Perineural invasion by squamous-cell carcinoma of the lower lip Review
of the literature
C. J. Mickalites, D.M.D.,” Long Beach, Calif.
and
report
of a case
and I. Rappaport, D.M.D.,
M.D.,**
Although perineural metastases have been studied extensively for various regions of the body, there is a relative paucity of data on cancers of the head and neck region. A case of perineural metastasis from a squamous-cell carcinoma of the lower lip is presented, with symptoms mimicking other neurologic diseases.
Squamous-cell
carcinoma of the lip is a relatively common malignant condition that comprises 2.2 percent of all cases of cancer annually. Fifteen percent of all oral malignancies are squamous-cell carcinomas of the lip; 93 percent involve the lower lip.’ Although this disease has been reported to be relatively benign2* 3 and to be slow to metastasize,4 the manner of metastasis may be so insidious that it lulls the surgeon into an approach that is too conservative. REVIEW OF THE LITERATURE
There are four pathways of malignant metastasis:seeding through body cavities (peritoneal, pleural, pericardial, subarachnoid,joint spaces,perineural); direct transplantation; lymphatic permeation; and embolization through blood vesse1s.jMany articles have been written on such modes of metastasisas lymphatic spread and embolization through blood vessels,but relatively few articles have dealt with perineural spread.The first significant reference to malignant invasion of nerves was by Cruveilhiel-6 in 1842. Neumann,7in 1862, reported a caseof carcinoma of the lower lip with bilateral invasion of the mental nerve. Since then, there have been reports of perineural tumor spread associatedwith carcinoma of the tongue,x breast,s skin,‘O pancreas,” and prostate,12 cylindroma of the parotid gland,13and sarcomaof the extremities.‘” *Former Resident in Oral Surgery, Veterans Administration Hospital, Long Beach, Calif. At present, StafYOral Surgeon, Mountain Home Veterans Administration Center, Johnson City, Tenn. **Chief, Department of Plastic and Reconstructive Surgery, Veterans Administration Hospital, Long Beach, Calif.
74
0030-4220/78/0146-0074$00.50/O
0
1978 The C. V. Mosby
Co.
Volume 46 Number I
Perineural invasion by carcinoma of lower lip
75
Emst,‘j in 1905, postulated that malignant cells spread along nerve fibers via perineural and endoneural lymphatics. In an attempt to elucidate the mechanism of perineural invasion, Larson and associatesi used injections of dye and ink to study the spread of these agents from the lymph channels via mental or inferior alveolar nerves. Material injected into nerve fibers in the lip progressed directly into the central nervous system via the inferior alveolar nerve. The implantation of clonal tumor cells intraneurally also resulted in free spread centrally beneath the perineurium. The most extensive report of perineural invasion of malignant cells is that of Ballantyne and associatesi which dealt with eighty cases in varied locations and having diverse histopathologic features. Evidence of perineural invasion was established by one of three means: (I) histopathologic finding of neural invasion; (2) radiographic evidence of widening of osseous canals or erosion of skull foramina with which the involved nerves were associated; (3) sensory complaints, such as burning, shooting or stinging pains, or numbness along a nerve distribution. Several interesting and clinically valuable points can be gleaned from the abovementioned report: (1) Of the seventeen cases of lower lip carcinoma, eight were without evidence of regional metastases. (2) In many cases, sensory complaints preceded clinical recognition of the primary lesion by many months. (3) If adequate treatment was given prior to extension into the cranial cavity or spinal cord, a possibility of cure existed. All patients with central extension, except one, have died. Radiographic evidence of perineural metastases was studied by Dodd,r8 who found a suggestion of invasion (erosion of foramina, widening of osseous canals, sclerotic bone about foramina) in cranial nerves in about twenty-six of forty-eight cases. CASE REPORT F. W., a 53-year-old white man, first presented on May 14, 1973, with a chief complaint of firm nodules in the right side of the lower lip. In December, 1972, the patient had undergone a U-shaped excision of an ulcerative lesion of the right side of the lower lip by a practitioner other than
