Proceedings of the North American Society of Head and Neck Pathology, Baltimore, MD, March 17, 2021: The Mistakes I Made When I Stepped Out of My Neck of the Woods

Abstract

Rapidly growing, symptomatic, non-hematological, malignant neck masses are unusual in young adults. We report a case of a 34-year-old African American male with sickle cell trait who presented with a large left supraclavicular/cervical mass comprising of poorly differentiated malignant epithelial cells consistent with metastatic carcinoma of unknown origin. Upon immunohistochemistry, the tumor showed loss of INI1 (BAF47) and retained PAX-8 expression. After extensive clinical and radiological work-up the primary tumor was found to be a 2.6 cm renal medullary carcinoma. This case highlights the role of multidisciplinary approach to the diagnosis of a neck mass and to understanding that certain genetically-defined tumors can occur at and metastasize to any site.

Introduction

The most common non-hematological malignancy affecting the lymph nodes of the neck is a metastasis from a head and neck primary, usually squamous cell carcinoma [1]. In younger patients, papillary thyroid carcinomas frequently metastasize to the lymph nodes in the neck. Metastasis from carcinoma of unknown origin (CUP) accounts for 5 to 10% of the head and neck cancers, and after ruling out a primary in the head and neck, and after extended clinical and radiological work up, a primary tumor elsewhere, usually in the lungs, breast, upper gastrointestinal and the genitourinary tract can ultimately be identified in the majority of cases [2]. Metastasis to neck lymph nodes for a non-head and neck primary indicates advanced stage. In older patients, involvement of left supraclavicular lymph nodes, the Virchow’s nodes, raises suspicion for a primary below the diaphragm. A combination of classic morphology and immunohistochemistry along with clinical and imaging findings may be required to help in the identification of the primary tumor, its staging and management.

Poorly differentiated carcinomas involving neck lymph nodes in young adults can be challenging and generate a broad differential diagnosis including poorly differentiated squamous cell carcinoma of the head and neck, high grade salivary gland carcinomas, nasopharyngeal and sinonasal carcinomas, high grade thyroid carcinomas, tumors arising from the ear and eye, and from skin and adnexal structures [1]. Imaging including positron emission tomography (PET) scan is usually helpful in finding the primary site in the head and neck

We present a case of metastatic poorly differentiated carcinoma involving the supraclavicular lymph nodes with negative head and neck imaging.

Case Report

A 34-year-old African American male presented with mass in the left lower neck associated with unintentional weight loss of up to 40 lbs, fatigue and non-specific abdominal pain that did not resolve with proton pump inhibitors. Imaging revealed a 4.7 cm left supraclavicular nodal mass.

A core biopsy revealed cords of discohesive epithelial cells infiltrating fibrous tissue. Tumor cells had large, irregular, atypical, hyperchromatic nuclei with prominent nucleoli and moderate amount of amphophilic cytoplasm which was foamy and vacuolated, reminiscent of histiocytes (Fig. 1). At times a single large intracytoplasmic vacuole pushed the nucleus to the periphery giving a signet ring appearance. Necrosis associated with acute and chronic inflammation but no mitoses were noted. Residual lymph nodal architecture was not identified.

Fig. 1.

Supraclavicular nodal mass: a core biopsy revealed (a) discohesive epithelial cells infiltrating fibrous tissue and associated acute inflammation and necrosis (10X). b Tumor cells had large, irregular, atypical and hyperchromatic nuclei with prominent nucleoli and moderate amount of amphophilic cytoplasm which was foamy and vacuolated, reminiscent of histiocytes (20X). c Tumor cells with a single large intracytoplasmic vacuole pushing the nucleus to the periphery giving a signet ring appearance were also identified (40X). (D) A mucicarmine special stain was negative for mucin within these cells

Special stain for mucicarmine was negative. Reticulin stain highlighted an alveolar architecture. Upon immunohistochemistry, the tumor cells diffusely expressed pancytokeratin (AE1/AE3), EMA, vimentin and WT1 but were negative for CK5/6, CK7, CK20, CDX-2, CK19 (few cells positive), p40, GATA3, CD30, CD31, CD34, CD10, CD45, CD56, chromogranin, synaptophysin, TTF-1, Napsin-A, S100, HMB-45, melan-A (Fig. 2). At this point, viable tumor cells became sparse and a second biopsy was performed to provide more tissue for diagnostic work up. Additional immunohistochemistry showed that the tumor cells were negative for CA-IX, OCT 3/4, PLAP, AFP, hCG, inhibin, MUC-2. MUC-5, ALK and p16. PAX-8 was positive in the second biopsy and INI1 was interpreted as weakly positive.

