast growing, shiny, dark red intradermal nodule, with visible surface capillary dilatation, firmness and no pressure pain, ranging from 0.5 to 5 cm in diameter. The swellings were all small at first and all showed fast growth. The swellings were isolated nodules, less than 2cm, relatively hard, no pressure pain, no ulcers on the surface skin, pink, and visible surface capillary dilation. However, the swelling does not correspond well to the clinical manifestations of cysts, fibroids or enlarged lymph nodes of the maxillofacial skin. When an isolated nodular mass is found in the maxillofacial region, which is initially small, has a fast-growing manifestation, has a relatively hard texture without pressure pain, has no ulceration on the surface skin, and has a pinkish color with dilated small blood vessels on the surface skin, which is not consistent with some common disease manifestations, the possibility of primary Merkel cell carcinoma or metastatic neuroendocrine carcinoma can be considered [8]. In the present patient, we first considered the possibility of lymphoma because the patient had an intact mucosa and the mass was located in the submucosa, which was significantly different from typical squamous cell carcinoma and from the typical presentation of malignant melanoma. This is supported by the frozen pathology report, but because neuroendocrine carcinoma itself is a rare case, as well as the pathological proximity of the two, there is some error in the frozen sections.
Histologically, neuroendocrine carcinoma can be seen under light microscopy as tumors located in the dermis and sometimes in the subcutaneous tissues, the epidermis covering the surface is usually not involved, the tumor consists of small round cells with the same nucleus and cytoplasm, mitosis is rare, the tumor cells are in sheets or form irregular trabeculae extending downward into the subcutaneous tissues, the cytoplasm is small but visible as a thin eosinophilic circle, the nucleus is round and has small vesicles, there are typical Small granular chromatin and multiple nucleoli are sometimes seen invading lymph nodes and blood vessels in fascia and muscle and dermis, and the tumor may resemble lymphoma, carcinoid tumor, sweat adenocarcinoma, or neuroblastoma [9, 10, 11]. The diagnosis of neuroendocrine carcinoma can be initially considered when images of small cell undifferentiated carcinoma or carcinoid tumor are found on conventionally stained histologic sections, or in non-endocrine tumor tissues with a large number of differentiated neuroendocrine cells, and the use of immunohistochemical methods and electron microscopic observation can help in differential diagnosis, including differentiation from malignant lymphoma and malignant melanoma.
Auxiliary examination and treatment of neuroendocrine cancer.
Imaging examinations are mainly used to help determine whether lesions exist in other parts or organs of the body. CT and MRI of the chest and abdomen are very useful tools to understand the presence of tumors, and recently, PET has been reported to be applied to aid in the diagnosis of neuroendocrine cancer patients [12-14], and Hu Min et al [8] also used these means to help determine whether the tumor is primary or metastatic.
Treatment of maxillofacial neuroendocrine carcinoma should include extensive resection of the primary site and cervical lymph node dissection surgery when necessary, and postoperative radiotherapy of the primary site and regional lymph nodes is beneficial. The local recurrence rate of neuroendocrine carcinoma after surgery is about 35-43%, with a mean recurrence time of 4.3 months, and Hu Min et al [8] reported that in five cases, one patient with primary neuroendocrine carcinoma also had recurrence at 4 months after surgery. 41% of patients had regional lymph node metastasis, 18% had visceral metastasis, and about 60% of patients without local recurrence had lymph node metastasis, while in patients with local About 60% of patients without local recurrence had lymph node metastasis, while about 86% of patients with local recurrence had lymph node metastasis. The location and extent of the tumor were associated with survival, with a 5-year survival rate of approximately 64% for localized neuroendocrine carcinoma only and 47% for those with lymph node involvement, and an average survival of approximately 5 months when distant metastases were detected. There is a gender difference in prognosis, with a 3-year survival rate of about 35% for men and 67% for women.
Surgery is the only complete cure, and resection of localized lesions and limited metastases can cure some patients with neuroendocrine tumors, and in Merkel cell carcinoma, the basic treatment is extensive resection of localized lesions to negative margins, ranging from 2.5 to 3.0 cm from the tumor margin [15, 16]. In our patient, the pathology was reported as: small cell neuroendocrine carcinoma, partially with squamous carcinoma differentiation, so although the margins were reported negative, prophylactic cervical lymphatic dissection should still be performed, and the postoperative pathology returned: (scaphohyoid muscle dissection, fat and lymphatic tissue) no metastatic carcinoma was seen in the lymph nodes (0/10). On the other hand, although the surgical principle is to excise beyond 2.5-3.0 cm from the tumor margin, the last pathological returns were negative for all cut margins, so the resection was not expanded again, but the primary focus should be closely observed and reviewed at any time.