ourselves. Histologic examination showed a moderately well-differentiated infiltrating squamouscell carcinoma, with the left medial margin not free of tumor. In April, 1973, the patient underwent an incisional biopsy of a mass in the right buccal vestibule near the mental foramen. The lesion was repotted as a foreign-body reaction with discrete foci of squamous-cell carcinoma. When seen in May, 1973, the patient had a well-healed vertical scar on the right lower lip, with three 1-mm. nodules palpable on the mucosal surface of the scar, and a I -cm. nodule in the buccal vestibule near the right mental foramen. No lymphadenopathy was observed. The nodules were thought to represent recurrent disease, and the patient was referred for radiotherapy. Upon completion of 5,021 rads of external-beam radiation, the nodules were no longer present. The patient was followed closely and presented no evidence of disease until June 24, 1974, at which time he complained of a sharp pain localized to the region of the right mandibular angle; the pain was initiated by mandibular movements. Radiographs of the mandible and temporomandibular joint showed decreased motion of the tempotomandibular joint (TMJ) bilaterally. No other pathologic condition was noted. On July 24, 1974, the patient complained of spontaneous, intermittent sharp pain over the right TMJ; the pain radiated along the mandible to the midline. Examination revealed slight hypalgesia of the right medial portion of the lower lip. The patient was referred for neurologic consultation, with the recommendation that the pain be treated as tic douloureux. Mandibular radiographs showed no evidence of disease.
76
Mickalites
Oral Surg. July, 1978
and Rappaport
Fig. 1. Right mental nerve, demonstrating
tumor
cells in perineurium
By Aug. 8, 1974, the patient had developed intermittent paresthesia alternating with pain along the right side of the head, behind the right eye. Pain to palpation was present along the mandibular division of the fifth nerve, as well as moderate anesthesia along the distribution of the maxillary nerve. The symptoms continued until a nodule was discovered in the area of the right mental foramen. This was biopsied in November, 1974, with the finding of recurrent squamous-cell carcinoma with perineural invasion (Fig. I). On Dec. 3, 1974, a right radical neck dissection and right marginal resection of the mandible, along with tumor excision were performed. Repair was effected with a transposition flap from the left side of the neck to the right side of the chin. Histologic findings at this time were moderately well-differentiated infiltrating squamous-cell carcinoma, with the posterior soft-tissue margin containing tumor, and perineural extension along the inferior alveolar nerve (Fig. 2). On Dec. 13, 1974, the patient underwent a right mandibular and soft-tissue resection, with delta-pectoral flap repair. The histologic examination showed perineural invasion all along the inferior alveolar nerve beyond the surgical margin. He was followed closely but showed no recurrence of symptoms. Staged repair of the facial defect was performed until March, 1976, when the patient complained of burning and numbness along the distribution of the right infraorbital nerve and along the gingiva of the right maxilla. Radiographs of the skull and a Delta CT brain scan showed no pathosis at that time. The patient is presently undergoing radiotherapy to the right Gasserian ganglion, with relief of symptoms. DISCUSSION In the case presented, we speculate that the perineural spread extended along the inferior alveolar nerve to the Gasserian ganglion and retrograde to the lingual and maxil-
Fig.
2. Right inferior
alveolar
nerve
in mental
foramen
area, demonstrating
tumor cells in perineurium.
lary nerves. The symptoms may have been secondary to radiation, operative trauma, or other variables. It is interesting to note that the patient never had radiographic evidence of perineural involvement. Anyone concerned with the treatment of the head and neck regions should be aware of the possibility of an unsuspected primary or recurrent carcinoma presenting as neural involvement. The criteria for evaluation include: (1) sensory symptoms of numbness, burning, or shooting pain along the distribution of a nerve; (2) histopathologic evidence of tumor invasion; (3) radiographic features, such as widening of an osseous canal, erosion of a foramen, or sclerotic changes around a foramen (early change). SUMMARY Presented is a case of perineural invasion by a squamous-cell carcinoma lip. The literature is reviewed and criteria for evaluating possible perineural presented.