Fig. 2.

Supraclavicular nodal mass: immunohistochemistry revealed that the tumor cells were positive for (a) pancytokeratin (AE1/AE3) and (b) vimentin

The immunoprofile was interpreted as non-site-specific and a diagnosis of metastatic poorly differentiated carcinoma of unknown origin was made with possible sites being upper gastrointestinal tract including gastric and pancreatobiliary and renal.

An abdominal computerized tomography with intravenous contrast revealed a 2.6 cm ill-defined right lower pole renal mass encasing the renal vein and inferior vena cava with an inferior vena cava thrombus, and retroperitoneal lymphadenopathy (Fig. 3). An open biopsy of the retroperitoneal lymph nodes showed a malignant neoplasm composed of discohesive single cells and cords of cells associated with a desmoplastic myxoid stroma similar to the neck metastasis. Occasional solid nests of tumor showed central breakdown with necrosis characterized by neutrophilic exudate. The tumor cells vary from small and spindled to plump, hyperchromatic and histiocyte-like (Fig. 4). Tumor emboli were seen in multiple blood vessels in the adipose tissue around the lymph node. Immunohistochemistry showed diffuse and strong expression of PAX-8 in the tumor cells and loss of INI-1 expression consistent with renal medullary carcinoma (see Fig. 5).

Fig. 3.

Computerized tomography (CT) chest abdomen pelvis with intravenous contrast: (a) Right lower pole renal mass with soft tissue encasing the inferior vena cava and (b) right renal vein

Fig. 4.

Retroperitoneal lymph node: an open biopsy (a) showed solid nests of malignant epithelioid cells with occasional breakdown with central necrosis characterized by a neutrophilic exudate (2X). Other areas demonstrated discohesive single cells and cords of cells associated with a desmoplastic myxoid stroma similar to the neck metastasis. The tumor cells varied from small and spindled to plump, hyperchromatic and histiocyte-like (20X)

Fig. 5.

Retroperitoneal lymph node: immunohistochemistry revealed nuclear positivity in tumor cells for (a) PAX-8 and (b) loss of nuclear staining for INI-1

The association of renal medullary carcinoma with hemoglobinopathies triggered subsequent studies which demonstrated abnormal Hemoglobin A (57.8%, Ref: 94-100%) and Hgb S (38.4%, Ref: 0%) levels consistent with sickle cell trait.

Despite chemo- and radiotherapy, the mass in the neck continued to enlarge to 10 cm involving the brachial plexus. The patient developed metastases to the liver, lungs, and mediastinal, mesenteric and retroperitoneal lymph nodes. The patient passed away from symptoms of uncontrollable tumor burden five months after the initial diagnosis.

Discussion

A large rapidly growing neck mass in a 34-year-old raises a wide differential diagnosis ranging from benign, e. g. abscess, to malignant with hematological malignancies at the top of the list. The investigation begins with a core biopsy which in this case ruled out benign and inflammatory processes, hematological malignancies and squamous or glandular differentiation.

Tumors of the head and neck that may present with neck metastasis from an occult primary include HPV-associated oropharyngeal squamous cell carcinoma and the undifferentiated nasopharyngeal carcinoma. Both tumors show diffuse expression of p63. This tumor was morphologically dissimilar to both tumors and did not express p63. Poorly differentiated adenocarcinomas of the sinonasal tract and salivary glands are almost never occult and are diffusely positive for CK7 and the latter may express GATA3.