The recurrence rate is high after treatment with surgery alone, and radiation therapy is beneficial to control local recurrence and after lymph node dissection surgery, to consolidate the treatment effect. Moreover, some studies have shown that such tumor cells are sensitive to radiotherapy, and it has also been reported in the literature that Merkel cell carcinoma is a highly radiosensitive tumor, and the radiation dose is similar to that of squamous cell carcinoma treatment, which is about 45-60 Gy [17, 18]. It is debated whether and when to administer chemotherapy for neuroendocrine carcinoma. Due to the slow progression of these tumors, poor efficacy of chemotherapy and toxic side effects, it is mainly used for patients with advanced stages and those with distant metastases, and the drugs applied include cyclosporine, vincristine, cisplatin and fluorouracil; however, the effect of chemotherapy may be very limited. Because of the high recurrence rate of neuroendocrine cancer, follow-up should be more intensive, preferably once a month for 6 months after surgery, every 2-3 months for 2 years afterwards, and once a year thereafter.
References.
1, Lawenda BD, Thiringer JK, Foss RD, et al. Merkel Cell Carcinoma Arising in the Head and Neck[J]. Am J Clin Oncol, 2001, 24(1):35-42
2, De Wolf-Peeters C, Marien K, Mebis J, et al. A cutaneousAPUDoma or Merkel cell tumor? A morphologically recognizable tumor with a biological and histological malignant aspect in contrast with its clinical behavior[J].Cancer, 1980, 46:1810-1816
3, Orsini G, Fiorini M, Rubini C, et al. Merkel cell carcinoma of the lip: Report of a case[J]. J Oral Maxillofac Surg, 2000, 58:1044-1047
4, Fornelli A, Eusebi V, Pasquinelli G, et al. Merkel cell carcinoma of the parotid gland associated with Warthin tumour: report of two cases[J]. Histopathology, 2001, 39:342-346
5, Yom SS, Rosenthal DI, El-Naggar AK, et al. Merkel cell carcinoma of the tongue and head and neck oral mucosal sites. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006, 101(6):761-8
6. Hu M. Journal of Oral and Maxillofacial Surgery. 2003, 13 (2):95-97
7. Liu Baoan, Su Zhansan, Liu Jian. Clinical and pathological features of oral primary malignant lymphoma. Chinese Clinical Oncology, 1999, 26 (6)
8. Hu M, Yang G, Wen W S, et al. Neuroendocrine carcinoma of the maxillofacial region. Chinese Journal of Geriatric Dentistry, 2003, 1(2):75-77
9, Holland JF, Bast Jr RC, Morton DL, et al. Cancer Medicine[M]. 4th ed. Williams & Wilkins, Baltimore, 1997:1571-1603
10, Vigneswaran N, Muller S, Lense E, et al. Merkel cell carcinoma of the labial mucosa: An immunohistochemical and ultrastructural study with a review of the literature on the literature on oral Merkel cell carcinomas[J]. Oral Surg, 1992, 74: 193-197
11, Hayter JP, Jaques K, James KA. Merkel cell tumour of the check.[J]. Br J Oral Maxillofac Surg, 1991, 29:114- 117
12, Moayed S, Maldjian C, Adam R, et al. Magnetic resonance imaging appearance of metastatic Merkel cell carcinoma to the sacrum and epidural space[J]. Magnetic ResonanceImaging, 2000, 18:1039-1042
13, Acland KM, O’Doherty MJ, Russell-Jones R. The value of positron emission tomography scanning in the detection of subclinical metastatic melanoma[J]. J Am Acad Dermatol, 2000, 42:606-611
14, Lampreave JL, Benard F, Alavi A, et al. PET evaluation of therapeutic limb perfusion in Merkel’s cell carcinoma [J]. J Nucl Med, 1998, 39:2087-2090
15, Shaw JH, Rumball E. Merkel cell tumour: clinical behaviour and treatment [J]. Br J Surg, 1991, 78:138-142
16, Kokoska ER, Kokoska MS, Collins BT, et al. Early aggressive treatment for Merkel cell carcinoma improves outcome [J]. Am J Surg, 1997, 174:688-693
17, Ashby MA, Jones DH, Tasker AD, et al. Primary cutaneous neuroendocrine (Merkel cell or trabecular carcinoma) tumour of the skin: A radioresponsive tumour [J]. Clin Radiol, 1989, 40:85-87
18, Fenig E, Brenner B, Katz A, et al. The role of radiation therapy and chemotherapy in the treatment of Merkel cellcarcinoma [J]. Cancer, 1997, 80:881-885