of the lower invasion are
REFERENCES
I. Schwartz, S. I., et al.: Principles of Surgery, ed. 2, New York, 1974, McGraw-Hill Book Company, p. 561. 2. Harris, T. J.: Squamous carcinoma of the Lip in Queensland: A Relatively Benign Lesion, Elr. J. Plast. Surg. 29: 68, 1976. 3. Durkovsky, J., Krajci, M., and Michalikova, B.: To the Problem of the Lip Cancer Metastases, Neoplasma 19:
653,
1972.
4. Shafer, W. G., Hine, M. K., and Levy, Saunders Company, p. 101
B. M.:
A Textbook
of Oral Pathology,
Philadelphia,
1963, W. B.
78
Mickalites
and Rappaport
6. Cruveilhier, J.: Maladies des Nerfs. Anatomie Pathologique du Corps Humain, Paris, 1835-1842, J. B. Balliere, 2 Pt., 35, p, 3. 7. Neumann, E.: Secondare cancroid-infiltration des Nervus Mentahs bei einem Fall vonHippencancroid, Virchows Arch. 24: 201, 1862. 8. Shattock, S. G.: Invasion of the Nerves in Carcinoma of the Sublingual Salivary Gland Associated With Carcinoma of the Tongue, Proc. R. Sot. Med. 3: 13, 1921. 9. Jentzer, A.: Neurotropisme des Cellules Cancereuses Clinique et Therapeutique des Cancers Neurotropes, Am. J. Cancer 16: 37, 1932. (Abstr.) 10. Mohs, F. E.: Chemosurgical Treatment of Cancer of the Face and Lips; A Microscopically Controlled Method of Excision, Surg. Clin. North Am. 38: 929, 1958. I I. Drapiewski, J. F.: Carcinoma of the Pancreas. A Study of Neoplastic Invasion of Nerves and Its Possible Clinical Significance. Ph.D. Thesis, 1942, Minneapolis, Graduate School, University of Minnesota, pp. 7-14.
12. Warren, S., Harris, P. N., and Graves, R. C.: Osseous metastasisof Carcinoma of the Prostate With Special Reference to the Perineural Lymphatics, Arch. Pathol. 22: 139, 1936. 13. Quattlebaum, F. W.: Adenocarcinoma, Cylindroma Type, of the Parotid Gland, Surg. Gynecol. Obstet. 82: 342, 1946.
14. Barber, J. R., Coventry, M. B., and McDonald, J. R.: The Spread of Soft Tissue Sarcomata of the Extremities Along Peripheral Nerve Trunks, J. Bone Joint Surg. (Am.) 39: 534, 1957. 15. Ernst, P.: Uber das Wachstum und die verbreitung hotsartizar Geschwulste insbesondere des Krebses in den Lymphbahnen der Nerven, Beitr. Pathol. Anat. 29: (Suppl. 7), 1905. 16. Larson, D. L., Rodin, A. E., Roberts, D. K., O’Steen, W. K., Rapperport, A. S., and Lewis, S. R.: Perineural Lymphatics: Myth or Fact, Am. J. Surg. 112: 488, 1966. 17. Ballantyne, A. J., McCarten, A. B., and Ibanez, M. L.: The Extension of Cancer of the Head and Neck Through Peripheral Nerves, Am. J. Surg. 106: 651, 1963. 18. Dodd, G. D., Dolan, P. A., Ballantyne, A. J., Ibanez, M. L., and Chau, P.: The Dissemination of Tumors of the Head and Neck Via the Cranial Nerves, Radio]. Clin. North Am. 8: 445, 1976. Reprint
requests to:
Dr. C. J. Mickalites Mountain Home VA Center Johnson City, Tenn. 37601
INFORMATION
FOR AUTHORS
Most of the provtsions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published.” Authors will be consulted, when possible, regarding republication of their material.
of the literature
C. J. Mickalites, D.M.D.,” Long Beach, Calif.
and
report
of a case
and I. Rappaport, D.M.D.,
M.D.,**
Although perineural metastases have been studied extensively for various regions of the body, there is a relative paucity of data on cancers of the head and neck region. A case of perineural metastasis from a squamous-cell carcinoma of the lower lip is presented, with symptoms mimicking other neurologic diseases.