Papillary thyroid carcinomas may be occult and present as a lateral neck mass. However, they spread to the central compartment lymph nodes first before spreading to lateral cervical lymph nodes, namely those in levels III-V. Moreover, this tumor did not show evidence of thyroid differentiation (TTF1 and Napsin A negative).

The location of the mass in the left supraclavicular region was unusual for metastatic tumors from the head and neck which involve the lateral cervical lymph nodes in a predictive manner starting from levels I or II and progressing to lower levels V. The absence of involvement of cervical lymph nodes in levels I-V suggested a non-head and neck primary. Based on the epithelioid morphology, the amphophilic cytoplasm, the atypical nuclei with large nucleoli, the differential diagnosis ranged from metastatic carcinoma to melanoma and sarcoma.

The left supraclavicular location and the presence of signet ring cells and tumor cells infiltrating in cords led to the consideration of metastasis from gastric adenocarcinoma, signet ring cell type. However, a mucicarmine stain failed to reveal intracytoplasmic mucin. Furthermore, absence of CK7, CK20, CDX2 and neuroendocrine markers did not support a gastrointestinal or neuroendocrine origin. Absence of TTF1 and Napsin A did not favor a lung adenocarcinoma. Metastatic melanoma was ruled out by the diffuse expression of pancytokeratin.

In a young male, testicular germ cell tumor may present as a distant metastasis from an occult primary, and involve the supraclavicular lymph nodes in 5% of cases [3]. However, this tumor showed absence of expression of SAL-4, OCT 3/4, PLAP, AFP, hCG, inhibin and CD30.

Other considerations included epithelioid sarcoma, an aggressive tumor that typically involves the distal acral region and can metastasize to regional lymph nodes. The trunk and head and neck are occasionally primarily involved. A proximal (large cell) variant of epithelioid sarcoma has been described [4]. This variant demonstrates morphological and clinical differences from conventional “distal type” epithelioid sarcoma, presenting in older adults, pursuing a more aggressive course and usually involving the pelvis, perineum, axilla, mediastinum or genital tract, unlike conventional epithelioid sarcoma. In both types, however, the primary tumor dominates the clinical presentation. Like the current tumor, both types of epithelioid sarcoma are keratin and vimentin positive and show loss of INI1 expression. This was strongly considered until imaging discovered the renal tumor.

The mucin-negative intracytoplasmic vacuoles resembled the blister cells in epithelioid hemangioendothelioma which are known to express keratins and vimentin as in this tumor. However, absence of CD31, CD34 and other markers of vascular differentiation did not support the diagnosis of epithelioid hemangioendothelioma.

The final diagnosis of metastasis from a renal medullary carcinoma was greatly aided by imaging of the abdomen. Renal medullary carcinoma is a rare, highly aggressive neoplasm affecting young patients. The association with sickle cell trait, as in the current patient. was first described by Davis et al. in 1995 as the 7th sickle cell nephropathy [5]. These patients usually present with advanced stage disease and despite surgery and chemotherapy, progress rapidly and relentlessly [6]. Our patient succumbed to disseminated tumor in less than six months after diagnosis. Initial presentation at an advanced stage at a metastatic site adds to the difficulty in making the diagnosis. Loss of INI-1 protein expression has recently emerged as a diagnostic feature of renal medullary carcinomas and other SMARCB1 family of tumors [7–9].

INI-1 protein is a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex which is a critical modulator of several cellular processes including DNA replication, damage repair, proliferation and differentiation [10]. Loss of this protein imparts a rhabdoid morphology to tumor cells [11, 12]. SMARCB1 deficient tumors in the head and neck are diffusely positive for keratin, p63 and display rhabdoid morphology with paranuclear filamentous cytoplasmic inclusions “rhabdoid body” that displaces the large vesicular nuclei with macronucleoli. The tumor cells in the current tumor had peripherally displaced large vesicular nuclei with macronucleoli but not the eosinophilic rhabdoid bodies.

The family of SMARCB1 deficient tumors is expanding and includes atypical teratoid/rhabdoid tumors of the central nervous system, renal/extrarenal malignant rhabdoid tumors, renal medullary carcinoma and some collecting duct carcinomas, a subset of benign and malignant soft tissue tumors including epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, extraskeletal myxoid chondrosarcoma, myoepithelial tumors, pediatric chordoma, and the rare rhabdoid carcinoma of the sinonasal, gastrointestinal and genitourinary tract and pancreas [13].

Several mistakes were made in this case. Renal carcinoma should have been considered at the time of the first biopsy despite the absence of clinical information and the patient’s young age. It is one of the more common tumors that metastasize to head and neck along with lung and breast (Table 1) [2]. If the battery of immunohistochemistry performed to evaluate the first biopsy had included PAX-8 and INI1, the second biopsy for more tissue for additional immunohistochemical work up could have been avoided. The second mistake made was in the interpretation of INI1. The loss of INI1 expression must be assessed against internal controls, e.g. endothelial cells, lymphocytes and other nonneoplastic cells. In retrospect, the reading of INI1 as being weakly expressed was a misinterpretation and needed at least a repeat stain. This might have avoided the open biopsy of the retroperitoneal lymph nodes.

Table 1.

Non-head & neck malignancies metastatic to cervical Lymph nodes

Primary tumor	Immunohistochemistry	Comments
Carcinomas
Lung	CK7+, CK20-, TTF1+, Napsin-A+	Primary may be occult
Breast	CK7+, CK20-, GATA3+, ER+, mammoglobin+	Primary usually known (may be remote history)
Gastrointestinal: upper and lower GI tract, pancreaticobiliary and hepatocellular)	CK7+ (stomach, pancreatobiliary), CK20+, CDX-2, SATB2 Hepatocellular (arginase1, HepPar1, glypican 3)	Primary may be occult
Genitourinary
Kidney*	PAX-8+	Primary may be occult
Bladder	GATA3+	Primary usually known
Prostate	NKX3.1+	Primary may be occult or remote history
Germ Cell Tumors	OCT3/4, PLAP, AFP, hCG, Inhibin, SAL-4, CD30	Primary may be occult or remote history
Adrenal	SF1, CK19	Primary usually large
Neuroendocrine	INSM1+, CD56+, panCK+, CK7+, CK20-, chromogranin-A+, synaptophysin+, TTF1+	Primary may be occult
Merkel Cell	CK7-, CK20+ (peri-nuclear dot like positivity), NF+, chromogranin-A+, synaptophysin+, TTF1-,	Primary may be occult
Melanoma	S100+, SOX-10+, Melan-A+, HMB-45+, Tyrosinase+	Primary may be occult or remote history
Sarcomas
Rhabdomyosarcoma	Desmin+, Myogenin+, Myo-D1+,	Primary may be occult or remote history
Epithelioid sarcoma	panCK+, INI1 loss, EMA+, CD34+ (50% of cases)	Primary may be occult
Ewing Sarcoma	CD99+ (membranous)	Primary usually known (may be remote history)
Malignant Peripheral Nerve Sheath Tumor	S100 focally positive, H3K27me3 loss	Primary usually known, may be diagnosed after ruling out other entities, clinical features of NF1 and relationship to nerve helpful
Epithelioid hemangioendothelioma	CD31+, CD34+, ERG+, CAMTA-1+	Primary usually known (may be remote history)

^*Clear cell carcinoma is the most common renal carcinoma to metastasize to head and neck sites

Conclusions

SMARCB1 deficient family of tumors can occur anywhere in the body, may metastasize to the head and neck and may not show the classic rhabdoid morphology. The current case highlights the challenge of a renal medullary carcinoma, a rare aggressive neoplasm that primarily affects young adults with sickle cell trait, presenting at an advanced stage as an enlarging supraclavicular mass with occult renal primary. Immunohistochemistry demonstrating the loss of INI1 expression in these tumors is invaluable in making the diagnosis, especially when the primary and a history of sickle cell disease is unknown. And finally, the lesson we learned is that renal origin in carcinomas of unknown origin must be considered irrespective of patient’s age, history, presentation and tumor morphology.

Funding

No external funding was obtained for this study.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflict of interest relating to this presentation.

Ethical Approval

The authors complied with all ethical standards set by their institution, professional organizations and the government.