Squamous-cell
carcinoma of the lip is a relatively common malignant condition that comprises 2.2 percent of all cases of cancer annually. Fifteen percent of all oral malignancies are squamous-cell carcinomas of the lip; 93 percent involve the lower lip.’ Although this disease has been reported to be relatively benign2* 3 and to be slow to metastasize,4 the manner of metastasis may be so insidious that it lulls the surgeon into an approach that is too conservative. REVIEW OF THE LITERATURE
There are four pathways of malignant metastasis:seeding through body cavities (peritoneal, pleural, pericardial, subarachnoid,joint spaces,perineural); direct transplantation; lymphatic permeation; and embolization through blood vesse1s.jMany articles have been written on such modes of metastasisas lymphatic spread and embolization through blood vessels,but relatively few articles have dealt with perineural spread.The first significant reference to malignant invasion of nerves was by Cruveilhiel-6 in 1842. Neumann,7in 1862, reported a caseof carcinoma of the lower lip with bilateral invasion of the mental nerve. Since then, there have been reports of perineural tumor spread associatedwith carcinoma of the tongue,x breast,s skin,‘O pancreas,” and prostate,12 cylindroma of the parotid gland,13and sarcomaof the extremities.‘” *Former Resident in Oral Surgery, Veterans Administration Hospital, Long Beach, Calif. At present, StafYOral Surgeon, Mountain Home Veterans Administration Center, Johnson City, Tenn. **Chief, Department of Plastic and Reconstructive Surgery, Veterans Administration Hospital, Long Beach, Calif.
74
0030-4220/78/0146-0074$00.50/O
0
1978 The C. V. Mosby
Co.
Volume 46 Number I
Perineural invasion by carcinoma of lower lip
75
Emst,‘j in 1905, postulated that malignant cells spread along nerve fibers via perineural and endoneural lymphatics. In an attempt to elucidate the mechanism of perineural invasion, Larson and associatesi used injections of dye and ink to study the spread of these agents from the lymph channels via mental or inferior alveolar nerves. Material injected into nerve fibers in the lip progressed directly into the central nervous system via the inferior alveolar nerve. The implantation of clonal tumor cells intraneurally also resulted in free spread centrally beneath the perineurium. The most extensive report of perineural invasion of malignant cells is that of Ballantyne and associatesi which dealt with eighty cases in varied locations and having diverse histopathologic features. Evidence of perineural invasion was established by one of three means: (I) histopathologic finding of neural invasion; (2) radiographic evidence of widening of osseous canals or erosion of skull foramina with which the involved nerves were associated; (3) sensory complaints, such as burning, shooting or stinging pains, or numbness along a nerve distribution. Several interesting and clinically valuable points can be gleaned from the abovementioned report: (1) Of the seventeen cases of lower lip carcinoma, eight were without evidence of regional metastases. (2) In many cases, sensory complaints preceded clinical recognition of the primary lesion by many months. (3) If adequate treatment was given prior to extension into the cranial cavity or spinal cord, a possibility of cure existed. All patients with central extension, except one, have died. Radiographic evidence of perineural metastases was studied by Dodd,r8 who found a suggestion of invasion (erosion of foramina, widening of osseous canals, sclerotic bone about foramina) in cranial nerves in about twenty-six of forty-eight cases. CASE REPORT F. W., a 53-year-old white man, first presented on May 14, 1973, with a chief complaint of firm nodules in the right side of the lower lip. In December, 1972, the patient had undergone a U-shaped excision of an ulcerative lesion of the right side of the lower lip by a practitioner other than
ourselves. Histologic examination showed a moderately well-differentiated infiltrating squamouscell carcinoma, with the left medial margin not free of tumor. In April, 1973, the patient underwent an incisional biopsy of a mass in the right buccal vestibule near the mental foramen. The lesion was repotted as a foreign-body reaction with discrete foci of squamous-cell carcinoma. When seen in May, 1973, the patient had a well-healed vertical scar on the right lower lip, with three 1-mm. nodules palpable on the mucosal surface of the scar, and a I -cm. nodule in the buccal vestibule near the right mental foramen. No lymphadenopathy was observed. The nodules were thought to represent recurrent disease, and the patient was referred for radiotherapy. Upon completion of 5,021 rads of external-beam radiation, the nodules were no longer present. The patient was followed closely and presented no evidence of disease until June 24, 1974, at which time he complained of a sharp pain localized to the region of the right mandibular angle; the pain was initiated by mandibular movements. Radiographs of the mandible and temporomandibular joint showed decreased motion of the tempotomandibular joint (TMJ) bilaterally. No other pathologic condition was noted. On July 24, 1974, the patient complained of spontaneous, intermittent sharp pain over the right TMJ; the pain radiated along the mandible to the midline. Examination revealed slight hypalgesia of the right medial portion of the lower lip. The patient was referred for neurologic consultation, with the recommendation that the pain be treated as tic douloureux. Mandibular radiographs showed no evidence of disease.
76
Mickalites
Oral Surg. July, 1978
and Rappaport
Fig. 1. Right mental nerve, demonstrating
tumor
cells in perineurium
By Aug. 8, 1974, the patient had developed intermittent paresthesia alternating with pain along the right side of the head, behind the right eye. Pain to palpation was present along the mandibular division of the fifth nerve, as well as moderate anesthesia along the distribution of the maxillary nerve. The symptoms continued until a nodule was discovered in the area of the right mental foramen. This was biopsied in November, 1974, with the finding of recurrent squamous-cell carcinoma with perineural invasion (Fig. I). On Dec. 3, 1974, a right radical neck dissection and right marginal resection of the mandible, along with tumor excision were performed. Repair was effected with a transposition flap from the left side of the neck to the right side of the chin. Histologic findings at this time were moderately well-differentiated infiltrating squamous-cell carcinoma, with the posterior soft-tissue margin containing tumor, and perineural extension along the inferior alveolar nerve (Fig. 2). On Dec. 13, 1974, the patient underwent a right mandibular and soft-tissue resection, with delta-pectoral flap repair. The histologic examination showed perineural invasion all along the inferior alveolar nerve beyond the surgical margin. He was followed closely but showed no recurrence of symptoms. Staged repair of the facial defect was performed until March, 1976, when the patient complained of burning and numbness along the distribution of the right infraorbital nerve and along the gingiva of the right maxilla. Radiographs of the skull and a Delta CT brain scan showed no pathosis at that time. The patient is presently undergoing radiotherapy to the right Gasserian ganglion, with relief of symptoms. DISCUSSION In the case presented, we speculate that the perineural spread extended along the inferior alveolar nerve to the Gasserian ganglion and retrograde to the lingual and maxil-
Fig.
2. Right inferior
alveolar
nerve
in mental
foramen
area, demonstrating
tumor cells in perineurium.
lary nerves. The symptoms may have been secondary to radiation, operative trauma, or other variables. It is interesting to note that the patient never had radiographic evidence of perineural involvement. Anyone concerned with the treatment of the head and neck regions should be aware of the possibility of an unsuspected primary or recurrent carcinoma presenting as neural involvement. The criteria for evaluation include: (1) sensory symptoms of numbness, burning, or shooting pain along the distribution of a nerve; (2) histopathologic evidence of tumor invasion; (3) radiographic features, such as widening of an osseous canal, erosion of a foramen, or sclerotic changes around a foramen (early change). SUMMARY Presented is a case of perineural invasion by a squamous-cell carcinoma lip. The literature is reviewed and criteria for evaluating possible perineural presented.
of the lower invasion are
REFERENCES
I. Schwartz, S. I., et al.: Principles of Surgery, ed. 2, New York, 1974, McGraw-Hill Book Company, p. 561. 2. Harris, T. J.: Squamous carcinoma of the Lip in Queensland: A Relatively Benign Lesion, Elr. J. Plast. Surg. 29: 68, 1976. 3. Durkovsky, J., Krajci, M., and Michalikova, B.: To the Problem of the Lip Cancer Metastases, Neoplasma 19:
653,
1972.
4. Shafer, W. G., Hine, M. K., and Levy, Saunders Company, p. 101
B. M.:
A Textbook
of Oral Pathology,
Philadelphia,
1963, W. B.
78
Mickalites
and Rappaport
6. Cruveilhier, J.: Maladies des Nerfs. Anatomie Pathologique du Corps Humain, Paris, 1835-1842, J. B. Balliere, 2 Pt., 35, p, 3. 7. Neumann, E.: Secondare cancroid-infiltration des Nervus Mentahs bei einem Fall vonHippencancroid, Virchows Arch. 24: 201, 1862. 8. Shattock, S. G.: Invasion of the Nerves in Carcinoma of the Sublingual Salivary Gland Associated With Carcinoma of the Tongue, Proc. R. Sot. Med. 3: 13, 1921. 9. Jentzer, A.: Neurotropisme des Cellules Cancereuses Clinique et Therapeutique des Cancers Neurotropes, Am. J. Cancer 16: 37, 1932. (Abstr.) 10. Mohs, F. E.: Chemosurgical Treatment of Cancer of the Face and Lips; A Microscopically Controlled Method of Excision, Surg. Clin. North Am. 38: 929, 1958. I I. Drapiewski, J. F.: Carcinoma of the Pancreas. A Study of Neoplastic Invasion of Nerves and Its Possible Clinical Significance. Ph.D. Thesis, 1942, Minneapolis, Graduate School, University of Minnesota, pp. 7-14.
12. Warren, S., Harris, P. N., and Graves, R. C.: Osseous metastasisof Carcinoma of the Prostate With Special Reference to the Perineural Lymphatics, Arch. Pathol. 22: 139, 1936. 13. Quattlebaum, F. W.: Adenocarcinoma, Cylindroma Type, of the Parotid Gland, Surg. Gynecol. Obstet. 82: 342, 1946.
14. Barber, J. R., Coventry, M. B., and McDonald, J. R.: The Spread of Soft Tissue Sarcomata of the Extremities Along Peripheral Nerve Trunks, J. Bone Joint Surg. (Am.) 39: 534, 1957. 15. Ernst, P.: Uber das Wachstum und die verbreitung hotsartizar Geschwulste insbesondere des Krebses in den Lymphbahnen der Nerven, Beitr. Pathol. Anat. 29: (Suppl. 7), 1905. 16. Larson, D. L., Rodin, A. E., Roberts, D. K., O’Steen, W. K., Rapperport, A. S., and Lewis, S. R.: Perineural Lymphatics: Myth or Fact, Am. J. Surg. 112: 488, 1966. 17. Ballantyne, A. J., McCarten, A. B., and Ibanez, M. L.: The Extension of Cancer of the Head and Neck Through Peripheral Nerves, Am. J. Surg. 106: 651, 1963. 18. Dodd, G. D., Dolan, P. A., Ballantyne, A. J., Ibanez, M. L., and Chau, P.: The Dissemination of Tumors of the Head and Neck Via the Cranial Nerves, Radio]. Clin. North Am. 8: 445, 1976. Reprint
requests to:
Dr. C. J. Mickalites Mountain Home VA Center Johnson City, Tenn. 37601
INFORMATION
FOR AUTHORS
Most of the provtsions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following statement, signed by each author: “The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published.” Authors will be consulted, when possible, regarding republication of their material.
